A Stability Indicating HPLC Assay Method for Analysis of Rivastigmine Hydrogen Tartrate in Dual-Ligand Nanoparticle Formulation Matrices and Cell Transport Medium

The objective of this study was to develop and validate a method for quantitative analysis of rivastigmine hydrogen tartrate (RHT) in dual-ligand polymeric nanoparticle formulation matrices, drug release medium, and cellular transport medium. An isocratic HPLC analysis method using a reverse phase C 18 column and a simple mobile phase without buffer was developed, optimised, and fully validated. Analyses were carried out at a flow rate of 1.5 mL/min at 50°C and monitored at 214 nm. This HPLC method exhibited good linearity, accuracy, and selectivity. The recovery (accuracy) of RHT from all matrices was greater than 99.2%. The RHT peak detected in the samples of a forced degradation study, drug loading study, release study, and cellular transport study was pure and free of matrix interference. The limit of detection (LOD) and limit of quantification (LOQ) of the assay were 60 ng/mL and 201 ng/mL, respectively. The method was rugged with good intra- and interday precision. This stability indicating HPLC method was selective, accurate, and precise for analysing RHT loading and its stability in nanoparticle formulation, RHT release, and cell transport medium

Pseudorapidity Window Size Dependence of Multiplicity Fluctuations in High-Energy Collisions with System Size and Beam Energies

An investigation of the critical behavior of strongly interacting QCD matter has been performed by analyzing fluctuation observables on event-by-event (ebe) basis measured in high-energy collision experiments. The fluctuation analysis is performed using nuclear interactions at different target sizes and at different colliding beam energies as a function of varying width of pseudorapidity interval. For the sake of comparison, event-by-event multiplicity fluctuations in hadronic and heavy-ion collisions (p-H, p-A and A-B) are studied within the framework of the Lund Monte Carlo based FRITIOF model. Charged particle multiplicity and the variance of the multiplicity distribution are estimated for the interactions involving different target sizes and beam momenta i.e., p-H, p-CNO, p-AgBr at 200A GeV/c and $^{16}$O-AgBr collisions at 14.6, 60 and 200A GeV/c. Further, multiplicity fluctuations are quantified in terms of intensive quantity, the scaled variances $\omega$ and the strongly intensive quantity $\Sigma_{FB}$ derived from the charged particle multiplicity and the width of the multiplicity distribution. Strongly intensive quantity $\Sigma_{FB}$ is a quantity of great significance to extract information about short and long-range multiplicity correlations. Furthermore, the collision centrality and centrality bin width dependent behavior of the multiplicity fluctuation have been examined in the framework of Lund Monte Carlo based FRITIOF model. Results based on the fluctuation analysis carried out in the present study are interpreted in terms of dynamics of collision process and the possibility of related QCD phase transition.Comment: 33 pages, 14 figures, published in Int. J. Mod. Phy. E Vol. 31, 2250056 (2022

Role of visual inspection of cervix with acetic acid and high risk human papilloma virus DNA testing in screening for cervical cancer

Background: To evaluate the role of VIA alone and in combination with high risk Human Papilloma virus DNA testing as a screening test for cervical dysplasia and cancer.Methods: 400 symptomatic patients from the gynecology outpatient department were screened using Pap smear and VIA. HPV DNA testing was done for 62 VIA positive and 100 VIA negative women. Colposcopy was done for all women. Those found positive on any or all of the screening tests were subjected to cervical biopsy. The results were analysed for PAP, VIA, HPV and a combined test using VIA and HPV both.Results: VIA had the highest sensitivity (91%) to detect any grade of dysplasia. The sensitivity of the combination test (VIA + HPV) was 80.6% which was lower than that of VIA (91%) and also lower than that of HR HPV DNA detection (86%). The specificity of the combination test (VIA + HPV) was 68.3 % which was significantly higher than that of VIA alone (39%) (p = 0.000) and also higher than that for HPV DNA detection when used alone (56%). Pap smear had the highest specificity (95.12 %) but sensitivity was much lower at 52.7 %.Conclusions: VIA is a highly sensitive screening test. The main disadvantage is its low specificity. However the combination test of VIA + HR HPV testing overcomes this and at the same time maintains a high sensitivity. Thus a test which combines VIA plus HR HPV testing is better screening method than either of the three tests (VIA, HPV, PAP) done alone

RGS Proteins and Septins Cooperate to Promote Chemotropism by Regulating Polar Cap Mobility

Background—Septins are well known to form a boundary between mother and daughter cells in mitosis, but their role in other morphogenic states is poorly understood. Results—Using microfluidics and live cell microscopy, coupled with new computational methods for image analysis, we investigated septin function during pheromone-dependent chemotropic growth in yeast. We show that septins colocalize with the regulator of G-protein signaling (RGS) Sst2, a GTPase-activating protein that dampens pheromone receptor signaling. We show further that the septin structure surrounds the polar cap, ensuring that cell growth is directed toward the source of pheromone. When RGS activity is abrogated, septins are partially disorganized. Under these circumstances the polar cap travels toward septin structures and away from sites of exocytosis, resulting in a loss of gradient tracking. Conclusion—Septin organization is dependent on RGS protein activity. When assembled correctly, septins promote turning of the polar cap and proper tracking of a pheromone gradient

Shock Wave Response of Iron-based In Situ Metallic Glass Matrix Composites

The response of amorphous steels to shock wave compression has been explored for the first time. Further, the effect of partial devitrification on the shock response of bulk metallic glasses is examined by conducting experiments on two iron-based in situ metallic glass matrix composites, containing varying amounts of crystalline precipitates, both with initial composition Fe_(49.7)Cr_(17.7)Mn_(1.9)Mo_(7.4)W_(1.6)B_(15.2)C_(3.8)Si_(2.4). The samples, designated SAM2X5-600 and SAM2X5-630, are X-ray amorphous and partially crystalline, respectively, due to differences in sintering parameters during sample preparation. Shock response is determined by making velocity measurements using interferometry techniques at the rear free surface of the samples, which have been subjected to impact from a high-velocity projectile launched from a powder gun. Experiments have yielded results indicating a Hugoniot Elastic Limit (HEL) to be 8.58 ± 0.53 GPa for SAM2X5-600 and 11.76 ± 1.26 GPa for SAM2X5-630. The latter HEL result is higher than elastic limits for any BMG reported in the literature thus far. SAM2X5-600 catastrophically loses post-yield strength whereas SAM2X5-630, while showing some strain-softening, retains strength beyond the HEL. The presence of crystallinity within the amorphous matrix is thus seen to significantly aid in strengthening the material as well as preserving material strength beyond yielding

Combinatorial pharmacodynamics of polymyxin B and tigecycline against heteroresistant Acinetobacter baumannii

The prevalence of heteroresistant Acinetobacter baumannii is increasing. Infections due to these resistant pathogens pose a global treatment challenge. Here, the pharmacodynamic activities of polymyxin B (PMB) (2–20 mg/L) and tigecycline (0.15–4 mg/L) were evaluated as monotherapy and in combination using a 4 × 4 concentration array against two carbapenem-resistant and polymyxin-heteroresistant A. baumannii isolates. Time Kill Experiments was employed at starting inocula of 106 and 108 CFU/mL over 48 h. Clinically relevant combinations of PMB (2 mg/L) and tigecycline (0.90 mg/L) resulted in greater reductions in the bacterial population compared with polymyxin alone by 8 h (ATCC 19606, −6.38 vs. −3.43 log10 CFU/mL; FADDI AB115, −1.38 vs. 2.08 log10 CFU/mL). At 10× the clinically achievable concentration (PMB 20 mg/L in combination with tigecycline 0.90 mg/L), there was bactericidal activity against FADDI AB115 by 4 h that was sustained until 32 h, and against ATCC 19606 that was sustained for 48 h. These studies show that aggressive polymyxin-based dosing in combination with clinically achievable tigecycline concentrations results in early synergistic activity that is not sustained beyond 8 h, whereas combinations with higher tigecycline concentrations result in sustained bactericidal activity against both isolates at both inocula. These results indicate a need for optimised front-loaded polymyxin-based combination regimens that utilise high polymyxin doses at the onset of treatment to achieve good pharmacodynamic activity whilst minimising adverse events

Refractive Status in Nepalese Pre-Term and Full-Term Infants Early in Life.

SIGNIFICANCE: This study suggests that pre-term infants, even without retinopathy of prematurity, are at risk for abnormal refractive development and informs the need for close monitoring of refractive error in such infants, regardless of their retinopathy of prematurity status. PURPOSE: The present study aims to investigate the refractive error trend in Nepalese pre-term infants without retinopathy of prematurity (ROP) in the first 6 months of life and explore the association of refractive error with birth weight (BW) and gestational age (GA). METHODS: Thirty-six pre-term infants without ROP and 40 full-term infants underwent cycloplegic retinoscopy at birth, term (for pre-term only), 3 months, and 6 months chronologically. Refractive status was classified into emmetropia (mean spherical equivalent refraction [SER] 0 to +3.00D), myopia (SER +3.00D). Refractive parameters at various age points were compared between the pre-term and full-term infants using general linear model repeated measures ANOVA. RESULTS: At birth, the SER in the pre-term infants was +0.84 ± 1.72D; however, there was a shift toward myopia at 6 months of age (SER = -0.33 ± 1.95D). There was a significant difference in SER, astigmatism, and anisometropia between pre-term and full-term infants by 6 months of age (P < .01). Astigmatism and anisometropia showed an increasing trend with age in pre-term infants (P < .05 at 6 months) in contrast to a decreasing trend in full-term infants (P < 0.05 at 3 and 6 months). In pre-term infants, there was a statistically significant positive relationship between GA and SER (β = 0.32, R = 17.6%, P < .05) but a negative relationship between BW and astigmatism (β = -1.25, R = 20.6%, P < .01). CONCLUSIONS: Pre-term infants who do not develop ROP show a trend toward increasing myopia and demonstrate greater astigmatism and anisometropia than full-term infants in their first 6 months of life

Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii

ABSTRACT Administering polymyxin antibiotics in a traditional fashion may be ineffective against Gram-negative ESKAPE ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species) pathogens. Here, we explored increasing the dose intensity of polymyxin B against two strains of Acinetobacter baumannii in the hollow-fiber infection model. The following dosage regimens were simulated for polymyxin B ( t 1/2 = 8 h): non-loading dose (1.43 mg/kg of body weight every 12 h [q12h]), loading dose (2.22 mg/kg q12h for 1 dose and then 1.43 mg/kg q12h), front-loading dose (3.33 mg/kg q12h for 1 dose followed by 1.43 mg/kg q12h), burst (5.53 mg/kg for 1 dose), and supraburst (18.4 mg/kg for 1 dose). Against both A. baumannii isolates, a rapid initial decline in the total population was observed within the first 6 h of polymyxin exposure, whereby greater polymyxin B exposure resulted in greater maximal killing of −1.25, −1.43, −2.84, −2.84, and −3.40 log 10 CFU/ml within the first 6 h. Unexpectedly, we observed a paradoxical effect whereby higher polymyxin B exposures dramatically increased resistant subpopulations that grew on agar containing up to 10 mg/liter of polymyxin B over 336 h. High drug exposure also proliferated polymyxin-dependent growth. A cost-benefit pharmacokinetic/pharmacodynamic relationship between 24-h killing and 336-h resistance was explored. The intersecting point, where the benefit of bacterial killing was equal to the cost of resistance, was an f AUC 0–24 (area under the concentration-time curve from 0 to 24 h for the free, unbound fraction of drug) of 38.5 mg · h/liter for polymyxin B. Increasing the dose intensity of polymyxin B resulted in amplification of resistance, highlighting the need to utilize polymyxins as part of a combination against high-bacterial-density A. baumannii infections

Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii : pharmacodynamics of new dosing strategies

Polymyxin B is being increasingly utilized as a last resort against resistant Gram-negative bacteria. We examined the pharmacodynamics of novel dosing strategies for polymyxin B combinations to maximize efficacy and minimize the emergence of resistance and drug exposure against Acinetobacter baumannii