Search

Objective Retaining adolescents and young adults (AYA) in medications for opioid use disorder (MOUD), like methadone maintenance treatment (MMT), is critical to reducing toxic drug fatalities. This analysis sought to identify factors associated with MMT discontinuation among AYA. Method Data were derived from the At-Risk Youth Study, a prospective cohort study of street-involved AYA in Vancouver, Canada, between December 2005 and June 2018. Multivariable extended Cox regression identified factors associated with time to MMT discontinuation among AYA who recently initiated MMT. In subanalysis, multivariable extended Cox regression analysis identified factors associated with time to “actionable” MMT discontinuation, which could be addressed through policy changes. Results A total of 308 participants reported recent MMT during the study period. Participants were excluded if they reported MMT in the past 6 months at baseline and were retained in MMT ( n = 94, 30.5%); were missing MMT status data ( n = 43, 14.0%); or completed an MMT taper ( n = 11, 3.6%). Of the remaining 160 participants who initiated MMT over the study period, 102 (63.8%) discontinued MMT accounting for 119 unique discontinuation events. In multivariable extended Cox regression, MMT discontinuation was positively associated with recent weekly crystal methamphetamine use (adjusted hazard ratio [AHR] = 1.67, 95% confidence interval [CI]: 1.19 to 2.35), but negatively associated with age of first “hard” drug use (per year older) (AHR = 0.95, 95% CI: 0.90 to 1.00) and female sex (AHR = 0.66, 95% CI: 0.44 to 0.99). In subanalysis, recent weekly crystal methamphetamine use (AHR = 4.61, 95% CI: 1.78 to 11.9) and weekly heroin or fentanyl use (AHR = 3.37, 95% CI: 1.21 to 9.38) were positively associated with “actionable” MMT discontinuation, while older age (AHR = 0.87, 95% CI: 0.76 to 0.99) was negatively associated. Conclusions Efforts to revise MMT programming; provide access to a range of MOUD, harm reduction, and treatments; and explore coprescribing stimulants to AYA with concurrent stimulant use may improve treatment retention and reduce toxic drug fatalities.

Autonomous robotic and AI assistive systems are becoming increasingly prevalent in public and private spheres—often heralded as having the potential to revolutionise the everyday lives of disabled people. The reality could not be more different: disabled young people are routinely excluded from such spheres and, significantly, from the recent efforts to ensure that autonomous systems are trustworthy. Our critical literature review explores how trustworthy autonomous systems (TAS) can be framed within a critical disability studies perspective. We introduce the field of TAS and explore the interdisciplinary field of critical disability studies. This brings us to a key question: how is disability conceptualised, methodologically explored and represented in the TAS literature? We address this question by considering the ways in which disability and TAS have hitherto connected in the literature. We conclude with suggestions for future research and innovation that place disabled young people at the core of research and innovation in TAS.

Background: Cancers do not exist in isolation, surrounding tumours are supportive cells, which create the microenvironment in which cancer cells reside. In the prostate cancer (PCa), androgen receptor (AR) signalling in the surrounding fibroblasts is strikingly distinct from that within PCa cells, and has specific functions to produce, maintain, and modulate the extracellular matrix (ECM) which surrounds and interacts with PCa cells. The supportive cells of metastatic sites differ from those in the primary site and produce different types of cellular microenvironments. Since the advent of second generation anti-androgen therapy there has been an increase in the presence of liver metastasis. This project investigates how AR and anti-androgen therapy affect the prostate liver microenvironment and the subsequent effects on cancer. Results: Analysis of microenvironment of primary and metastatic sites indicates transcriptional responses distinct from that seen in PCa cells. This is exemplified by proliferation responses to androgen and anti-androgens in microenvironment cells being the reverse to that seen in Pca cells. Dichotomising microdissected PCa patient material of matched cancer and stromal tissue, based on stromal AR level shows distinct transcriptional profiles in the matched cancer cells. From previous studies, we know AR status in cancer adjacent fibroblasts (CAFs) of the primary tumor inversely associates with patient outcomes. Analysis of single cell CAFs and microdissected stromal samples points to a potential sub population of CAFs with this AR status. Conditioned media from liver and prostate fibroblast cells suggests that inactivation of AR signalling produces proliferative paracrine signals that can affect cancer cell growth. AR in primary site fibroblast and liver stellate cells regulates secretome and ECM production in the primary and metastatic site. Prostates and livers from enzalutamide treated mice showed changes in collagen fibres compared to control mice, as visualised by picro-direct-red staining. We cultured PCa cells within 3D-ECM microenvironments created in vitro from prostate fibroblasts or liver cells. The different 3D-ECM were able to produce changes in PCa cells, including gene transcription, intracellular signalling pathways, and proliferation and apoptotic responses. These data suggest that the responses of primary and metastatic microenvironments to androgens and anti-androgens can influence phosphorylation of intracellular pathways leading to alterations in gene transcription. Furthermore, the transcriptional responses of cancer cells in vitro to changes in microenvironmental AR signalling can be used to predict patient outcomes. Conclusions: Our data suggests that anti-AR therapy produces organ microenvironment-specific signals that influence the response of prostate cancer to treatments and affects patient outcomes.

Thirsty rats made 10, 30, or 90 licks at an empty spout for 10, 30, or 90 licks at a water spout. In the first experiment, three groups of six experienced a perfect positive, negative, or zero correlation between the number of empty licks required and the consequent number of water licks. The behavioral price of the water lick was the same for all three groups in terms of total empty licks/total water licks. But in terms of the arithmetic mean of the individual prices, the positive correlation imposed the lowest price, the negative correlation the highest. As the mean price increased the rats made fewer water licks, in accordance with the demand law, and licked more efficiently, getting more water per lick. In the second experiment, six rats chose between perfect positive and perfect negative correlational episodes. They showed at best only a slight preference for the positive, 55% on average, but started positive episodes much sooner than negative episodes. In the third experiment five rats chose between an imperfect positive and an imperfect negative correlation that represented a relatively small difference in terms of mean price. They chose each correlation 50% of the time on average, and they started positive episodes no sooner than negative ones. The overall pattern of results suggests that rats code price in terms of the arithmetic mean of the individual prices they have experienced and not in terms of the total cost relative to the total amount consumed over a particular interval of time.

Thirsty rats tested in 60-min sessions licked an empty spout for access to a water spout. We raised the behavioral price of the water lick by requiring more licks at the empty spout per lick at the water spout. At relatively high prices the rats made relatively few water licks but licked more efficiently, getting more water per lick. Controls showed that the rise in efficiency with price was not attributable to two variables previously confounded with price: the total number of water licks, and the temporal pattern of access. At a higher price the rats also licked more persistently, making more extra water licks before the shutter could occlude the spout. However, yoked controls showed that the greater persistence resulted not from price, but from the relatively stringent pattern of access that accompanied the higher price. Extra water licks diminished as the session progressed, apparently from satiety, not fatigue. The results have implications for behavioral ecology, behavioral economics, motivation, and the methodology of reward.

We tested cholinergic agents in delayed matching and nonmatching to position. Each task had a delay between the presentation of information and the chance to act on it later. We used a titrating procedure, new to experiments with rats, to determine the delay. Linopirdine (0.1 mg/kg), which releases acetylcholine, and physostigmine (0.1 mg/kg), a cholinesterase inhibitor, ameliorated the impairment of accuracy produced by scopolamine hydrobromide (0.1 mg/kg). In some cases, scopolamine hydrobromide decreased the number of trials, but physostigmine and linopirdine did not ameliorate that impairment. Both the muscarinic receptor antagonist, scopolamine hydrobromide (0.1 and 0.3 mg/kg), and its peripherally acting analog, scopolamine methylbromide (0.1 and 0.3 mg/kg), decreased accuracy. The impairment produced by scopolamine methylbromide suggests that the deficit produced by muscarinic receptor antagonism may have both a central and peripheral component. At the highest dose, scopolamine hydrobromide decreased the number of trials completed. Thus, some of the effects of scopolamine hydrobromide involve nonmnemonic performance factors. The performance deficits produced by scopolamine hydrobromide suggest that it may be necessary to qualify drug effects in terms of their action on both memorial and nonmemorial aspects of performance.

In 60-min test sessions, thirsty rats licked an empty metal spout for 0.2-milliliter shots of water delivered audibly to a neighboring spout that remained accessible after the first delivery. As the instrumental empty-lick requirement increased they drank less water, in accordance with the demand law, but made the same number of licks at the water delivery spout. In terms of water licks/milliliter they, therefore, licked less efficiently at higher behavioral prices, opposite to the relation obtained when rats respond for licks at a spout full of water. Given a continuous supply of free water they licked more efficiently, and licks varied in strict proportion to the amount drunk. Yoked controls with no instrumental requirement drank the same amount and made the same number of water licks as their price-paying experimental partners. Thus, intermittent delivery of a small amount of water induced rats to lick the delivery spout at a relatively high average rate that was unaffected by the behavioral price of the delivery or the interdelivery interval. Opposite efficiency effects suggest that external constraint on any dimension of drinking will affect that dimension more than any other left unconstrained.

Three experiments explored responses to molar and local schedule constraints. Thirsty rats pressed a lever for access to a water spout. In Experiment 1, response totals were unaffected by two local schedule characteristics—the variability of the instrumental requirement and the variability of the magnitude of contingent reward. Experiment 2 manipulated the correlation between the instrumental requirement and the magnitude of reward. This correlation did not affect the behavioral price ratio (presses per lick) at a molar level. At a local level, the positive correlation created a lower mean lick price than did the negative correlation. The rats licked more, and licked less efficiently, under the positive correlation than under the negative correlation. Experiment 3 compared two ways of manipulating the molar presses/lick ratio: The instrumental (contingent) series varied the instrumental (contingent) requirement, but held the other requirement constant. As the ratio increased, total leverpresses increased, and total licks decreased linearly; the two series did not differ significantly. At higher lick prices, the rats licked more efficiently and made more extra licks at the spout as it closed. The results help delimit the applicability of molar models of the organism’s response to schedule constraints.