Novel approaches for the treatment of psychostimulant and opioid abuse-focus on opioid receptor-based therapies

INTRODUCTION: Psychostimulant and opioid addiction are poorly treated. The majority of abstinent users relapse back to drug-taking within a year of abstinence, making ‘anti-relapse’ therapies the focus of much current research. There are two fundamental challenges to developing novel treatments for drug addiction. Firstly, there are 3 key stimuli that precipitate relapse back to drug-taking: stress, presentation of drug-conditioned cue, taking a small dose of drug. The most successful novel treatment would be effective against all 3 stimuli. Secondly, a large number of drug users are poly-drug users: taking more than one drug of abuse at a time. The ideal anti-addiction treatment would therefore be effective against all classes of drugs of abuse. AREAS COVERED: In this review, the authors discuss the clinical need and animal models used to uncover potential novel treatments. There is a very broad range of potential treatment approaches and targets currently being examined as potential anti-relapse therapies. These broadly fit into 2 categories: ‘memory-based’ and ‘receptor-based’ and the authors discuss the key targets here within. EXPERT OPINION: Opioid receptors and ligands have been widely studied, and research into how different opioid subtypes affect behaviours related to addiction (reward, dysphoria, motivation) suggests that they are tractable targets as anti-relapse treatments. Regarding opioid ligands as novel ‘anti-relapse’ medications targets - research suggests that a ‘non-selective’ approach to targeting opioid receptors will be the most effective

Principal Component Analysis with Noisy and/or Missing Data

We present a method for performing Principal Component Analysis (PCA) on noisy datasets with missing values. Estimates of the measurement error are used to weight the input data such that compared to classic PCA, the resulting eigenvectors are more sensitive to the true underlying signal variations rather than being pulled by heteroskedastic measurement noise. Missing data is simply the limiting case of weight=0. The underlying algorithm is a noise weighted Expectation Maximization (EM) PCA, which has additional benefits of implementation speed and flexibility for smoothing eigenvectors to reduce the noise contribution. We present applications of this method on simulated data and QSO spectra from the Sloan Digital Sky Survey.Comment: Accepted for publication in PASP; v2 with minor updates, mostly to bibliograph

Semitransparent organic photovoltaic cells

We demonstrate semitransparent, small molecular weight organic solar cells employing a thin silver/indium tin oxide compound cathode with a maximum transmission of (60±6)%(60±6)% averaged over the visible spectral range and with a power conversion efficiency, ηp = (0.28±0.03)%ηp=(0.28±0.03)% under simulated, AM1.5G, 1 sun illumination. By increasing the Ag thickness, an average transmission of (26±3)%(26±3)% is achieved with ηp = (0.62±0.06)%ηp=(0.62±0.06)%, a value approximately half of that obtained for the same structure employing a conventional, reflective, and thick Ag cathode. A semitransparent tandem organic solar cell with ηp = (0.48±0.02)%ηp=(0.48±0.02)% and an average transmission of (44±4)%(44±4)% is also demonstrated. Semitransparent organic photovoltaic cells have potential uses as tinted and power-generating thin-film coatings on architectural surfaces, such as windows and walls. The use of a transparent top electrode also significantly simplifies the design of tandem cells, relaxing requirements for the placement of different absorbing materials at the maxima of optical fields introduced by reflective cathodes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87783/2/233502_1.pd

Cryogenic Orbital Nitrogen Experiment (CONE): Phase A/B design study

Subcritical cryogenic fluid management (CFM) has long been recognized as an enabling technology for future space missions. Subcritical liquid storage and supply are two of the five CFM technology areas that need to be studied in the low gravity on-orbit environment. The Cryogenic Orbital Nitrogen Experiment (CONE) is a LN2 cryogenic storage and supply system demonstration placed in orbit by the National Space Transportation System (NSTS) Orbiter and operated as an in-bay payload. In-space demonstration of CFM using LN2 with a few well defined areas of focus would provide the confidence level required to implement subcritical cryogen use and is the first step towards the more far reaching issue of cryogen transfer and tankage resupply. A conceptual approach for CONE was developed and an overview of the program is described including the following: (1) a description of the background and scope of the technology objectives; (2) a description of the payload design and operation; and (3) the justification for CONE relating to potential near term benefits and risk mitigation for future systems. Data and criteria is provided to correlate in-space performance with analytical and numerical modeling of CFM systems

Strategic placement of automated external defibrillators (AEDs) for cardiac arrests in public locations and private residences

Aim: The aim of our study was to determine whether businesses can be identified that rank highly for their potential to improve coverage of out-of-hospital cardiac arrests (OHCAs) by automated external defibrillators (AEDs), both in public locations and private residences. Methods: The cohort comprised 10,422 non-traumatic OHCAs from 2014 to 2020 in Perth, Western Australia. We ranked 115 business brands (across 5,006 facilities) for their potential to supplement coverage by the 3,068 registered public-access AEDs in Perth, while accounting for AED access hours. Results: Registered public-access AEDs provided 100 m coverage of 23% of public-location arrests, and 4% of arrests in private residences. Of the 10 business brands ranked highest for increasing the coverage of public OHCAs, six brands were ranked in the top 10 for increased coverage of OHCAs in private residences. A public phone brand stood out clearly as the highest-ranked of all brands, with more than double the coverage-increase of the second-ranked brand. If all 115 business brands hosted AEDs with 24–7 access, 57% of OHCAs would remain without 100 m coverage for public arrests, and 92% without 100 m coverage for arrests in private residences. Conclusion: Many businesses that ranked highly for increased coverage of arrests in public locations also rank well for increasing coverage of arrests in private residences. However, even if the business landscape was highly saturated with AEDs, large gaps in coverage of OHCAs would remain, highlighting the importance of considering other modes of AED delivery in metropolitan landscapes

Fall from standing height, or greater, and mortality among ambulance-transported patients with major trauma from falls

Introduction: This study describes the relationship between falls from standing height, or greater, and mortality in ambulance-transported patients with major trauma from falls. Methods: Road ambulance records from 1 January 2013 to 31 December 2016 were linked with WA State Trauma Registry records to identify ambulance-transported falls patients with major trauma. Results: Of the patients who fell from standing level, 114/460 (25%) died within 30 days, compared with 47/222 (21%) who fell from height (p=0.64). Conclusion: Mortality is relatively high, and fall height is not associated with 30-day survival, among ambulance-transported patients with major trauma in metropolitan Perth, Western Australia

Combined administration of buprenorphine and naltrexone produces antidepressant-like effects in mice

Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focussed on the development of kappa opioid receptor (κ-receptor) antagonists. Buprenorphine acts as a partial μ-opioid receptor agonist and a κ-receptor antagonist. By combining buprenorphine with the opioid antagonist naltrexone, the activation of μ-opioid receptors would be reduced and the κ-antagonist properties enhanced. We have established that a combination dose of buprenorphine (1mg/kg) with naltrexone (1mg/kg) functions as a short-acting κ-antagonist in the mouse tail withdrawal test. Furthermore, this dose combination is neither rewarding nor aversive in the conditioned place preference paradigm and is without significant locomotor effects. We have shown for the first time that systemic co-administration of buprenorphine (1mg/kg) with naltrexone (1mg/kg) in CD-1 mice produced significant antidepressant-like responses in behaviours in both the forced swim test and novelty induced hypophagia task. Behaviours in the elevated plus maze and light dark box were not significantly altered by treatment with buprenorphine alone, or in combination with naltrexone. We propose that the combination of buprenorphine with naltrexone represents a novel, and potentially a readily translatable approach, to the treatment of depression

Impact of a carbohydrate mouth rinse on corticomotor excitability after mental fatigue in healthy college-aged subjects

Mental Fatigue (MF) has been associated with reduced physical performance but the mechanisms underlying this result are unclear. A reduction in excitability of the corticomotor system is a way mental fatigue could negatively impact physical performance. Carbohydrate (CHO) mouth rinse (MR) has been shown to increase corticomotor excitability. The purpose of this study was to determine if CHO MR impacts corticomotor excitability after MF. Fifteen subjects (nine females, six males; age = 23 ± 1 years; height = 171 ± 2 cm; body mass = 69 ± 3 kg; BMI = 23.8 ± 0.7) completed two sessions under different MR conditions (Placebo (PLAC), 6.4% glucose (CHO)) separated by at least 48 h and applied in a double-blinded randomized fashion. Motor-evoked potential (MEP) of the left first dorsal interosseous (FDI) was determined by transcranial magnetic stimulation (TMS) before and after MF. Perceived MF was recorded before and after the MF task using a 100 mm visual analog scale (VAS). MF was greater following PLAC (+30.4 ± 4.0 mm) than CHO (+19.4 ± 3.9 mm) ( = 0.005). MEP was reduced more following PLAC (-16.6 ± 4.4%) than CHO (-3.7 ± 4.7%) ( < 0.001). CHO MR was successful at attenuating the reduction in corticomotor excitability after MF. Carbohydrate mouth rinse may be a valuable tool at combating the negative consequences of mental fatigue