Human Laboratory Research Articles

Anatomoclinical and surgical correlation of the radial artery with the surface branch of the radial nerve

The present study aimed to correlate the clinical and surgical anatomy of the radial artery with the superficial branch of the radial nerve, looking for injuries to this nerve in the literature through surgery of the mentioned vessel. Thus, the present study consisted of observational and descriptive research. Eleven upper limbs and a digital caliper were used to measure the distance between the radial artery and the superficial branch of the radial nerve (vasculonervous bundle). Dissections of the anterior, posterior, lateral and medial sides of the arm, forearm, and hand were performed. The 11 cadaverous pieces belong to the Human Anatomy Laboratory of Universidade Brasil. For the development of the study, cadaveric pieces were used as a reference to measure the distance between the radial artery and the superficial branch of the radial nerve and, thus, analyzing in the literature the findings for anatomical and surgical correlation of the vasculonervous bundle. It is concluded that the middle and distal third of the forearm and the wrist are frequent sites of surgical procedures, whether percutaneous or open, where injury to the superficial branch of the radial nerve can occur and, generally, with undesirable and even disastrous results, therefore, the surgeon must be extremely careful in surgical procedures in the studied region, mainly vascular and in those so called percutaneous that expose to SBRN injuries. More work is suggested related to vascular events associated with SBRN injuries. Therefore, one must be aware of the possibility of occurrence, especially when these situations occur anatomical variation or even the lack of anatomical knowledge, which can be a determining factor for nerve damage.

Effects of Alcohol Cue Reactivity on Subsequent Treatment Outcomes Among Treatment-Seeking Individuals with Alcohol Use Disorder: A Multisite Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Varenicline.

The alcohol cue reactivity paradigm is increasingly used to screen medications for the treatment of alcohol use disorder (AUD) and other substance use disorders. Yet, its prospective association with craving and naturalistic drinking outcomes in clinical trials remains unknown. This study embedded repeated human laboratory assessments of alcohol cue reactivity within the context of a randomized controlled trial to examine the effects of varenicline tartrate (Chantix® ), a partial agonist of α4β2 nicotinic acetylcholine receptors, on alcohol craving among treatment-seeking heavy drinkers with AUD. Our main objectives were to test whether varenicline, as compared to placebo, blunts alcohol cue-elicited craving and test whether alcohol cue reactivity observed in the human laboratory predicts subsequent alcohol craving and use during the remainder of the trial. This double-blind, randomized, 2-site study compared the effects of varenicline (up to 2mg/d) and placebo on responses to in vivo alcohol cue and affective picture cue exposure in the human laboratory. Forty-seven volunteers (18 females, 29 males), ages 23 to 67years (M=43.7, SD=11.5), were recruited from the community via advertisements to participate in a clinical trial designed to study the effects of varenicline on alcohol use. Participants were randomized to either varenicline or placebo for 6weeks. Varenicline did not attenuate cue-induced alcohol craving relative to placebo, but craving captured during the cue reactivity paradigm significantly predicted subsequent alcohol use in real-world settings during the clinical trial. Higher craving predicted heavier alcohol use. Our results are among the first to show alcohol cue-induced craving captured during a human laboratory paradigm predicts drinking outcomes in the context of a clinical trial.

Predictors and reproducibility of urinary organophosphate ester metabolite concentrations during pregnancy and associations with birth outcomes in an urban population

BackgroundOrganophosphate esters (OPEs) are synthetic chemicals used as flame retardants and plasticizers in a variety of goods. Despite ubiquitous human exposures and laboratory evidence that prenatal OPE exposures may disrupt offspring metabolism, perinatal studies of OPE health effects are limited. The objectives of this study were to: 1) Determine predictors and reproducibility of urinary OPE biomarker concentrations during pregnancy, and 2) Estimate the relation of prenatal OPE exposures with birth outcomes and cord blood adipokine and insulin concentrations.MethodsWe analyzed five OPE metabolites in urine samples collected at up to three visits during pregnancy from 90 women enrolled in the ORigins of Child Health And Resilience in Development (ORCHARD) pregnancy cohort in Baltimore, MD from 2017 to 2019. To quantify the variability of metabolite concentrations during pregnancy, we calculated intraclass correlation coefficients (ICCs) for each metabolite using mixed effects regression models. Using self-reported questionnaire data collected during gestation, we assessed possible sociodemographic and environmental/behavioral predictors of each OPE metabolite using generalized estimating equations to account for repeated exposure measures. We ascertained birth outcomes of 76 offspring from medical records, including weight-for-gestational age, length, ponderal index, and gestational age. In a subset of 37 infants, we measured cord blood concentrations of leptin, adiponectin, and insulin. To account for repeated exposure measures, we used linear structural equation models to assess the relations of standard deviation (SD) increases in prenatal OPE metabolite factor scores with continuous birth outcomes and cord blood biomarker concentrations.ResultsICCs ranged from 0.09 for isopropylphenyl-phenyl phosphate (ip-PPP) to 0.59 for bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We observed little consistency in environmental or behavioral predictors of OPE exposures, although concentrations were generally lower for samples collected in the afternoon compared to morning and winter compared to other seasons. In adjusted analyses, a SD increase in BDCIPP concentration was associated with a 0.06 g/cm3 (95% CI: 0.00, 0.12) greater ponderal index. A SD increase in BDCIPP was associated with a 0.37 (95% CI: − 0.62, − 0.13) SD lower insulin concentration and 0.24 (95% CI: − 0.39, − 0.08) SD lower leptin concentration. Other OPEs were not associated with infant outcomes.ConclusionsThese findings suggest some OPEs may be metabolic disruptors warranting investigation in larger studies.

Alcohol Cue-Induced Ventral Striatum Activity Predicts Subsequent Alcohol Self-Administration.

Human laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self-administration, is warranted. The current study is a secondary analysis examining whether alcohol cue-induced activation in the ventral striatum is predictive of subsequent alcohol self-administration in the laboratory. Non-treatment-seeking heavy drinkers of East Asian descent (n=41) completed a randomized, placebo-controlled, double-blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue-reactivity task. On the following day (day 5), participants completed a 60-minute alcohol self-administration paradigm. Multilevel Cox regressions indicated a significant effect of taste cue-elicited ventral striatum activation on latency to first drink, Wald χ2 =2.88, p=0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38)=5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self-administration outcomes. Neuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self-administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development.

Therapeutic Potential of Peroxisome Proliferator-Activated Receptor (PPAR) Agonists in Substance Use Disorders: A Synthesis of Preclinical and Human Evidence.

Targeting peroxisome proliferator-activated receptors (PPARs) has received increasing interest as a potential strategy to treat substance use disorders due to the localization of PPARs in addiction-related brain regions and the ability of PPAR ligands to modulate dopamine neurotransmission. Robust evidence from animal models suggests that agonists at both the PPAR-α and PPAR-γ isoforms can reduce both positive and negative reinforcing properties of ethanol, nicotine, opioids, and possibly psychostimulants. A reduction in the voluntary consumption of ethanol following treatment with PPAR agonists seems to be the most consistent finding. However, the human evidence is limited in scope and has so far been less promising. There have been no published human trials of PPAR agonists for treatment of alcohol use disorder, despite the compelling preclinical evidence. Two trials of PPAR-α agonists as potential smoking cessation drugs found no effect on nicotine-related outcomes. The PPAR-γ agonist pioglitazone showed some promise in reducing heroin, nicotine, and cocaine craving in two human laboratory studies and one pilot trial, yet other outcomes were unaffected. Potential explanations for the discordance between the animal and human evidence, such as the potency and selectivity of PPAR ligands and sex-related variability in PPAR physiology, are discussed.

Psychosis-Relevant Effects of Intravenous Delta-9-Tetrahydrocannabinol: A Mega Analysis of Individual Participant-Data from Human Laboratory Studies.

There is increasing interest in the relationship between cannabinoids and psychosis. While individual human laboratory studies have been critical in demonstrating that cannabinoids (e.g., delta-9-tetrahydrocannabinol [THC]) can induce acute transient psychosis-like effects in healthy human volunteers, combining data from multiple studies offers a fine-grained view of these effects. THC-induced psychosis-relevant effects were examined using a data repository of 10 double-blind, randomized, placebo-controlled, crossover studies with 400 i.v. THC infusions in healthy human volunteers. The Positive and Negative Syndrome scale was used to measure psychotomimetic effects. The profile of symptoms, frequency of a response, its relationship to THC dose and substance use, latent structure in Positive and Negative Syndrome scale response, and the relationships between psychotomimetic and perceptual alteration symptoms were evaluated. Clinically meaningful increases in positive symptoms were noted in 44.75% infusions; conceptual disorganization, hallucinations, blunted affect, somatic concern, motor retardation, and poor attention were the items most frequently altered by THC. The increase in Positive and Negative Syndrome scale positive symptoms was positively associated with THC dose (beta = 11.13, SE = 4.94, Wald χ 2 = 19.88, P < .001) and negatively associated with frequent cannabis use (beta = -0.575, SE = 0.14, Wald χ 2 = 18.13, P < .001). Furthermore, positive symptoms were strongly correlated with Clinician Administered Dissociative States Scale perceptual alterations score (rs = 0.514, P < .001). Intravenous administration of THC consistently induces psychotomimetic effects that include symptoms across Positive and Negative Syndrome scale domains. Moreover, healthy individuals who frequently use cannabis have a blunted psychotomimetic response.

Acute effects of cannabinoids on symptoms of obsessive‐compulsive disorder: A human laboratory study

Preclinical data implicate the endocannabinoid system in the pathology underlying obsessive-compulsive disorder (OCD), while survey data have linked OCD symptoms to increased cannabis use. Cannabis products are increasingly marketed as treatments for anxiety and other OCD-related symptoms. Yet, few studies have tested the acute effects of cannabis on psychiatric symptoms in humans. We recruited 14 adults with OCD and prior experience using cannabis to enter a randomized, placebo-controlled, human laboratory study to compare the effects on OCD symptoms of cannabis containing varying concentrations of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on OCD symptoms to placebo. We used a within-subjects design to increase statistical power. Across three laboratory sessions, participants smoked three cannabis varietals in random order: placebo (0% THC/0% CBD); THC (7.0% THC/0.18% CBD); and CBD (0.4% THC/10.4% CBD). We analyzed acute changes in OCD symptoms, state anxiety, cardiovascular measures, and drug-related effects (e.g., euphoria) as a function of varietal. Twelve participants completed the study. THC increased heart rate, blood pressure, and intoxication compared with CBD and placebo. Self-reported OCD symptoms and anxiety decreased over time in all three conditions. Although OCD symptoms did not vary as a function of cannabis varietal, state anxiety was significantly lower immediately after placebo administration relative to both THC and CBD. This is the first placebo-controlled investigation of cannabis in adults with OCD. The data suggest that smoked cannabis, whether containing primarily THC or CBD, has little acute impact on OCD symptoms and yields smaller reductions in anxiety compared to placebo.

The Mayo Clinic Cellular Therapy Fellowship: Training the Next Generation of Cellular Therapy Leaders

Background & Aim The field of cellular therapy is rapidly evolving with promising clinical outcomes and multiple potential therapeutic targets. This rapid expansion, while exciting, has quickly led to a deficit of qualified directors for burgeoning human cellular therapy laboratories. Unlike conventional drug therapies, cellular based therapies require an added layer of expertise in policy, good manufacturing practices (cGMP) and regulatory elements. Academic medical centers, both nationally and internationally, are in desperate need of well-trained, experienced leaders capable of directing the labs which both oversee and produce these therapeutic agents. To meet this need, we have established the Mayo Clinic School of Graduate Medical Education (MSGME) Cellular Therapy Fellowship; an intensive one-year program for M.D. and Ph.D. candidates consisting of didactic, experiential, and project-driven training with an emphasis on laboratory management and graduated responsibility. Mayo Clinic is a multidisciplinary academic medical and research institution, which houses a lab that directly supports the bone marrow transplant service in addition to a multifaceted immune and progenitor cell program focusing on investigational cell therapies such as mesenchymal stem cells, dendritic cells, and CAR T cells. The program is robust performing more than 500 clinical stem cell transplants annually and encompassing more than 25 active investigator-initiated trials in addition to greater than 30 external manufacturing protocols. Our aim is to produce scientific and clinical leaders fluent in cGMP regulations, quality control and regulatory components, clinical laboratory management, current methodologies in cell therapy manufacturing, IND preparation and clinical trial oversight. Methods, Results & Conclusion Our curriculum mirrors this aim with rotations in the BMT and progenitor cell laboratories, our commercial processing unit, CAR-T manufacturing, quality, apheresis and infusions and leadership and management each with varying levels of graduated responsibility and on-call duties. The fellows actively participate in director level conversations and decisions, which, in combination with the aforementioned experiences and their research projects, provides a thorough and comprehensive training experience for the next generation of cell therapy leaders.

Fluctuations in Vestibular Afferent Excitability in Menière's Disease.

To determine if Menière's disease is associated with fluctuations in afferent excitability in four human subjects previously implanted with vestibular stimulators. Longitudinal repeated measures. Tertiary referral center, human vestibular research laboratory. Four human subjects with previously uncontrolled Menière's disease unilaterally implanted in each semicircular canal with a vestibular stimulator. One subject had only two canals implanted. Repeated measures of electrically-evoked slow phase eye velocity and vestibular electrically-evoked compound action potentials (vECAP) over 2 to 4 years. Slow phase eye velocity and N1-P1 vECAP amplitudes as a function of time. There were statistically significant fluctuations in electrically evoked slow phase eye velocity over time in at least one semicircular canal of each subject. vECAP N1-P1 amplitudes measured at similar time intervals and stimulus intensities seem to show somewhat correlated fluctuations. One of the subjects had a single Menière's attack during this time period. The others did not. In these four subjects originally diagnosed with Menière's disease, there was fluctuating electrical excitability of the ampullar nerve of at least one canal in each subject. These fluctuations occurred without active symptoms of Menière's disease.

The Impact of Music on Nociceptive Processing.

Music has been shown to modulate pain, although the impact of music on specific aspects of nociceptive processing is less well understood. Using quantitative sensory testing (QST), we assessed the impact of a novel music app on specific aspects of nociceptive processing. Within-subjects paired comparison of pain processing in control vs music condition. Human psychophysical laboratory. Sixty healthy adult volunteers. Subjects were assessed for baseline anxiety, depression, and catastrophizing using validated questionnaires. QSTs measured included 1) pain threshold and tolerance to deep muscle pressure, 2) pain with mechanical pinprick, 3) temporal summation of pain (TSP) with a repeated pain stimulus, and 4) conditioned pain modulation (CPM) with a second painful stimulus. QSTs were performed in the absence and presence of music delivered through a music app. We found an increase in pressure pain thresholds in both the forearm (P = 0.007) and trapezius (P = 0.002) with music, as well as a decrease in the amount of pinprick pain (P < 0.001) and TSP (P = 0.01) with music. Interestingly, CPM was also significantly diminished (P < 0.001) in the music condition. No significant difference in cold pain, anxiety, or situational catastrophizing was observed with music. Higher baseline pain catastrophizing scores were associated with less music-induced pressure pain reduction. Several measures of mechanical pain sensitivity were reduced with music. TSP, a measure of central sensitization, also decreased with music, but CPM, a measure of descending modulation of pain, was not further augmented by music.

Effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals: Results from two human laboratory studies

The ghrelin system has been garnering interest for its role in different neuropsychiatric disorders, including alcohol use disorder (AUD). Accordingly, targeting the ghrelin system is under investigation as a potential novel therapeutic approach. While alcohol provokes the immune system and inflammatory responses, ghrelin has potent immunomodulatory and anti-inflammatory properties. The present study aimed to shed light on the “crosstalk” between ghrelin and inflammation by examining the effects of exogenous ghrelin administration and ghrelin receptor blockade on peripheral inflammatory markers in the context of two human laboratory studies with alcohol administration. Non-treatment-seeking, heavy-drinking individuals with alcohol dependence, the majority of whom were African American males, were enrolled. In the first randomized, crossover, double-blind, placebo-controlled human laboratory study, participants underwent two experimental paradigms – an intravenous alcohol self-administration (IV-ASA) and an intravenous alcohol clamp (IV-AC) – each consisting of two counterbalanced sessions (ghrelin, placebo). A loading dose of intravenous ghrelin (3 mcg/kg) or placebo, followed by a continuous ghrelin (16.9 ng/kg/min) or placebo infusion was administered. In the second dose-escalating, single-blind, placebo-controlled human laboratory phase 1b study, participants were dosed with an oral ghrelin receptor blocker (PF-5190457) and underwent an oral alcohol challenge. Repeated blood samples were collected, and plasma concentrations of the following inflammatory markers were measured: C-reactive protein (CRP), interleukin (IL)-6, IL-10, IL-18, and tumor necrosis factor alpha (TNF-α). During the IV-ASA experiment, significant drug × time interaction effects were observed for IL-6 (F3,36 = 3.345, p = 0.030) and IL-10 (F3,53.2 = 4.638, p = 0.006), indicating that ghrelin, compared to placebo, significantly reduced blood concentrations of the proinflammatory cytokine IL-6, while increasing blood concentrations of the anti-inflammatory cytokine IL-10. No significant drug × time interaction effects were observed during the IV-AC experiment, possibly because of its much shorter duration and/or smaller sample. Treatment with PF-5190457, compared to placebo, had no significant effect on the inflammatory markers investigated. In conclusion, a supraphysiologic pharmacological challenge with exogenous ghrelin in heavy-drinking individuals produced anti-inflammatory effects in the context of intravenous alcohol administration. On the contrary, ghrelin receptor blockade did not lead to any change in the inflammatory markers included in this study. Mechanistic studies are required to better understand the interaction between ghrelin, alcohol, and inflammatory processes.

Inclusion of Cannabis Users in Alcohol Research Samples: Screening In, Screening Out, and Implications.

Alcohol and cannabis are frequently co-used, as 20-50% of those who drink alcohol report co-using cannabis. This study is based on the argument that alcohol researchers should enroll cannabis users in human laboratory studies of alcohol use disorder (AUD) to strengthen generalizability. This study examines how heavy drinking cannabis users differ from non-cannabis using heavy drinkers. In a community sample of non-treatment-seeking heavy drinkers (n=551, 35% female), cannabis users were identified through: (a) self-reported cannabis use in the past 6months and (b) positive urine toxicology test for tetrahydrocannabinol (THC). Cannabis users, identified as described previously, were compared with non-cannabis users on demographic and clinical characteristics. Those who endorsed cannabis use in the past 6months reported more binge drinking days. Participants who tested positive for THC had higher Alcohol Use Disorder Identification Test scores and more binge drinking days. Younger age and being a tobacco smoker were associated with an increased likelihood of cannabis use in the past 6months, whereas male gender and being a tobacco use were associated with a greater likelihood of testing positive for THC. Individuals with cannabis use disorder (CUD) endorsed more depression and anxiety and had higher AUD symptom counts than cannabis users without CUD. The inclusion of cannabis users in AUD samples allows for increased clinical severity. Excluding cannabis users from AUD studies may limit representativeness and expend unnecessary study resources. Lastly, tobacco use may explain a large portion of the effects of cannabis use on sample characteristics. Alcohol and cannabis are frequently co-used substances. In a sample of non-treatment-seeking heavy drinkers (n=551, 35% female), cannabis users reported higher alcohol use and higher likelihood of tobacco use than non-cannabis users. Including cannabis users in alcohol research studies will improve representativeness and likely increase clinical severity.

Correlation of neurological level and sweating level of injury in persons with spinal cord injury

Objective: Thermoregulatory dysfunction after spinal cord injury (SCI) impairs quality of life and predisposes persons to life-threatening sequela of heat-related illness (HRI) in conditions of high ambient temperature. SCI clinicians currently have no objective way to predict which persons are at greatest risk of HRI. Evaporative cooling via sweating is the body’s most efficient mechanism of heat dissipation. The relationship between the neurological level of injury (NLOI) and the degree of sudomotor dysfunction is not well defined. This study examines the relationship between the NLOI and sweating level of injury (SwLOI). This information can assist SCI clinicians in identifying individuals with SCI who have most impaired sudomotor function and thus highest risk of HRI. Design: Observational. Setting: Human physiology laboratory. Participants: 10 persons with tetraplegia (TP), 14 with paraplegia (PP) and 10 able-bodied (AB). Intervention: Passive heat stress (1°C rise in core temperature) with sweat responses (SR) quantified with the starch iodine test. Outcome measures: The most caudal dermatomal level in which sweating was visualized was recorded as the SwLOI, which was compared to the NLOI. Minimum, maximum and median differences between NLOI and SwLOI were calculated. Results: Persons with tetraplegia demonstrated no SR. Persons with paraplegia demonstrated SR at a median of 1 level below NLOI. Able-bodied controls demonstrated sweating on all skin surface areas. Conclusions: Persons with motor complete tetraplegia lack evaporative cooling capacity through SR during passive heat stress predisposing them to HRI. Meanwhile, persons with paraplegia sweat on average 1 dermatomal level below their NLOI.

Development of a mismatch amplification mutation assay to correctly serotype isolates of Streptococcus suis serotypes 1, 2, 1/2, and 14.

Streptococcus suis is one of the most important bacterial swine pathogens worldwide and is an emerging pathogen in humans. There are 29 serotypes, and serotyping, which is based on the antigenicity of the capsular polysaccharide (CPS) or on its coding genes, is often part of routine identification and provides further information regarding S. suis virulence and zoonotic potential. Serotypes 2 and 14 possess high zoonotic potential, and serotype 1/2 is the serotype most frequently isolated from diseased pigs in North America. PCR has replaced antibody-based techniques to perform serotyping. However, traditional PCR is not able to differentiate serotype 2 from 1/2 and serotype 1 from 14, given that the only difference in the cps loci of those serotype pairs is a nonsynonymous single-nucleotide polymorphism. We developed a mismatch amplification mutation assay (MAMA)-PCR that was able to correctly serotype 148 isolates previously known to be serotypes 1, 2, 1/2, or 14. This technique will be highly useful in animal and human health laboratories performing PCR serotyping of S. suis isolates.

Frequency and classification of errors in laboratory medicine at a veterinary teaching hospital in the United States.

The accuracy of laboratory data is of utmost importance. Data regarding laboratory error in human laboratories are often extrapolated into veterinary settings. One study investigated the rate and type of errors in a European commercial veterinary laboratory, but that data might not directly apply to an educational setting. This study determined the frequency and type of errors in laboratory medicine at a veterinary teaching hospital. Errors associated with clinical pathology samples were recorded over two 60-day periods. The first period included a time when new students and house officers started at the veterinary school. The second time period was 6months later. The errors were assigned to categories, and the frequency of each was calculated. Sample hemolysis, icterus, and lipemia were evaluated separately using an automated index, as these conditions could be pathologic or the result of error. Frequencies of error and hemolysis, icterus, and lipemia were assessed between the groups. Total error rates were 4.7% and 3.5% for the first and second periods, respectively. The frequency of each error subclassification was similar to those observed in the veterinary and human literature, with preanalytic error predominating. Statistically significant differences in the overall error rate and percentage of preanalytic errors that occurred outside of and within the laboratory were observed comparing differences between the two periods. The overall error rate in this veterinary teaching hospital was slightly higher than that previously reported in other settings, although a proportion of errors was as expected. Areas needing improvement were identified, and strategies to reduce error could be developed.

Evaluation of the Reinforcing Strength of Phendimetrazine Using a Progressive-Ratio Schedule of Reinforcement in Rhesus Monkeys.

Stimulant abuse is a persistent public health problem with no Food and Drug Administration-approved pharmacotherapy. Although monoamine-releasing drugs such as d-amphetamine can decrease cocaine self-administration in human and animal laboratory studies, their potential for abuse limits clinical utility. "Abuse-deterrent" formulations of monoamine releasers, such as prodrugs, hold greater clinical promise if their abuse potential is, as theorized, lower than that of cocaine. In these studies, we determined the reinforcing strength of phendimetrazine (PDM), a prodrug for the amphetamine-like monoamine releaser phenmetrazine; both drugs have been shown to decrease cocaine self-administration in laboratory animals. To date, no study has directly compared PDM (Schedule III) with cocaine (Schedule II) under progressive-ratio (PR) schedules of reinforcement, which are better suited than fixed-ratio schedules to directly compare reinforcing strength of drugs. Dose-response curves for cocaine (saline, 0.001-0.3 mg/kg per injection) and PDM (0.1-1.0 mg/kg per injection) were generated in six cocaine-experienced male rhesus monkeys during 4-hour sessions with a 20-minute limited hold (LH). Under these conditions, the maximum number of injections was not significantly different between cocaine and PDM. The reinforcing strength of doses situated on the peaks of the cocaine and PDM dose-effect curves were redetermined with a 60-minute LH. The mean number of injections increased for both drugs, but not for saline. Cocaine presentations resulted in significantly higher peak injections than PDM with a 60-minute LH, which is consistent with the lower scheduling of PDM. These results support PDM as Schedule III and highlight the importance of schedule parameters when comparing reinforcing strength of drugs using a PR schedule of reinforcement. SIGNIFICANCE STATEMENT: One strategy for reducing cocaine use is to identify a treatment that substitutes for cocaine but has lower abuse potential. In a rhesus monkey model of drug abuse, this study compared the reinforcing strength of cocaine and phendimetrazine, a drug that has been shown to decrease cocaine use in some studies.

Therapeutic potential of opioid/cannabinoid combinations in humans: Review of the evidence

The endogenous opioid and cannabinoid receptor systems are widely distributed and co-localized throughout central and peripheral nervous system regions. A large body of preclinical evidence suggests that there are functional interactions between these two systems that may be leveraged to address various health conditions. Numerous animal studies have shown that cannabinoid agonists (e.g., delta-9-tetrahydrocannabinol [Δ9-THC]) enhance the analgesic effects of µ-opioid analgesics as evidenced by decreasing the opioid dose required for analgesia (i.e., opioid sparing) and extending the duration of the opioid analgesia. In contrast, controlled human laboratory studies and clinical trials have not demonstrated robust analgesic or opioid-sparing effects from opioid-cannabinoid combinations. Meta-analyses of the literature (clinical trials, controlled laboratory studies; some non-controlled studies/case reports) have examined the effects of cannabis/cannabinoids for pain relief in those taking a wide variety of analgesics, including prescription opioid medications. These data do not strongly support the use of cannabinoids for chronic pain nor do prospective studies demonstrate significant cannabinoid-mediated opioid-sparing effects. Preclinical studies have also suggested a role for cannabinoids for the treatment of opioid withdrawal. Controlled laboratory and clinical studies suggest that there may be a modest signal for Δ9-THC to suppress some opioid signs and symptoms but they are not completely ameliorated and there may also be concerns around safety of Δ9-THC administration in a state of heightened autonomic arousal as occurs with opioid withdrawal. Despite anecdotal and correlational reports suggesting a benefit of cannabis on reducing opioid overdose, there is no strong data supporting this contention and emerging reports have conflicting results. In summary, there is a groundswell of public advocacy supporting the use of cannabis and cannabinoids to replace opioid analgesics or to reduce opioid use; however, the extant controlled clinical data do not support the role of cannabinoids for opioid replacement or opioid-sparing effects when treating opioid use disorder or chronic pain.

Ready to Launch: Student Performance in a Fully Online Laboratory Pilot Course

The undergraduate human laboratory course at the University of Missouri provides anatomical education to a large population of health sciences undergraduates. To meet demand, an interdisciplinary team developed and implemented a fully online laboratory section in the fall of 2019 to complement the established hybrid laboratory sections. The current laboratory course is hybrid with one weekly meeting and a substantial online component. The model‐based face‐to‐face lab component of the hybrid sections was replaced by online virtual labs using the 3d4Medical Complete Anatomy app. Students were provided with worksheets to accompany a curated series of screens within the app to replicate the models and stations used in the face‐to‐face labs. Weekly meetings were held via a video conferencing platform to provide additional practice, assistance and opportunities to discuss clinical applications. The purpose of this study is to analyze student performance and satisfaction in a fully online section of a human anatomy laboratory course.The study sample included students enrolled in the fully online lab section (n=10) and the established hybrid lab section (n=405) in the fall of 2019. Student performance data include pre‐course assessments, post‐course assessments and three course exams. Exams consisted of 50 multiple choice questions on tagged models or specimens (physical models and donor materials in the hybrid lab sections, digital 3D models in the online section), histology slides, and radiology images. Questions on the assessments and exams were consistent across lab sections. Scores were statistically compared between the two lab modalities. Other data also collected during the semester included demographic data, mid‐semester evaluations and end‐of semester evaluations.Late semester results indicate that the students enrolled in the online course have higher exam scores compared to students enrolled in the hybrid sections, which possibly reflect the high level of motivation of the students enrolled in the online course. Students in the fully online section have expressed frustration with the app used in lieu of the in‐class models. Data from the pilot course will be used to inform future course organizational decisions.

Bringing Anatomy Back

The paradigm shift from the longstanding “2+2” medical school model to a contemporary curriculum aimed at competencies in clinical reasoning and decision making has challenged medical educators to consider pedagogical and content reform. The integrated curriculum model is an attempt at reform. To date, the outcome of the paradigm shift is uncertain. From a curriculum development view, there is no shortage of desired curricular content; there are time restraints. With the advent of open sources and virtual technologies specific to anatomy, costs of operating human anatomy laboratories, and curricular demands for truncated time dedicated to anatomical foundation, our institution has implemented a variety of curricular and co‐curricular initiatives for multiple learners to engage with anatomy in active learning settings. Most of the initiatives take advantage of collaborative learning between learners from different disciplines and all emphasize the value of understanding cadaveric anatomy from a functional approach to focus on diagnostic reasoning.Examples of three successful curricular initiatives include: 1) Diagnostic imaging of our Silent Mentors. Diagnostic Imaging (DI) students who have completed a Human Anatomy course, prepare CT scans of Silent Mentors (cadaver donors) for students taking Human Anatomy courses in Occupational Therapy (OT), Pathology Assistant (PathA), Physical Therapy (PT), Physician Assistant (PA), and for 1st year medical students in system blocks of the undergraduate medical education (UME) curriculum. The scans are used for horizontal and vertical integration of sectional anatomy. 2) PathA students who have completed a Human Anatomy course return to the lab to partner with 1st year medical students on a 6‐month pathology project. 3) Students taking 4th year electives in medical education or pathology have the option to return to the human anatomy laboratory.Examples of three successful co‐curricular initiatives include: 1) A series of interprofessional case‐based continuing medical education courses with a dissection component. Practicing clinicians and students from medicine, nursing, OT, PA, and PT review a patient case and share discipline‐specific perspectives. 2) IPE60. A peer learning strategy modeled after collegiate athlete “power hours”. Theme‐based series of one‐hour study groups of medical and PT students in the human anatomy lab. 3) Pipeline programs. Anatomy modules delivered by faculty and healthcare profession students interprofessionally or discipline‐specific to local high school and college students.Assessment of curricular initiatives support their utility of meeting learning objectives with a high degree of student satisfaction.

Abuse liability of electronic cigarettes in men who are experienced electronic cigarette users.

Most electronic cigarettes (e-cigs) aerosolize a nicotine-containing liquid that users inhale. Few experimental studies have examined e-cig abuse liability (the extent to which use of these products may lead to persistent and/or problematic use). In this study, 24 experienced male e-cig users completed 4 sessions that differed byproduct used: own e-cig (OWN), an eGo e-cig filled with participants' own brand/flavor liquid in 0 mg/mL nicotine (e-cig0), an eGo e-cig filled with the highest nicotine concentration available in participants' own brand/flavor (e-cighighest), and a U.S. Food and Drug Administration-approved nicotine inhaler (IN). Outcome measures included crossover point on the multiple-choice procedure, plasma nicotine delivery, and subjective effect profile. After 10 puffs, a significantly higher mean crossover point was observed for OWN at $1.35 (SD = 0.90) compared to e-cighighest at $0.88 (SD = 0.89), e-cig0 at $0.83 (SD = 0.79), and IN at $0.72 (SD = 0.84). Significant increases in mean plasma nicotine concentration were observed for OWN at 7.94 ng/mL (SD = 6.19) and e-cighighest at 7.51 ng/mL (SD = 5.39). Significant reductions in abstinence symptom suppression and higher ratings of satisfaction were observed for OWN and e-cighighest, with significantly less suppression and lower ratings of satisfaction for e-cig0 and IN. These findings suggest that human laboratory methods can be used to assess e-cig abuse liability and that nicotine-containing e-cigs have greater abuse liability than nicotine-free e-cigs and the IN. Potential regulations intended to limit e-cig abuse liability should be tested using these or similar procedures. (PsycInfo Database Record (c) 2020 APA, all rights reserved).