Farmakokinetika eprinomektina u ovaca nakon potkožne primjene.

The pharmacokinetics of eprinomectin was determined in lactating sheep following subcutaneous administration at a dose rate of 0.2 mg kg-1. The eprinomectin concentration in plasma was determined using High Performance Liquid Chromatography (HPLC) with a fluorescence detector. The kinetics of plasma concentrations were analysed using the non-compartment model. The maximum plasma concentration of 24.44 ng/mL occurred 2 days post-administration. Following subcutaneous administration of eprinomectin in sheep, the value of plasma elimination half-life, the area under the plasma concentration time curve (AUC) and mean residence time (MRT) were 388.52 ± 0.25 h. 4282.10 ng.h/mL and 374.50 h, respectively. The values of V (area), Vd(ss) and Cl(B) were 20.50 mL/kg, 13.70 mL/kg and 0.04 mL/h/kg, respectively. This study demonstrates that subcutaneous administration of eprinomectin led to higher bioavailability and longer mean residence time with a lower dose than a pour-on application, and that an injectable formulation may be applied in lactating sheep with zero withdrawal period.Farmakokinetika eprinomektina određivana je u ovaca u laktaciji nakon potkožne primjene u dozi od 0,2 mg/kg. Njegova koncentracija u plazmi utvrđena je visoko učinkovitom tekućinskom kromatografijom s fluorescentnim detektorom. Kinetika koncentracija u plazmi analizirana je na osnovi modela bez odjeljaka. Najveća koncentracija u plazmi od 24,44 ng/mL dokazana je dva dana nakon primjene. Poluživot eliminacije iz plazme iznosio je 388,52 ± 0,25 sati, površina ispod krivulje koncentracije u plazmi (AUC) 4282,10 ng/h/mL, a prosječno vrijeme zadržavanja iznosilo je 374,50 sati. Vrijednost prividnog volumena raspodjele, Vd(area), iznosila je 20,50 mL/kg, prosječni vidljivi volumen raspodjele, Vd(ss), 13,70 mL/kg, a ukupni klirens 0,04 mL/sat/kg. Istraživanje je pokazalo da potkožna primjena eprinomektina pruža veću bioraspoloživost, duže vrijeme zadržavanja s manjom dozom u odnosu na veliku te da se injekcijska formulacija može primijeniti u ovaca u laktaciji

Study of knowledge, attitude, and practices towards current updates of pharmacovigilance and adverse drug reaction reporting among doctors in a tertiary care teaching hospital of Western India

Background: In general, adverse drug reactions (ADRs) are global problems causing both morbidity and mortality. Spontaneous ADR reporting is important to monitor adverse effects of medicines but under reporting is still very prevalent so, there is a need of constant monitoring and rectification of system of Pharmacovigilance. The objective of this study was to evaluate the knowledge, attitude, and practices (KAP) of the healthcare professionals about Pharmacovigilance and to identify the reason for under reporting of ADRs.Methods: A cross-sectional study was carried out using a pretested questionnaire among doctors with minimum qualification MBBS or B.D.S. including faculties, senior and junior residents. Subsequently, analysis of association between education and experience was done by chi square test at P-value <0.05.Results: A pretested questionnaire was distributed among 403 doctors and 240 (59.16%) responded voluntarily. In general, 131 (54.58%) participants noted lack of time to report ADR while 90 (37.50%) participants noted no benefit of reporting already known ADR. On the other hand, total 104 (43.33%) participants were aware about need to report a serious adverse event during “Clinical Trial” within 24 hours to the Ethics Committee. Only 87 (36.25%) participants noted a need of reporting of already known ADR.Conclusions: Participants had good knowledge and attitude towards pharmacovigilance, but the actual practice of ADR reporting is still deficient among them that can be improved by sensitization training and involvement of grass root level health care workers

Učinak pretkondicioniranja piperinom na farmakokinetiku peroralno primijenjenog marbofloksacina u štakora

The present study was carried out to evaluate the effect of piperine pre-conditioning on the pharmacokinetics of marbofloxacin in Wistar rats. Marbofloxacin was administrated at a dose rate of 5 mg/kg body weight alone, and along with piperine pre-conditioning at a dose of 10 mg/kg of body weight, orally for 5 days in Wistar rats. The mean values of the half-life (t1⁄2β), maximum drug concentration (Cmax) and area under the curve (AUC) were 1.19 ± 0.17 h, 2.71 ± 0.09 μg/mL and 12.25 ± 0.77 μg.h/mL, respectively, in piperine pretreated rats. The values were significantly higher than the values observed in rats administered with marbofloxacin alone (1.12 ± 0.31 h, 2.28 ± 0.20 μg/mL and 9.24 ± 0.59 μg.h/mL, respectively). The drug clearance (ClB) in piperine pretreated rats was 0.04 ± 0.02 L/h/kg, which was significantly lower than the clearance rate of the drug (0.53 ± 0.03 L/h/kg) in the animals administered with marbofloxacin alone. The study reveals that piperine has a significant effect on the pharmacokinetics of marbofloxacin, which may be due to an increase in the drug absorption and inhibition of elimination of the drug in rats.U ovom je radu istražen učinak pretkondicioniranja piperinom na farmakokinetiku marbofloksacina Wistar štakora. Marbofloksacin je apliciran u dozi od 5 mg/kg tjelesne mase peroralno, samostalno i nakon pretkondicioniranja piperinom u dozi od 10 mg/kg tjelesne mase peroralno tijekom 5 dana. U štakora tretiranih piperinom prosječne vrijednosti poluživota (t1⁄2β) bile su 1,19 ± 0,17 h, maksimalna koncentracija lijeka (Cmax) 2,71 ± 0,09 μg/mL, a površina ispod krivulje (AUC) 12,25 ± 0,77 μg.h/mL. Navedene vrijednosti bile su znakovito više od onih utvrđenih u štakora tretiranih samo marbofloksacin (1,12 ± 0,31 h, 2,28 ± 0,20 μg/mL i 9,24 ± 0,59 μg.h/mL). Klirens lijeka (ClB) u štakora tretiranih piperinom bio je 0,04 ± 0,02 L/h/kg što je bilo znakovito niže od klirensa lijeka (0,53 ± 0,03 L/h/ kg) u životinja koje su dobivale samo marbofloksacin. Ovo istraživanje pokazuje da piperin znakovito utječe na farmakokinetiku marbofloksacina, što može biti posljedica povećane apsorpcije lijeka i inhibicije uklanjanja lijeka u štakora

Batch and match: black-box variational inference with a score-based divergence

Most leading implementations of black-box variational inference (BBVI) are based on optimizing a stochastic evidence lower bound (ELBO). But such approaches to BBVI often converge slowly due to the high variance of their gradient estimates and their sensitivity to hyperparameters. In this work, we propose batch and match (BaM), an alternative approach to BBVI based on a score-based divergence. Notably, this score-based divergence can be optimized by a closed-form proximal update for Gaussian variational families with full covariance matrices. We analyze the convergence of BaM when the target distribution is Gaussian, and we prove that in the limit of infinite batch size the variational parameter updates converge exponentially quickly to the target mean and covariance. We also evaluate the performance of BaM on Gaussian and non-Gaussian target distributions that arise from posterior inference in hierarchical and deep generative models. In these experiments, we find that BaM typically converges in fewer (and sometimes significantly fewer) gradient evaluations than leading implementations of BBVI based on ELBO maximization.Comment: 49 pages, 14 figures. To appear in the Proceedings of the 41st International Conference on Machine Learning (ICML), 202

SIMBIG{\rm S{\scriptsize IM}BIG}: Mock Challenge for a Forward Modeling Approach to Galaxy Clustering

Simulation-Based Inference of Galaxies (${\rm S{\scriptsize IM}BIG}$) is a forward modeling framework for analyzing galaxy clustering using simulation-based inference. In this work, we present the ${\rm S{\scriptsize IM}BIG}$ forward model, which is designed to match the observed SDSS-III BOSS CMASS galaxy sample. The forward model is based on high-resolution ${\rm Q{\scriptsize UIJOTE}}$ $N$-body simulations and a flexible halo occupation model. It includes full survey realism and models observational systematics such as angular masking and fiber collisions. We present the "mock challenge" for validating the accuracy of posteriors inferred from ${\rm S{\scriptsize IM}BIG}$ using a suite of 1,500 test simulations constructed using forward models with a different $N$-body simulation, halo finder, and halo occupation prescription. As a demonstration of ${\rm S{\scriptsize IM}BIG}$, we analyze the power spectrum multipoles out to $k_{\rm max} = 0.5\,h/{\rm Mpc}$ and infer the posterior of $\Lambda$CDM cosmological and halo occupation parameters. Based on the mock challenge, we find that our constraints on $\Omega_m$ and $\sigma_8$ are unbiased, but conservative. Hence, the mock challenge demonstrates that ${\rm S{\scriptsize IM}BIG}$ provides a robust framework for inferring cosmological parameters from galaxy clustering on non-linear scales and a complete framework for handling observational systematics. In subsequent work, we will use ${\rm S{\scriptsize IM}BIG}$ to analyze summary statistics beyond the power spectrum including the bispectrum, marked power spectrum, skew spectrum, wavelet statistics, and field-level statistics.Comment: 28 pages, 6 figure

SIMBIG{\rm S{\scriptsize IM}BIG}: A Forward Modeling Approach To Analyzing Galaxy Clustering

We present the first-ever cosmological constraints from a simulation-based inference (SBI) analysis of galaxy clustering from the new ${\rm S{\scriptsize IM}BIG}$ forward modeling framework. ${\rm S{\scriptsize IM}BIG}$ leverages the predictive power of high-fidelity simulations and provides an inference framework that can extract cosmological information on small non-linear scales, inaccessible with standard analyses. In this work, we apply ${\rm S{\scriptsize IM}BIG}$ to the BOSS CMASS galaxy sample and analyze the power spectrum, $P_\ell(k)$, to $k_{\rm max}=0.5\,h/{\rm Mpc}$. We construct 20,000 simulated galaxy samples using our forward model, which is based on high-resolution ${\rm Q{\scriptsize UIJOTE}}$ $N$-body simulations and includes detailed survey realism for a more complete treatment of observational systematics. We then conduct SBI by training normalizing flows using the simulated samples and infer the posterior distribution of $\Lambda$CDM cosmological parameters: $\Omega_m, \Omega_b, h, n_s, \sigma_8$. We derive significant constraints on $\Omega_m$ and $\sigma_8$, which are consistent with previous works. Our constraints on $\sigma_8$ are $27\%$ more precise than standard analyses. This improvement is equivalent to the statistical gain expected from analyzing a galaxy sample that is $\sim60\%$ larger than CMASS with standard methods. It results from additional cosmological information on non-linear scales beyond the limit of current analytic models, $k > 0.25\,h/{\rm Mpc}$. While we focus on $P_\ell$ in this work for validation and comparison to the literature, ${\rm S{\scriptsize IM}BIG}$ provides a framework for analyzing galaxy clustering using any summary statistic. We expect further improvements on cosmological constraints from subsequent ${\rm S{\scriptsize IM}BIG}$ analyses of summary statistics beyond $P_\ell$.Comment: 9 pages, 5 figure

A Parameter-Masked Mock Data Challenge for Beyond-Two-Point Galaxy Clustering Statistics

The last few years have seen the emergence of a wide array of novel techniques for analyzing high-precision data from upcoming galaxy surveys, which aim to extend the statistical analysis of galaxy clustering data beyond the linear regime and the canonical two-point (2pt) statistics. We test and benchmark some of these new techniques in a community data challenge "Beyond-2pt", initiated during the Aspen 2022 Summer Program "Large-Scale Structure Cosmology beyond 2-Point Statistics," whose first round of results we present here. The challenge dataset consists of high-precision mock galaxy catalogs for clustering in real space, redshift space, and on a light cone. Participants in the challenge have developed end-to-end pipelines to analyze mock catalogs and extract unknown ("masked") cosmological parameters of the underlying $\Lambda$CDM models with their methods. The methods represented are density-split clustering, nearest neighbor statistics, BACCO power spectrum emulator, void statistics, LEFTfield field-level inference using effective field theory (EFT), and joint power spectrum and bispectrum analyses using both EFT and simulation-based inference. In this work, we review the results of the challenge, focusing on problems solved, lessons learned, and future research needed to perfect the emerging beyond-2pt approaches. The unbiased parameter recovery demonstrated in this challenge by multiple statistics and the associated modeling and inference frameworks supports the credibility of cosmology constraints from these methods. The challenge data set is publicly available and we welcome future submissions from methods that are not yet represented.Comment: New submissions welcome! Challenge data available at https://github.com/ANSalcedo/Beyond2ptMoc

BIOFILM PRODUCTION AND ANTIMICROBIAL RESISTANCE IN VENTILATOR ASSOCIATED PNEUMONIA (VAP) PATHOGENS OF ICUs OF TERTIARY CARE CENTER OF CENTRAL GUJARAT.

Background:  In critical care units, Ventilator-associated pneumonia (VAP) is a common device-associated infection in mechanically ventilated patients. Problem gets worst of associated with biofilm producing organism with higher antimicrobial resistance. The current study was carried out to observe the pattern of antimicrobial resistance, biofilm forming capacity of isolates causing Ventilator-associated pneumonia and other risk factors associated with VAP patients in intensive care units of Shree Krishna Hospital, Karamsad.&#x0D; Methodology:  97 total tracheal aspirate culture isolates recovered from 83 mechanically ventilated patients diagnosed to be suffering from VAP as per NHSN definition, admitted in various ICUs of Shree Krishna Hospital, Karamsad during the study duration were included in the study. Relevant clinical history of the patients and other details taken for various patient variable factors like age, gender, co-morbid conditions, indoor days, ventilator days, final patient outcome and other lab based investigations done as indicator of active pneumonia or sepsis from the electronic hospital database available on hospital information system. The tracheal aspirate culture isolates were then tested for antimicrobial susceptibility testing by Vitek2compact and in-vitro biofilm production assay using microtitre plate method. Objective of the present study was to determine the incidence of antimicrobial resistance, biofilm forming capacity of VAP pathogens, to determine risk factors associated and final outcome in VAP patients infected with biofilm forming pathogens. Chi-square test was used to check the relation between the categorical variables while t test was applied in case of continuous variables. A p value less than 0.05 was considered as statistically significant.&#x0D; Results:  Out of total 83 patients of VAP, 97 isolates recovered in tracheal aspirate culture. Out of total 83 patients, 42 patients (49 isolates) were found Biofilm producer (BFP) and 41 patients (48 isolates) were found Biofilm non-producer (BFNP). Out of 97 culture total isolates, the most common organisms grew were Klebsiella pneumoniae (29 isolates), Acinetobacter baumani (28 isolates) and Pseudomonas aeruginosa (19 isolates) apart from them lesser number of isolates of Staphylococcus aureus (6), Escherichia coli (5), Pantoea spp. (2), Serretia marcescens (2), Pseudomonas putida (1), Sphingomonas paucimobilis (1), Stenotrophomonas maltophila (1), Enterococcus faecium (1), Candida famata (1) and Candida tropicalis (1). The antimicrobial resistance was compared in three major pathogen between BFP and BFNP isolates, i.e. Klebsiella pneumoniae, Acinetobacter baumani and Pseudomonas aeruginosa, which was found to be statistically insignificant. Mortality was recorded higher in BFP patients (16.67%) compared to BFNP patients (7.3%) of VAP, but statistically it was not found to be significant (p value &gt; 0.05).&#x0D; Conclusions:  Incidence of BFP and BFNP associated VAP seen 50.51% and 49.49% respectively out of total 97 isolates. Biofilm forming pathogen causing VAP may not influence the outcome of the patient but, biofilm producer pathogens continue to be associated with pathogens causing VAP in significant amount of total cases. Typical hospital acquired strains like Klebsiella pneumoniae, Acinetobacter baumani and Pseudomonas aeruginosa is recorded frequently compared to other pathogens.&#x0D; Key words: Intensive Care Unit, anti-microbial resistance, VAP, Bio film, Health care associated infection, Indwelling device associated infection.</jats:p