Altered Irinotecan Pharmacokinetics in Diet-Induced Obesity

Title: Altered Irinotecan Pharmacokinetics in Diet-Induced Obesity Authors: Pranav Shah*, Adarsh Gandhi and Romi Ghose Affiliation: University of Houston, Department of Pharmacological and Pharmaceutical Sciences, Houston, TX - 77030 Purpose: Irinotecan (CPT-11) is a topoisomerase I inhibitor that has been shown to be highly effective in treatment of colon, stomach, pancreas, and non-small cell lung cancers. It has recently been shown that CPT-11 administration is associated with liver toxicity and this effect is compounded by baseline obesity. It was found that patients with a BMI index of \u3e25 were twice as much susceptible to developing liver toxicity than patients with BMI index of Methods: For drug metabolism studies, liver S9 fractions were prepared from diet-induced obese (DIO, 60% Kcal diet fed mice) and lean mice (10% Kcal diet fed mice). UGT1A-mediated metabolism of SN-38 was determined in liver S9 fractions (2 mg/ml protein) incubated with SN-38 (15 µmol) for 60 min. For pharmacokinetic studies, mice were injected with a single oral dose of 10 mg/kg CPT-11 and blood samples were collected from 0-480 minutes. Plasma and feces samples were analyzed for CPT-11 and SN-38 concentrations using LC-MS/MS. Liver tissues were harvested for real-time PCR studies. The mRNA and serum TNF-α levels were measured in liver and plasma samples, respectively. Results: We found that the rate of formation of SN-38G was ~2 fold lower in the DIO mice compared to the lean controls. This corresponded with reduced expression of UGT1A1 in DIO mice livers. We did not observe significant changes in the area under the curve (AUC) or clearance of CPT-11 between the DIO and lean mice. However, plasma and fecal exposure (AUC) of SN-38 was increased by ~2 folds in the DIO mice compared to the lean controls. We also observed significantly higher mRNA and serum levels of TNF-α in the DIO mice as compared to the lean mice. Higher TNF-α levels are known to be associated with liver toxicity. Conclusion: CPT-11 dosage should be closely monitored for effective and safe chemotherapy in obese patients who are at a higher risk of developing liver toxicity

A review of commonly performed bariatric surgeries: Imaging features and its complications

Obesity is a disease that has achieved the level that can be considered an epidemic. According to the National Center for Health Statistics data, the prevalence of obesity has increased from 30.5% in 1999-2000 to 42.4% in 2017-2018. During the same period, severe obesity has increased from 4.7% to 9.2%. With the growing prevalence of obesity, related conditions such as coronary artery disease, diabetes, and strokes have also become more prevalent. In the past few years, the need for bariatric surgeries such as laparoscopic Roux-en-Y gastric bypass, sleeve gastrectomy, and laparoscopic adjustable gastric banding has increased considerably. With an increasing number of bariatric surgeries, multiple postoperative complications have become common. In this review, we have attempted to describe normal postsurgical anatomical findings after bariatric surgeries and pictorial review of a few common postoperative complications

An item-level response shift study on the change of health state with the rating of asthma-specific quality of life: a report from the PROMIS® Pediatric Asthma Study

To examine item-level response shift associated with the change in asthma-related health state (i.e., change in asthma control status and global rating of change (GRC) in breathing problems)

Exploring factors influencing asthma control and asthma-specific health-related quality of life among children

Abstract Background Little is known about factors contributing to children’s asthma control status and health-related quality of life (HRQoL). The study objectives were to assess the relationship between asthma control and asthma-specific HRQoL in asthmatic children, and to examine the extent to which parental health literacy, perceived self-efficacy with patient-physician interaction, and satisfaction with shared decision-making (SDM) contribute to children’s asthma control and asthma-specific HRQoL. Methods This cross-sectional study utilized data collected from a sample of asthmatic children (n = 160) aged 8–17 years and their parents (n = 160) who visited a university medical center. Asthma-specific HRQoL was self-reported by children using the National Institutes of Health’s Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Asthma Impact Scale. Satisfaction with SDM, perceived self-efficacy with patient-physician interaction, parental health literacy, and asthma control were reported by parents using standardized measures. Structural equation modeling (SEM) was performed to test the hypothesized pathways. Results Path analysis revealed that children with better asthma control reported higher asthma-specific HRQoL (β = 0.4, P < 0.001). Parents with higher health literacy and greater perceived self-efficacy with patient-physician interactions were associated with higher satisfaction with SDM (β = 0.38, P < 0.05; β = 0.58, P < 0.001, respectively). Greater satisfaction with SDM was in turn associated with better asthma control (β = −0.26, P < 0.01). Conclusion Children’s asthma control status influenced their asthma-specific HRQoL. However, parental factors such as perceived self-efficacy with patient-physician interaction and satisfaction with shared decision-making indirectly influenced children’s asthma control status and asthma-specific HRQoL

Exploring factors influencing asthma control and asthma-specific health-related quality of life among children

Abstract Background Little is known about factors contributing to children’s asthma control status and health-related quality of life (HRQoL). The study objectives were to assess the relationship between asthma control and asthma-specific HRQoL in asthmatic children, and to examine the extent to which parental health literacy, perceived self-efficacy with patient-physician interaction, and satisfaction with shared decision-making (SDM) contribute to children’s asthma control and asthma-specific HRQoL. Methods This cross-sectional study utilized data collected from a sample of asthmatic children (n = 160) aged 8–17 years and their parents (n = 160) who visited a university medical center. Asthma-specific HRQoL was self-reported by children using the National Institutes of Health’s Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Asthma Impact Scale. Satisfaction with SDM, perceived self-efficacy with patient-physician interaction, parental health literacy, and asthma control were reported by parents using standardized measures. Structural equation modeling (SEM) was performed to test the hypothesized pathways. Results Path analysis revealed that children with better asthma control reported higher asthma-specific HRQoL (β = 0.4, P < 0.001). Parents with higher health literacy and greater perceived self-efficacy with patient-physician interactions were associated with higher satisfaction with SDM (β = 0.38, P < 0.05; β = 0.58, P < 0.001, respectively). Greater satisfaction with SDM was in turn associated with better asthma control (β = −0.26, P < 0.01). Conclusion Children’s asthma control status influenced their asthma-specific HRQoL. However, parental factors such as perceived self-efficacy with patient-physician interaction and satisfaction with shared decision-making indirectly influenced children’s asthma control status and asthma-specific HRQoL

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Determination of ergocalciferol in human plasma after Diels-Alder derivatization by LCâMS/MS and its application to a bioequivalence study

An accurate, sensitive and selective method is developed for determination of ergocalciferol (vitamin D2) in human plasma using LCâMS/MS. After liquid-liquid extraction with n-hexane, ergocalciferol was derivatized by reacting with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD), a strong dienophile based on Diels-Alder reaction. Ergocalciferol and its deuterated internal standard, ergocalciferol-d6, were analyzed on X Select CSH C18 (100 mmÃ4.6 mm, 2.5 µm) column using acetonitrile and 0.1% (v/v) formic acid in water containing 0.14% methylamine within 6.0 min under gradient elution mode. Tandem mass spectrometry in positive ionization mode was used to quantify ergocalciferol by multiple reaction monitoring (MRM). Entire data processing was done using Watson LIMS⢠software which provided excellent data integrity and high throughput with improved operational efficiency. The major advantage of this method includes higher sensitivity (0.10 ng/mL), superior extraction efficiency (â¥83%) and small sample volume (100 µL) for processing. The method was linear in the concentration range of 0.10â100 ng/mL for ergocalciferol. The intra-batch and inter-batch accuracy and precision (% CV) values varied from 97.3% to 109.0% and 1.01% to 5.16%, respectively. The method was successfully applied to support a bioequivalence study of 1.25 mg ergocalciferol capsules in 12 healthy subjects. Keywords: Ergocalciferol, Diels-Alder reaction, 4-phenyl-1,2,4-triazoline-3,5-dione, LCâMS/MS, Human plasm

Effect of iTRAQ Labeling on the Relative Abundance of Peptide Fragment Ions Produced by MALDI-MS/MS

The identification of proteins in proteomics experiments is usually based on mass information derived from tandem mass spectrometry data. To improve the performance of the identification algorithms, additional information available in the fragment peak intensity patterns has been shown to be useful. In this study, we consider the effect of iTRAQ labeling on the fragment peak intensity patterns of singly charged peptides from MALDI tandem MS data. The presence of an iTRAQ-modified basic group on the N-terminus leads to a more pronounced set of b-ion peaks and distinct changes in the abundance of specific peptide types. We performed a simple intensity prediction by using a decision-tree machine learning approach and were able to show that the relative ion abundance in a spectrum can be correctly predicted and distinguished from closely related sequences. This information will be useful for the development of improved method-specific intensity-based protein identification algorithms.