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Global testing of a consensus solubility assessment to enhance robustness of the WHO biopharmaceutical classification system
No full textThe WHO Biopharmaceutical Classification System (BCS) is a practical tool to identify active pharmaceutical ingredients (APIs) that scientifically qualify for a waiver of in vivo bioequivalence studies. The focus of this study was to engage a global network of laboratories to experimentally quantify the pH-dependent solubility of the highest therapeutic dose of 16 APIs using a harmonized protocol. Intra-laboratory variability was ≤5 %, and no apparent association of inter-laboratory variability with API solubility was discovered. Final classification “low solubility” vs “high solubility” was consistent among laboratories. In comparison to the literature-based provisional 2006 WHO BCS classification, three compounds were re-classified from “high” to “low-solubility”. To estimate the consequences of these experimental solubility results on BCS classification, dose-adjusted in silico predictions of the fraction absorbed in humans were performed using GastroPlus®. Further expansion of these experimental efforts to qualified APIs from the WHO Essential Medicines List is anticipated to empower regulatory authorities across the globe to issue scientifically-supported guidance regarding the necessity of performing in vivo bioequivalence studies. Ultimately, this will improve access to affordable generic products, which is a critical prerequisite to reach Universal Health Coverage
Lipid levels and major adverse cardiovascular events in patients initiated on statins for primary prevention: an international population-based cohort study protocol
No full textBackground: Clinical guidelines recommend specific targets for low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) for primary prevention of cardiovascular disease (CVD). Furthermore, individual variability in lipid response to statin therapy requires assessment of the association in diverse populations. Aim: To assess whether lower concentrations of LDL-C and non-HDL-C are associated with a reduced risk of major adverse cardiovascular events (MACE) in primary prevention of CVD. Design & setting: An international, new-user, cohort study will be undertaken. It will use data from three electronic health record databases from three global regions: Clinical Practice Research Datalink, UK; PREDICT-CVD, New Zealand (NZ); and the Clinical Data and Analysis Reporting System, Hong Kong (HK). Method: New statin users without a history of atherosclerotic CVD, heart failure, or chronic kidney disease, with baseline and follow-up lipid levels will be eligible for inclusion. Patients will be classified according to LDL-C (\u3c1.4, 1.4–1.7, 1.8–2.5, and ≥2.6 mmol/l) and non-HDL-C (\u3c2.2, 2.2–2.5, 2.6–3.3, and ≥3.4 mmol/l) concentrations 24 months after initiating statin therapy. The primary outcome of interest is MACE, defined as the first occurrence of coronary heart disease, stroke, or cardiovascular death. Secondary outcomes include all-cause mortality and the individual components of MACE. Sensitivity analyses will be conducted using lipid levels at 3 and 12 months after starting statin therapy. Conclusion: Results will inform clinicians about the benefits of achieving guideline recommended concentrations of LDL-C for primary prevention of CVD
Association between Vancomycin Area under the Curve and Nephrotoxicity: A single center, retrospective cohort study in a veteran population
No full textBackground: It is unclear which vancomycin area under the curve (AUC) values are most associated with risk for acute kidney injury (AKI). Methods: This retrospective cohort study was undertaken to determine if vancomycin AUC\u3e550 is associated with a higher rate of AKI than an AUC\u3c550. Patients treated with vancomycin for at least 4 days at the VA St. Louis Health Care System from 1/1/2016 to 9/31/2018 were included. The primary outcome was AKI (defined as an increase in serum creatinine by 0.3 mg/dL or 50% from baseline). Secondary outcomes included length of stay, readmission in 30 days, and mortality in 30 days. A bivariate analysis was used to determine other potential factors affecting AKI rate, with significant variables (P\u3c.2) to be included in the multivariate logistic regression analysis to determine independent risk for AKI. Results: Two hundred patients were included in the analysis; 100 patients with an AUC≥550 and 100 with an AUC\u3c550. Only mean vancomycin dose (1722.50 mg vs 2361.25 mg; P\u3c.05), mean AUC (465.88 vs 696.45; P\u3c.05), and peak SCr (1.22 mg/dL vs 1.48 mg/dL; P=.015) were significantly different between groups (AUC\u3c550 vs AUC≥550, respectively). AKI occurred in 42% (42/100) of patients with AUC≥550 compared with 2% (2/100) of patients with AUC\u3c550 (P\u3c.05). Secondary outcomes were not different between the groups. In the bivariate analysis, age≥70, CrCl\u3c50 mL/min, and AUC≥550 (odds ratio, 49.5; 95% CI, 10.1-242.3; P\u3c.05) were found to be independently associated with risk for developing AKI. Conclusions: Patients with a vancomycin AUC≥550 were found to have a significantly higher rate of AKI compared with those with an AUC\u3c550
Corticosteroids in Community-Acquired Pneumonia: A Review of Current Literature
No full textObjective: To review the evidence and recommendations for the use of adjunctive corticosteroid therapy in community-acquired pneumonia (CAP). Data Sources: A literature search was conducted using PubMed (1993 to November 2020) using the search terms corticosteroids AND community-acquired pneumonia. Study Selection and Data Extraction: Pertinent randomized controlled trials, systematic reviews, and meta-analyses assessing the efficacy and safety of adjunctive corticosteroids in patients with pneumonia were evaluated for inclusion. Data Synthesis: Studies suggest that corticosteroids reduce time to clinical stability and length of hospital stay, but data regarding other important clinical outcomes, such as mortality, are limited. The greatest margin of benefit appears to be in patients with severe CAP. Evidence consistently demonstrates hyperglycemia as the most common adverse effect of corticosteroid therapy in CAP. Safety concerns regarding the potential impact of corticosteroids on the rate of CAP-related rehospitalizations require further investigation. Relevance to Patient Care and Clinical Practice: This review summarizes literature evaluating the efficacy and safety of adjunctive corticosteroids in patients with CAP. It also includes a discussion on current guideline recommendations, patient selection, corticosteroid regimens, adverse effect considerations, limitations, and future directions in this area of research. Conclusions: Studies reviewed suggest that corticosteroids are relatively beneficial and safe in patients with CAP, with the greatest benefit in severe CAP. Currently, the routine use of corticosteroids is not recommended by clinical practice guidelines with the exception of CAP and refractory septic shock. Further research is needed to better define the ideal role of corticosteroids in CAP
Remote Work Guidelines - Faculty
No full textUHSP seeks to have a campus and workplace culture that is highly effective toward meeting the institution’s goals while being sensitive to the needs of faculty, staff and students. In the right circumstances, remote work can improve flexibility and work-life balance while potentially improving productivity.
Faculty have routinely operated with latitude to complete certain types of work away from the physical campus. This document presents guidelines that apply to faculty now in a concise document to ensure that critical institutional needs around data security, risk and compliance are met while recognizing that individual faculty should rely on department or college rules regarding when they need to be on campus. Department chairs are expected to work closely with faculty regarding what type of work can be done remotely, or off-campus, and what work must be completed on-campus.
Work off campus for the University must still comply with federal, state and local laws, as well as University policies that apply to employees at University of Health Sciences and Pharmacy in St. Louis. This includes, but is not limited to, the Fair Labor Standards Act (FLSA) and the Occupational Safety and Health Act (OSHA)
Taxonomic hypotheses and the biogeography of speciation in the Tiger Whiptail complex (Aspidoscelis tigris: Squamata, Teiidae)
No full textBiodiversity in southwestern North America has a complex biogeographic history involving tectonism interspersed with climatic fluctuations. This yields a contemporary pattern replete with historic idiosyncrasies often difficult to interpret when viewed from through the lens of modern ecology. The Aspidoscelis tigris (Tiger Whiptail) complex (Squamata: Teiidae) is one such group in which taxonomic boundaries have been confounded by a series of complex biogeographic processes that have defined the evolution of the clade. To clarify this situation, we first generated multiple taxonomic hypotheses, which were subsequently tested using mitochondrial DNA sequences (ATPase 8 and 6) evaluated across 239 individuals representing five continental members of this complex. We then evaluated the manner by which our models parsed phylogenetic and biogeographic patterns. We found considerable variation among species ‘hypotheses,’ which we interpret as reflecting inflated levels of inter-population genetic divergence caused by historical demographic expansion and contraction cycles. Inter-specific boundaries with A. marmoratus juxtaposed topographically with the Cochise Filter Barrier that separates Sonoran and Chihuahuan deserts (interpreted herein as an example of ‘soft’ allopatry). Patterns of genetic divergence were consistent across the Cochise Filter Barrier, regardless of sample proximity. Surprisingly, this also held true for intraspecific comparisons that spanned the Colorado River. These in turn suggest geomorphic processes as a driver of speciation in the A. tigris complex, with intraspecific units governed by local demographic processes
Kinetics and thermodynamics of thermal inactivation for recombinant Escherichia coli cellulases, cel12B, cel8C, and polygalacturonase, peh28; biocatalysts for biofuel precursor production
No full textLignocellulosic biomass conversion using cellulases/polygalacturonases is a process that can be progressively influenced by several determinants involved in cellulose microfibril degradation. This article focuses on the kinetics and thermodynamics of thermal inactivation of recombinant Escherichia coli cellulases, cel12B, cel8C and a polygalacturonase, peh 28, derived from Pectobacterium carotovorum sub sp. carotovorum. Several consensus motifs conferring the enzymes\u27 thermal stability in both cel12B and peh28 model structures have been detailed earlier, which were confirmed for the three enzymes through the current study of their thermal inactivation profiles over the 20-80°C range using the respective activities on carboxymethylcellulose and polygalacturonic acid. Kinetic constants and half-lives of thermal inactivation, inactivation energy, plus inactivation entropies, enthalpies and Gibbs free energies, revealed high stability, less conformational change and protein unfolding for cel12B and peh28 due to thermal denaturation compared to cel8C. The apparent thermal stability of peh28 and cel12B, along with their hydrolytic efficiency on a lignocellulosic biomass conversion as reported previously, makes these enzymes candidates for various industrial applications. Analysis of the Gibbs free energy values suggests that the thermal stabilities of cel12B and peh28 are entropy-controlled over the tested temperature range
A mixed-methods study describing behavioral factors that influenced general practitioners’ experiences using triage during the COVID-19 pandemic
No full textBackground: Early in the COVID-19 pandemic, general practices were asked to expand triage and to reduce unnecessary face-to-face contact by prioritizing other consultation modes, e.g., online messaging, video, or telephone. The current study explores the potential barriers and facilitators general practitioners experienced to expanding triage systems and their attitudes towards triage during the COVID-19 pandemic. Method: A mixed-method study design was used in which a quantitative online survey was conducted along with qualitative interviews to gain a more nuanced appreciation for practitioners’ experiences in the United Kingdom. The survey items were informed by the Theoretical Domains Framework so they would capture 14 behavioral factors that may influence whether practitioners use triage systems. Items were responded to using seven-point Likert scales. A median score was calculated for each item. The responses of participants identifying as part-owners and non-owners (i.e., “partner” vs. “non-partner” practitioners) were compared. The semi-structured interviews were conducted remotely and examined using Braun and Clark’s thematic analysis. Results: The survey was completed by 204 participants (66% Female). Most participants (83%) reported triaging patients. The items with the highest median scores captured the ‘Knowledge,’ ‘Skills,’ ‘Social/Professional role and identity,’ and ‘Beliefs about capabilities’ domains. The items with the lowest median scores captured the ‘Beliefs about consequences,’ ‘Goals,’ and ‘Emotions’ domains. For 14 of the 17 items, partner scores were higher than non-partner scores. All the qualitative interview participants relied on a phone triage system. Six broad themes were discovered: patient accessibility, confusions around what triage is, uncertainty and risk, relationships between service providers, job satisfaction, and the potential for total digital triage. Suggestions arose to optimize triage, such as ensuring there is sufficient time to conduct triage accurately and providing practical training to use triage efficiently. Conclusions: Many general practitioners are engaging with expanded triage systems, though more support is needed to achieve total triage across practices. Non-partner practitioners likely require more support to use the triage systems that practices take up. Additionally, practical support should be made available to help all practitioners manage the new risks and uncertainties they are likely to experience during non-face-to-face consultations
Knowledge, perceptions and practices of pharmacists regarding generic substitution in China: A cross-sectional study
No full textObjective To evaluate pharmacists\u27 knowledge, perceptions and practices towards generic substitution in the 11 pilot locations in China. Design An online cross-sectional survey using questionnaires was conducted. A convenience sampling technique was implemented to recruit pharmacists. Setting and participants The study took place in medical institutions of 11 pilot locations that participated in the pilot national centralised procurement programme in 2019. Two thousand two hundred and ninety-one pharmacists including hospital pharmacists or community pharmacists based on health-systems or clinics participated in the study. Results Most of the participants had the good knowledge of requirements for evaluating the quality and efficacy of generic drugs (n=2118; 92.4%), and the definition of generic drugs (n=2078; 90.7%). In terms of perceptions, 67.3% of respondents were of the opinion that generic drugs are equally as effective as the brand-name drugs, and 69.0% of respondents were of the opinion that generic drugs are as safe as brand equivalents. A high percentage of participants supported the policy of generic substitution (n=1634; 71.4%). A significant positive correlation was demonstrated between total knowledge score and total perception score (ρ=0.267; p\u3c0.001). Efficacy, safety and the direction of national policies and hospital regulations were the main factors affecting pharmacists\u27 willingness to dispense generic drugs. Conclusions The study identified gaps in respondents\u27 knowledge and perceptions of generic substitution. Pharmacists who are more knowledgeable in generic drugs tend to hold a more supportive attitude towards generic substitution. Although it appeared that pharmacists in China have largely accepted generic substitution, they still have concerns regarding the reliability and quality of generic drugs. The current issues need to be addressed for the realisation of the true value of generic drugs as part of the country\u27s healthcare cost-containment strategy as well as the implementation of generic substitution policy in China
Recent Advances in the Medicinal Chemistry of Farnesoid X Receptor
No full textFarnesoid X receptor (FXR) is an important regulator of bile acid, lipid, amino acid, and glucose homeostasis, hepatic inflammation, regeneration, and fibrosis. FXR has been recognized as a promising drug target for various metabolic diseases such as lipid disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and chronic kidney disease. A large number of FXR ligands have been developed by pharmaceutical companies and academic institutions, and several candidates have progressed into clinical trials in the past decade. However, it is continually a challenge to discover drugs targeting FXR due to side effects associated with long-term administration. In this perspective, we summarize the research progress on medicinal chemistry of FXR modulators from 2018 to the present by discussing the diverse structures of synthetic FXR modulators including steroidal and non-steroidal ligands, their structure–activity relationships (SARs), and their therapeutic applications