Biodistribution Comparison of Fentanyl and Morphine Following Acute and Repeated Expsoure

The ongoing opioid crisis constitutes a dire public health threat that has resulted in staggering loss of life. In 2021, opioids were implicated in over 75% of the approximately 107,000 deaths attributed to drug overdose (CDC), and synthetic opioids such as fentanyl and its analogues are key drivers of the surge in opioid fatalities in recent years. Although fentanyl is a μ opioid receptor agonist, it has several distinct attributes compared to other drugs in this category, such as morphine. These include enhanced lipophilicity, heightened potency to induce respiratory depression, more rapid entry into the central nervous system, reduced sensitivity to naloxone rescue after overdose, reduced cross-tolerance to fentanyl even with a previous history of opioid exposure, and promotion of skeletal muscle rigidity, or “wooden chest syndrome,” which increases risk of overdose death. However, there are relatively few extensive comparisons of potential differences in biodistribution between fentanyl and classical opioids such as morphine in mouse models, despite the fact that mice are often used in preclinical studies of parameters relevant to the opioid crisis, i.e. respiratory depression. Therefore, the objective of the present dissertation was to compare acute biodistribution of fentanyl and morphine in blood and 12 murine tissues at doses demonstrated to cause respiratory depression and to gauge potential differences in biodistribution following repeated administration of these opioids. To this end, whole-body plethysmography studies were run to evaluate doses of fentanyl and morphine that produced comparable respiratory depression in male Swiss Webster mice. Then, an LC/MS-MS method was developed to quantify fentanyl, morphine, and select metabolites (norfentanyl and 4-ANPP, or despropionyl fentanyl, and morphine-3-β-D-glucuronide, respectively) in mouse whole blood, whole brain, lung, heart, kidney, small intestine, large intestine, spleen, stomach, muscle, fat, and skin. Afterwards, mice received acute doses of subcutaneous (sc) fentanyl (0.3 mg/kg) or morphine (30 mg/kg) selected based on whole-body plethysmography studies, and samples were collected at 5, 15, 60, and 240 min. A separate cohort received repeated daily injections of these doses for 5 days prior to sample collection 60 min after the last treatment. The data indicate that, after acute administration, time course of drug distribution varied by tissue, with fentanyl and morphine demonstrating similar time courses in tissues like lung, stomach, and small intestine, but differing in others, like brain and spleen. Moreover, fentanyl exhibits greater distribution out of the blood and into brain, liver, lung, and heart than morphine early after administration and accumulates out of blood into fat at later time points after administration to a greater extent than morphine. Ratios of total drug distribution (expressed as area under the curve) in tissue and blood over the observed acute administration time course suggest that fentanyl accumulation in tissue relative to blood in several regions of the body, such as lung, heart, kidney, spleen, fat, and small intestine, is greater than morphine. These findings indicate that, even though fentanyl’s fatal effects are largely centrally-mediated, this synthetic opioid could potentially have deleterious effects on several organs to a larger degree than morphine, both those involved in respiration and those not directly involved in respiration. The data also suggest that temporary storage of fentanyl in adipose tissue is greater relative to opiates like morphine. Repeatedly-treated mice did not demonstrate tolerance or altered biodistribution compared to drug-naïve mice, implying that repeated fentanyl or morphine exposure that does not induce tolerance is not sufficient to modify tissue distribution. Broadly speaking, this body of work provides an assessment of fentanyl, morphine, and associated metabolite levels in diverse matrices of a model organism widely used for studying physiological and behavioral effects of synthetic opioids. In addition, a useful bioanalytical method was generated for measuring fentanyl concentration in various mouse tissues, which could be applied to other preclinical studies conducting work related to the opioid crisis

Dimensional perturbation theory for vibration-rotation spectra of linear triatomic molecules

A very efficient large-order perturbation theory is formulated for the nuclear motion of a linear triatomic molecule. To demonstrate the method, all of the experimentally observed rotational energies, with values of $J$ almost up to 100, for the ground and first excited vibrational states of CO$_2$ and for the ground vibrational states of N$_2$O and of OCS are calculated. All coupling between vibration and rotation is included. The perturbation expansions reported here are rapidly convergent. The perturbation parameter is $D^{-1/2}$, where $D$ is the dimensionality of space. Increasing $D$ is qualitatively similar to increasing the angular momentum quantum number $J$. Therefore, this approach is especially suited for states with high rotational excitation. The computational cost of the method scales only as $JN_v^{5/3}$, where $N_v$ is the size of the vibrational basis set.Comment: submitted to Journal of Chemical Physics, 23 pages, REVTeX, no figure

Examining 'window dressing' : the views of black police associations on recruitment and training

In a previous issue of this journal, Ellis Cashmore (2002 Cashmore, E. 2002. ‘Behind the window dressing: minority ethnic police perspectives on cultural diversity’. Journal of Ethnic and Migration Studies, 28(2): 327–41. [Taylor & Francis Online], [CSA], [Google Scholar] ) discussed two key issues currently confronting police constabularies in England and Wales: the recruitment of minority ethnic officers and civilian staff, and the impact of diversity training now in place for all police officers. Cashmore argued that not only are these policies ineffective in enhancing cultural diversity within constabularies, but that they are harmful, presenting a false outward image of effective action. This article examines Cashmore's arguments and develops them in light of findings from recent research on Black Police Associations (BPAs) in England and Wales. Our findings firstly suggest that, because of heavy involvement with these initiatives and the close relationship BPAs have developed with senior management (in comparison to non-BPA members), they must be considered in any discussion of minority ethnic recruitment and diversity training. In addition, the majority of the officers we interviewed were supportive of current recruitment and training programmes. Secondly, we argue that BPAs are helping to change the nature of the overall police culture to a certain extent. Many minority ethnic officers no longer feel they must downplay their ethnicity as members of constabularies

Magnetospheric Accretion and Ejection of Matter in Resistive Magnetohydrodynamic Simulations

The ejection of matter in the close vicinity of a young stellar object is investigated, treating the accretion disk as a gravitationally bound reservoir of matter. By solving the resistive MHD equations in 2D axisymmetry using our version of the Zeus-3D code with newly implemented resistivity, we study the effect of magnetic diffusivity in the magnetospheric accretion-ejection mechanism. Physical resistivity was included in the whole computational domain so that reconnection is enabled by the physical as well as the numerical resistivity. We show, for the first time, that quasi-stationary fast ejecta of matter, which we call {\em micro-ejections}, of small mass and angular momentum fluxes, can be launched from a purely resistive magnetosphere. They are produced by a combination of pressure gradient and magnetic forces, in presence of ongoing magnetic reconnection along the boundary layer between the star and the disk, where a current sheet is formed. Mass flux of micro-ejection increases with increasing magnetic field strength and stellar rotation rate, and is not dependent on the disk to corona density ratio and amount of resistivity.Comment: 18 pages, many revisions from previous version, accepted in Ap

The Importance of Clarification of Auditors\u27 Responsibilities Under the New Audit Reporting Standards*

Given the uncertainty regarding auditors\u27 responsibilities, standard setters considered the need for clarification of technical terms such as reasonable assurance in the new audit reporting models. The PCAOB ultimately decided to exclude clarifying language from its final standard, while the Auditing Standards Board and IAASB made such language mandatory. Given the difference in reporting models, this study investigates the role clarification of reasonable assurance plays in auditor negligence. We predict and find that, absent clarification, jurors judge auditors to be more negligent when the audit report includes a related critical audit matters disclosure than when it does not. However, consistent with our prediction, clarifying what is meant by reasonable assurance mitigates this increase in auditors\u27 liability exposure by reducing jurors\u27 perceptions of auditors\u27 personal control over the misstatement at the time of the audit. Thus, our evidence suggests that the PCAOB\u27s decision to not include such language in the new audit reporting model may have been shortsighted given the potential for clarification to mitigate a potential negative unintended consequence to auditors\u27 litigation exposure under the new audit reporting model

Invariance of the correlation energy at high density and large dimension in two-electron systems

We prove that, in the large-dimension limit, the high-density correlation energy \Ec of two opposite-spin electrons confined in a $D$-dimensional space and interacting {\em via} a Coulomb potential is given by \Ec \sim -1/(8D^2) for any radial confining potential $V(r)$. This result explains the observed similarity of \Ec in a variety of two-electron systems in three-dimensional space.Comment: 4 pages, 1 figure, to appear in Phys. Rev. Let

Distributed variance regularized Multitask Learning

Past research on Multitask Learning (MTL) has focused mainly on devising adequate regularizers and less on their scalability. In this paper, we present a method to scale up MTL methods which penalize the variance of the task weight vectors. The method builds upon the alternating direction method of multipliers to decouple the variance regularizer. It can be efficiently implemented by a distributed algorithm, in which the tasks are first independently solved and subsequently corrected to pool information from other tasks. We show that the method works well in practice and convergences in few distributed iterations. Furthermore, we empirically observe that the number of iterations is nearly independent of the number of tasks, yielding a computational gain of O(T) over standard solvers. We also present experiments on a large URL classification dataset, which is challenging both in terms of volume of data points and dimensionality. Our results confirm that MTL can obtain superior performance over either learning a common model or independent task learning

Enhanced X-ray variability from V1647 Ori, the young star in outburst illuminating McNeil's Nebula

We report a ~38 ks X-ray observation of McNeil's Nebula obtained with XMM on 2004 April 4. V1647 Ori, the young star in outburst illuminating McNeil's Nebula, is detected with XMM and appears variable in X-rays. We investigate the hardness ratio variability and time variations of the event energy distribution with quantile analysis, and show that the large increase of the count rate from V1647 Ori observed during the second half of the observation is not associated with any large plasma temperature variations as for typical X-ray flares from young low-mass stars. X-ray spectral fitting shows that the bulk (~75%) of the intrinsic X-ray emission in the 0.5-8 keV energy band comes from a soft plasma component (0.9 keV) reminiscent of the X-ray spectrum of the classical T Tauri star TW Hya, for which X-ray emission is believed to be generated by an accretion shock onto the photosphere of a low-mass star. The hard plasma component (4.2 keV) contributes ~25% of the total X-ray emission, and can be understood only in the framework of plasma heating sustained by magnetic reconnection events. We find a hydrogen column density of NH=4.1E22 cm-2, which points out a significant excess of hydrogen column density compared to the value derived from optical/IR observations, consistent with the picture of the rise of a wind/jet unveiled from ground optical spectroscopy. The X-ray flux observed with XMM ranges from roughly the flux observed by Chandra on 2004 March 22 (~10 times greater than the pre-outburst X-ray flux) to a value two times greater than that caught by Chandra on 2004 March 7 (~200 times greater than the pre-outburst X-ray flux). We have investigated the possibility that V1647 Ori displays a periodic variation in X-ray brightness as suggested by the combined Chandra+XMM data set (abridged).Comment: 11 pages and 8 Figures. Accepted for publication by Astronomy & Astrophysic