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"Edwards, Chris"
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Restructuring the U.S. Postal Service
The U.S. Postal Service (USPS) is a large business enterprise operated by the federal government. It has more than 600,000 employees and more than $70 billion in annual revenues. Revenues are supposed to cover the postal service's costs, but mail volume is plunging, and the USPS has been losing billions of dollars a year for more than a decade. The USPS has a legal monopoly over letters and mailboxes. That policy is an anomaly because the federal government's general economic stance is to encourage open competition in markets, yet the USPS monopoly prevents entrepreneurs from entering postal markets and trying to improve quality and reduce costs for consumers. While mail volumes have fallen, the USPS has expanded its package business. But it makes no sense for a privileged federal entity to take business from private, taxpaying companies in the package industry. Postal and package markets are evolving rapidly, and the goal of federal policy should be to create a level playing field open for competition and innovation. Europe is facing the same challenge of declining mail volume, and it has focused on opening postal markets and privatizing postal providers. The U.S. Congress should follow suit by privatizing the USPS and opening postal markets to competition. These reforms would give the USPS the flexibility it needs to cut costs and diversify, while providing equal treatment to businesses across postal and package markets.
Journal Article
Development of a Novel Quantitative Structure-Activity Relationship Model to Accurately Predict Pulmonary Absorption and Replace Routine Use of the Isolated Perfused Respiring Rat Lung Model
Purpose
We developed and tested a novel Quantitative Structure-Activity Relationship (QSAR) model to better understand the physicochemical drivers of pulmonary absorption, and to facilitate compound design through improved prediction of absorption. The model was tested using a large array of both existing and newly designed compounds.
Methods
Pulmonary absorption data was generated using the isolated perfused respiring rat lung (IPRLu) model for 82 drug discovery compounds and 17 marketed drugs. This dataset was used to build a novel QSAR model based on calculated physicochemical properties. A further 9 compounds were used to test the model’s predictive capability.
Results
The QSAR model performed well on the 9 compounds in the “Test set” with a predicted
versus
observed correlation of R
2
= 0.85, and >65% of compounds correctly categorised. Calculated descriptors associated with permeability and hydrophobicity positively correlated with pulmonary absorption, whereas those associated with charge, ionisation and size negatively correlated.
Conclusions
The novel QSAR model described here can replace routine generation of IPRLu model data for ranking and classifying compounds prior to synthesis. It will also provide scientists working in the field of inhaled drug discovery with a deeper understanding of the physicochemical drivers of pulmonary absorption based on a relevant respiratory compound dataset.
Journal Article
The Differential Absorption of a Series of P-Glycoprotein Substrates in Isolated Perfused Lungs from Mdr1a/1b Genetic Knockout Mice can be Attributed to Distinct Physico-Chemical Properties: an Insight into Predicting Transporter-Mediated, Pulmonary Specific Disposition
Purpose
To examine if pulmonary P-glycoprotein (P-gp) is functional in an intact lung; impeding the pulmonary absorption and increasing lung retention of P-gp substrates administered into the airways. Using calculated physico-chemical properties alone build a predictive Quantitative Structure-Activity Relationship (QSAR) model distinguishing whether a substrate’s pulmonary absorption would be limited by P-gp or not.
Methods
A panel of 18 P-gp substrates were administered into the airways of an isolated perfused mouse lung (IPML) model derived from
Mdr1a
/
Mdr1b
knockout mice. Parallel intestinal absorption studies were performed. Substrate physico-chemical profiling was undertaken. Using multivariate analysis a QSAR model was established.
Results
A subset of P-gp substrates (10/18) displayed pulmonary kinetics influenced by lung P-gp. These substrates possessed distinct physico-chemical properties to those P-gp substrates unaffected by P-gp (8/18). Differential outcomes were not related to different intrinsic P-gp transporter kinetics. In the lung, in contrast to intestine, a higher degree of non-polar character is required of a P-gp substrate before the net effects of efflux become evident. The QSAR predictive model was applied to 129 substrates including eight marketed inhaled drugs, all these inhaled drugs were predicted to display P-gp dependent pulmonary disposition.
Conclusions
Lung P-gp can affect the pulmonary kinetics of a subset of P-gp substrates. Physico-chemical relationships determining the significance of P-gp to absorption in the lung are different to those operative in the intestine. Our QSAR framework may assist profiling of inhaled drug discovery candidates that are also P-gp substrates. The potential for P-gp mediated pulmonary disposition exists in the clinic.
Journal Article
Deadly fable
\"The Might Beyond the Mirror, the great threat that Batman assembled the Justice League of America to stop, has finally arrived in the form of the Queen of Fables. With her reality-warping power, her intent is to take over the real world and the imaginary and rule over everything--and without Batman, does the Justice League stand a chance against her? Can their mysetrious new member, Promethea, help them? Or will reality crumble at the Queen's whim?\"-- Provided by publisher.
Book
Reducing blood pressure variability–results from a single-arm proof of concept prospective trial
Increased variability in systolic blood pressure, expressed as the coefficient of variation (BPCoV), is associated with poor cardiovascular outcomes. Variability could be due to episodic non-adherence to medical recommendations in some patients. Reports of targeted attempts to mitigate such variation are lacking. A behavioral intervention targeted at patients with initially high BPCoV may decrease variability. In this single-site, single arm prospective proof-of-concept trial, an electronic health record review identified patients with excessive variability (BPCov>10%). Enrolled patients received a blood pressure monitor and a remotely delivered behavioral intervention for 3 months. The primary outcome was mean blood pressure variability before versus after the intervention. Of 551 initially screened patients, 107 (19.4%) met the BPCoV criteria, and 25 consented (6 females and 19 males, mean age 64.24 years). Average BPCoV for the 6 months pre-enrollment was 12.96 (
SD
=2.11) compared to 7.02 (
SD
=3.54) during intervention (
p
<0.001). Other variability metrics also improved. Sensitivity analyses (different timeframes, using measurements obtained in the clinic vs. home monitor) all showed significant improvement. This proof-of-concept trial suggests that patients with high systolic blood pressure variability can successfully engage in a remotely delivered behavioral intervention, and that such an intervention can reduce such variability.
Trial Registration:
NCT05814562, ClinicalTrials.gov.
Journal Article
Physiologically Based Pharmacokinetic Modelling of Inhaled Nemiralisib: Mechanistic Components for Pulmonary Absorption, Systemic Distribution, and Oral Absorption
Background and Objectives
Physiologically based pharmacokinetic (PBPK) modelling has evolved to accommodate different routes of drug administration and enables prediction of drug concentrations in tissues as well as plasma. The inhalation route of administration has proven successful in treating respiratory diseases but can also be used for rapid systemic delivery, holding great promise for treatment of diseases requiring systemic exposure. The objective of this work was to develop a PBPK model that predicts plasma and tissue concentrations following inhalation administration of the PI3Kδ inhibitor nemiralisib.
Methods
A PBPK model was built in GastroPlus
®
that includes a complete mechanistic description of pulmonary absorption, systemic distribution and oral absorption following inhalation administration of nemiralisib. The availability of clinical data obtained after intravenous, oral and inhalation administration enabled validation of the model with observed data and accurate assessment of pulmonary drug absorption. The PBPK model described in this study incorporates novel use of key parameters such as lung systemic absorption rate constants derived from human physiological lung blood flows, and implementation of the specific permeability-surface area product per millilitre of tissue cell volume (SpecPStc) to predict tissue distribution.
Results
The inhaled PBPK model was verified using plasma and bronchoalveolar lavage fluid concentration data obtained in human subjects. Prediction of tissue concentrations using the permeability-limited systemic disposition tissue model was further validated using tissue concentration data obtained in the rat following intravenous infusion administration to steady state.
Conclusions
Fully mechanistic inhaled PBPK models such as the model described herein could be applied for cross molecule assessments with respect to lung retention and systemic exposure, both in terms of pharmacology and toxicology, and may facilitate clinical indication selection.
Journal Article
Acute Effects of Various Stretching Techniques on Range of Motion: A Systematic Review with Meta-Analysis
Background
Although stretching can acutely increase joint range of motion (ROM), there are a variety of factors which could influence the extent of stretch-induced flexibility such as participant characteristics, stretching intensities, durations, type (technique), and muscle or joint tested.
Objective
The objective of this systematic review and meta-analysis was to investigate the acute effects of stretching on ROM including moderating variables such as muscles tested, stretch techniques, intensity, sex, and trained state.
Methods
A random-effect meta-analysis was performed from 47 eligible studies (110 effect sizes). A mixed-effect meta-analysis subgroup analysis was also performed on the moderating variables. A meta-regression was also performed between age and stretch duration. GRADE analysis was used to assess the quality of evidence obtained from this meta-analysis.
Results
The meta-analysis revealed a small ROM standard mean difference in favor of an acute bout of stretching compared to non-active control condition (ES = −0.555; Z = −8.939; CI (95%) −0.677 to −0.434;
p
< 0.001; I
2
= 33.32). While there were ROM increases with sit and reach (
P
= 0.038), hamstrings (
P
< 0.001), and triceps surae (
P
= 0.002) tests, there was no change with the hip adductor test (
P
= 0.403). Further subgroup analyses revealed no significant difference in stretch intensity (
P
= 0.76), trained state (
P
= 0.99), stretching techniques (
P
= 0.72), and sex (
P
= 0.89). Finally, meta-regression showed no relationship between the ROM standard mean differences to age (R
2
= −0.03;
P
= 0.56) and stretch duration (
R
2
= 0.00;
P
= 0.39), respectively. GRADE analysis indicated that we can be moderately confident in the effect estimates.
Conclusion
A single bout of stretching can be considered effective for providing acute small magnitude ROM improvements for most ROM tests, which are not significantly affected by stretch intensity, participants’ trained state, stretching techniques, and sex.
Key Points
The meta-analysis on joint range of motion (ROM) increases revealed a small effect size in favor of an acute bout of stretching compared to the control condition.
Subgroup analysis revealed a significant increase in ROM with sit and reach, hamstrings, and triceps surae tests, but no improvement with the hip adductor tests. Whereas all moderating variables presented significant increases in ROM, further subgroup analyses revealed no significant difference in ROM gains with the stretch intensity, trained state of the participants, stretching techniques, and sex.
A meta-regression showed no relationship between the effect sizes to age and stretch duration, respectively.
Journal Article