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In this study, we report a biological temperature-sensing electrical regulator in the cytochrome c oxidase of the Devil Worm, Halicephalobus mephisto. This extremophile metazoan was isolated 1.3 km underground in a South African goldmine, where it adapted to heat and potentially to hypoxia, making its mitochondrial sequence a likely target of adaptational change. We obtained the complete mitochondrial genome sequence of this organism and show through dN/dS analysis evidence of positive selection in H. mephisto cytochrome c oxidase subunits. Seventeen of these positively selected amino acid substitutions were located in proximity to the H- and K-pathway proton channels of the complex. Surprisingly, the H. mephisto cytochrome c oxidase completely shuts down at low temperatures (20 °C), leading to a 4.8-fold reduction in the transmembrane proton gradient (ΔΨm) compared to optimal temperature (37 °C). Direct measurement of oxygen consumption found a corresponding 4.6-fold drop at 20 °C compared to 37 °C. Correspondingly, the lifecycle of H. mephisto takes four times longer at low temperature than at higher. This elegant evolutionary adaptation creates a finely-tuned mitochondrial temperature sensor, allowing this ectothermic organism to maximize its reproductive success across varying environmental temperatures. Here, an evolutionary adaptation converting mitochondrial respiration into a thermometer is reported. The adaptive changes center around the proton channels of cytochrome c oxidase. [ABSTRACT FROM AUTHOR]

Introduction: Published data on the safety of natural medical cannabis (MC) when used in the real-world clinical practice setting are lacking. This study aimed to describe adverse events (AEs) reported across three years following MC initiation. Methods: The Quebec Cannabis Registry (QCR) was a prospective registry of adults enrolled through participating physicians when they initiated MC between May 2015 and October 2018. Follow-up ended at MC discontinuation, loss to follow-up, three years, or end of data collection (May 2019). Data were collected at baseline and at follow-up visits every three months for the first two years, then once in the third year. Physicians filled adverse event (AE) reports, which were coded using MedDRA® preferred terms (PTs), and descriptive analyses were conducted. Results: A total of 2991 patients were enrolled (mean age 50.9 years, 50.2% females). During follow-up, 108 patients (3.6%) experienced moderate or severe AEs, yielding 111 AE reports (three patients had two reports) and 214 AEs (average 1.9 AEs per report). Mild AEs were recorded as a reason for MC discontinuation for nine patients, but no AE reports were available. The most common PTs for ingested MC (62 reports) were dizziness (12.9%), nausea (11.3%), somnolence (9.7%), and vomiting (8.1%), and for inhaled MC (23 reports), headache (13.0%) was the most common. The most frequent PTs associated with tetrahydrocannabinol (THC)-dominant MC (25 reports) were dizziness and somnolence (12.0% each); for cannabidiol (CBD)-dominant MC (20 reports), vomiting (20.0%) was most common; and dizziness (17.2%), nausea (13.8%), somnolence (10.3%), and headache (8.6%) were the most frequent for balanced MC (58 reports). Conclusion: No new safety concerns were identified relative to the published literature, although notable differences in AE profile between modes of administration and cannabinoid content ratios should be considered by health professionals. Further work identifying and managing risk factors for AEs is warranted to maintain a favorable benefit-risk balance for MC. [ABSTRACT FROM AUTHOR]

Lack of guidance and regulation for authorizing medical cannabis for conditions involving the health and neurodevelopment of children is ethically problematic as it promulgates access inequities, risk-benefit inconsistencies, and inadequate consent mechanisms. In two virtual sessions using participatory action research and consensus-building methods, we obtained perspectives of stakeholders on ethics and medical cannabis for children and youth. The sessions focused on the scientific and regulatory landscape of medical cannabis, surrogate decision-making and assent, and the social and political culture of medical cannabis. We found that evidence-gathering and data dissemination, pressures on clinical relationships, and the lack of integration of culturally diverse perspectives and Indigenous knowledges were key areas of concern. Participants emphasized the importance of utilizing adaptive study designs, highlighted the importance of trust-building between clinicians, patients and caregivers, and discussed barriers including historical and ongoing stigmatization of medical cannabis. We conclude that continued public consultation and strength-based research that integrate diverse perspectives are critical steps forward. [ABSTRACT FROM AUTHOR]

Purpose: Cannabichromene (CBC) is a phytocannabinoid commonly found in cannabis, yet its acute post-dose pharmacokinetics (PK) have not been examined in humans. This is a secondary data analysis from a trial investigating Spectrum Yellow oil, an oral cannabis product used for medical purposes that contained 20 mg cannabidiol (CBD), 0.9 mg Δ9-tetrahydrocannabinol (THC), and 1.1 mg CBC, per 1 mL of oil. Methods: Participants (N = 43) were randomized to one of 5 groups: 120 mg CBD, 5.4 mg THC, and 6.6 mg CBC daily; 240 mg CBD, 10.8 mg THC, and 13.2 mg CBC daily; 360 mg CBD, 16.2 mg THC, and 19.8 mg CBC daily; 480 mg CBD, 21.6 mg THC, and 26.4 mg CBC daily; or placebo. Study medication was administered every 12 h for 7 days. Plasma CBC concentrations were analyzed by a validated two-dimensional high-performance liquid chromatography–tandem mass spectrometry assay. Results: After a single dose and after the final dose, the Cmax of CBC increased by 1.3–1.8-fold for each twofold increase in dose; the tmax range was 1.6–4.3 h. Based on the ratio of administered CBD, THC, and CBC to the plasma concentration, the dose of CBD was 18 times higher than the dose of CBC, yet the AUC0–t of CBD was only 6.6–9.8-fold higher than the AUC0–t of CBC; the dose of THC was similar to the dose of CBC, yet THC was quantifiable in fewer plasma samples than was CBC. Conclusions: CBC may have preferential absorption over CBD and THC when administered together. Trial Registration: Australian New Zealand Clinical Trials Registry #ACTRN12619001450101, registered 18 October 2019. [ABSTRACT FROM AUTHOR]

Background: Despite evidence supporting the benefits of cannabinoids for symptom control across a wide range of medical conditions, concerns have been raised regarding the potential misuse and/or problematic use of cannabinoids (CBs).Objective: The first objective of this study was to examine the incidence of problematic prescription cannabinoid use (PPCBU) over a 12-month period among patients initiating cannabinoid therapy. The second objective was to examine the factors associated with PPCBU. A total of 265 patients who were prescribed oral cannabinoid therapy as part of usual medical practice were enrolled into this prospective observational study. Patients first completed a series of baseline questionnaires assessing demographic, clinical, and substance use variables. Three measures designed to assess PPCBU were then administered at 3, 6, and 12 months after initiation of cannabinoid therapy.Results: At each of the follow-up assessment time points, a significantly greater number of patients scored below (vs above) cutoff scores on the three main PPCBU outcomes (all p’s < .001). At any follow-up time point, a maximum of roughly 25% of patients demonstrated PPCBU. Heightened odds of PPCBU were observed among patients with a history of psychiatric problems, tobacco smokers, and recreational cannabis users (all p’s < .05). Results indicated that past-year substance abuse, assessed using the DAST-20, was the strongest predictor of PPCBU (p < .005).Conclusion: Findings from the present study could have implications for clinicians considering the use of cannabinoids for the management of patients with medical conditions. Although results indicated that the majority of patients included in this study did not reach cutoff scores on the three main PPCBU outcomes, our findings suggest that PPCBU should be routinely assessed and monitored over the course of cannabinoid therapy, particularly among patients with a history of psychiatric or substance use problems. [ABSTRACT FROM AUTHOR]

Numerous advances in ligand binding assay (LBA) real-time measurement technologies have been made within the last several years, ranging from the development of novel platforms to drive technology expansion to the adaptation of existing platforms to optimize performance and throughput. In this review, we have chosen to focus on technologies that provide increased value to two distinct segments of the LBA community. First, experimentally, by measuring real-time binding events, these technologies provide data that can be used to interrogate receptor/ligand binding interactions. While overall the platforms are not new, they have made significant advances in throughput, multiplexing, and/or sensitivity. Second, clinically, these point-of-care (POC) technologies provide instantaneous information which facilitates rapid treatment decisions. [ABSTRACT FROM AUTHOR]

An updated systematic review of randomized controlled trials examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to PRISMA guidelines for systematic reviews reporting on health care outcomes. Eleven trials published since our last review met inclusion criteria. The quality of the trials was excellent. Seven of the trials demonstrated a significant analgesic effect. Several trials also demonstrated improvement in secondary outcomes (e.g., sleep, muscle stiffness and spasticity). Adverse effects most frequently reported such as fatigue and dizziness were mild to moderate in severity and generally well tolerated. This review adds further support that currently available cannabinoids are safe, modestly effective analgesics that provide a reasonable therapeutic option in the management of chronic non-cancer pain. [ABSTRACT FROM AUTHOR]

Over the last few years, numerous ligand binding assay technologies that utilize real-time measurement have been introduced; however, an assemblage and evaluation of these technologies has not previously been published. Herein, we describe six emerging real-time measurement technologies: Maverick™, MX96 SPR™, NanoDLSay™, AMMP®/ViBE®, SoPrano™, and two Lab-on-a-Chip (LoC) microfluidic devices. The development stage gate of these technologies ranges from pre-commercial to commercially available. Due to the novelty, the application and utility of some of the technologies regarding bioanalysis are likely to evolve but it is our hope that this review will provide insight into the direction the development of real-time measurement technologies is moving and the vision of those that are taking us there. Following the technology discussions, a comprehensive summary table is presented. [ABSTRACT FROM AUTHOR]

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Map data are usually derived from a source that is based on a particular scale of representation and hence are subject to a particular degree of map generalization. Attempts to display data at scales smaller than the source can result in spatial conflict, whereby map symbols become too close or overlap. Several map generalization operators may be applied to resolve the problem, including displacement. In this paper we address the problem of displacing multiple map objects in order to resolve graphic conflict. Each of n objects is assigned k candidate positions into which it can possibly move, resulting in a total of $k^\{n\}$ map realizations. The assumption is that some of these realizations will contain a reduced level of conflict. Generating and evaluating all realizations is however not practical, even for relatively small values of n and k. We present two iterative improvement algorithms, which limit the number of realizations processed. The first algorithm adopts a steepest gradient descent approach; the second uses simulated annealing. They are tested on a number of data sets and while both are successful in reducing conflict while limiting the number of realizations that are examined, the simulated annealing approach is superior with regard to the degree of conflict reduction. The approach adopted is regarded as generic, in the context of map generalization, in that it appears possible in principle to employ several map generalization operators combined with more sophisticated evaluation functions. [ABSTRACT FROM AUTHOR]

Naturalistic environments have been demonstrated to promote relaxation and wellbeing. We assess opposing theoretical accounts for these effects through investigation of autonomic arousal and alterations of activation and functional connectivity within the default mode network (DMN) of the brain while participants listened to sounds from artificial and natural environments. We found no evidence for increased DMN activity in the naturalistic compared to artificial or control condition, however, seed based functional connectivity showed a shift from anterior to posterior midline functional coupling in the naturalistic condition. These changes were accompanied by an increase in peak high frequency heart rate variability, indicating an increase in parasympathetic activity in the naturalistic condition in line with the Stress Recovery Theory of nature exposure. Changes in heart rate and the peak high frequency were correlated with baseline functional connectivity within the DMN and baseline parasympathetic tone respectively, highlighting the importance of individual neural and autonomic differences in the response to nature exposure. Our findings may help explain reported health benefits of exposure to natural environments, through identification of alterations to autonomic activity and functional coupling within the DMN when listening to naturalistic sounds. [ABSTRACT FROM AUTHOR]

The authors argue that Canada should lead in facilitating research on cannabis. Topics include laws on access to herbal cannabis in Canada, the need for clinical data on the therapeutic use of cannabis, and the need for funding of a peer-reviewed cannabis research programme that allows for the procurement of research licenses. The use of funds from the herbal cannabis industry for research is addressed.

Presents a letter to the editor commenting on the preference of authors of online submission in submitting their manuscripts.