Early morning sport scheduling is associated with poorer subjective sleep characteristics in British student-athletes.

This study presents the sleep characteristics of British student-athletes and examines the relationships between sport scheduling and time demands on sleep outcomes. Student-athletes (n = 157, 51% male) completed the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and the Sleep Hygiene Index (SHI). Self-reported sleep characteristics on weekdays and weekends, weekly frequencies of early morning and late evening sport sessions, and academic-related and sport-related time demands were also collected. Questionnaires revealed a high prevalence of undesired sleep characteristics including poor sleep quality (global PSQI >5 in 49.0%) and low sleep durations on weekdays (25% reporting <7 h). Paired t-tests revealed significant differences in bedtime, waketime, sleep duration, and sleep onset latency between weekdays and weekends (all p < 0.01). Hierarchical regression analyses indicated that early morning sport frequency was a significant predictor of PSQI (ß = 0.30) and SHI (ß = 0.24) global scores, weekday waketimes (ß = -0.17), and weekday sleep durations (ß = -0.25; all p < 0.05) in models adjusted for participant characteristics. Late evening sport frequency, and academic-related and sport-related time demands, were not significant predictors of any sleep outcome. Adjusting sport scheduling to avoid early start times could provide a means to improve sleep outcomes and may improve sporting performance and academic attainment.

Behavioral interventions and behavior change techniques used to improve sleep outcomes in athlete populations: A scoping review.

BACKGROUND: Athletes display a high prevalence of undesired sleep characteristics that may affect both performance and wellbeing. OBJECTIVES: This scoping review aimed to identify and map the existing evidence of behavioral sleep interventions and their effects on sleep outcomes in athletes, and retrospectively code the behavior change techniques (BCTs) implemented using the Behavior Change Technique Taxonomy (BCTTv1). METHODS: Conducted following the JBI methodology for scoping reviews, four online databases were used to identify prospective interventions with at least one behavioral component in competitive athletes, and reporting a sleep outcome pre- and post-intervention. RESULTS: Thirty-three studies met the inclusion criteria, encompassing 892 participants with a median age of 23. Five intervention categories were identified (education, mind-body practices, direct, multi-component, and other), with each demonstrating mixed efficacy but the potential to improve sleep outcomes. The BCTs varied in type and frequency between each category, with only 18 unique BCTs identified across all studies. CONCLUSIONS: The varied efficacy of previous studies at improving sleep outcomes may be attributed to the lack of behavior change theory applied during intervention development. Designing interventions following a targeted specification of the behavioral problem, and the integration of corresponding BCTs should be considered in future research.

Heteroarylureas with fused bicyclic diamine cores as inhibitors of fatty acid amide hydrolase.

A series of mechanism-based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with fused bicyclic diamine cores is described. In contrast to compounds built around a piperazine core, most of the fused bicyclic diamine bearing analogs prepared exhibited greater potency against rFAAH than the human enzyme. Several compounds equipotent against both species were identified and profiled in vivo.

The SAR of brain penetration for a series of heteroaryl urea FAAH inhibitors.

The SAR of brain penetration for a series of heteroaryl piperazinyl- and piperadinyl-urea fatty acid amide hydrolase (FAAH) inhibitors is described. Brain/plasma (B/P) ratios ranging from >4:1 to as low as 0.02:1 were obtained through relatively simple structural changes to various regions of the heteroaryl urea scaffold. It was not possible to predict the degree of central nervous system (CNS) penetration from the volumes of distribution (Vd) obtained from pharmacokinetic (PK) experiments as very high Vds did not correlate with high B/P ratios. Similarly, calculated topological polar surface areas (TPSAs) did not consistently correlate with the degree of brain penetration. The lowest B/P ratios were observed for those compounds that were significantly ionized at physiological pH. However, as this class of compounds inhibits the FAAH enzyme through covalent modification, low B/P ratios did not preclude effective central target engagement.

From primary nurse to collaborative nursing care team: Early feedback on a new model.

This article discusses key findings from a preliminary review of a nursing care delivery model implemented in Winnipeg, Manitoba, by the Winnipeg Regional Health Authority Home Care Program in 2014. Results suggest that the model is generally seen positively by staff but challenging to implement, given established administrative practices. To meet future demands on the healthcare system, home care programs need policies and procedures that empower nurses to perform as true community health nurses.

Heteroarylureas with spirocyclic diamine cores as inhibitors of fatty acid amide hydrolase.

A series of mechanism based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with spirocyclic diamine cores is described. A potent member of this class, (37), was found to inhibit FAAH centrally, elevate the brain levels of three fatty acid ethanolamides [FAAs: anandamide (AEA), oleoyl ethanolamide (OEA) and palmitoyl ethanolamide (PEA)], and was moderately efficacious in a rat model of neuropathic pain.

1-Aryl-2-((6-aryl)pyrimidin-4-yl)amino)ethanols as competitive inhibitors of fatty acid amide hydrolase.

A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain.

Knockout of AMPA receptor binding protein Neuron-Specific Gene 2 (NSG2) enhances associative learning and cognitive flexibility.

The vast majority of gene mutations and/or gene knockouts result in either no observable changes, or significant deficits in molecular, cellular, or organismal function. However, in a small number of cases, mutant animal models display enhancements in specific behaviors such as learning and memory. To date, most gene deletions shown to enhance cognitive ability generally affect a limited number of pathways such as NMDA receptor- and translation-dependent plasticity, or GABA receptor- and potassium channel-mediated inhibition. While endolysosomal trafficking of AMPA receptors is a critical mediator of synaptic plasticity, mutations in genes that affect AMPAR trafficking either have no effect or are deleterious for synaptic plasticity, learning and memory. NSG2 is one of the three-member family of Neuron-specific genes (NSG1-3), which have been shown to regulate endolysosomal trafficking of a number of proteins critical for neuronal function, including AMPAR subunits (GluA1-2). Based on these findings and the largely universal expression throughout mammalian brain, we predicted that genetic knockout of NSG2 would result in significant impairments across multiple behavioral modalities including motor, affective, and learning/memory paradigms. However, in the current study we show that loss of NSG2 had highly selective effects on associative learning and memory, leaving motor and affective behaviors intact. For instance, NSG2 KO animals performed equivalent to wild-type C57Bl/6n mice on rotarod and Catwalk motor tasks, and did not display alterations in anxiety-like behavior on open field and elevated zero maze tasks. However, NSG2 KO animals demonstrated enhanced recall in the Morris water maze, accelerated reversal learning in a touch-screen task, and accelerated acquisition and enhanced recall on a Trace Fear Conditioning task. Together, these data point to a specific involvement of NSG2 on multiple types of associative learning, and expand the repertoire of pathways that can be targeted for cognitive enhancement.

Nutritional Status of Vegetarian Patients Before and After Bariatric Surgery: a Monocentric Retrospective Observational Case-Control Study.

The obesity pandemic is associated with an increasing number of bariatric surgeries which allow improvement in obesity-related comorbidities and life expectancy but potentially induce nutritional deficiencies. Vegetarianism becomes more and more popular and exposes as well to vitamin and micronutrient deficiencies. Only one study has explored the impact of vegetarianism on the preoperative nutritional status of eligible patients for bariatric surgery, but none in postoperative care. MATERIALS AND METHODS: We conducted a retrospective case-control study in our cohort of bariatric patients, matching 5 omnivores for each vegetarian. We compared their biological profile regarding vitamin and micronutrient blood levels before and 3, 6, 12, and 30 months after surgery. RESULTS: We included 7 vegetarians including 4 lacto-ovo-vegetarians (57%), 2 lacto-vegetarians (29%), and one lacto-ovo-pesco-vegetarian (14%). Three years after surgery with equivalent daily standard vitamin supplementation, the two groups showed a similar biological profile including blood levels of ferritin (p = 0.6), vitamin B1 (p = 0.1), and B12 (p = 0.7), while the total median weight loss at 3 years was comparable (39.1% [27.0-46.6] in vegetarians vs 35.7% [10.5-46.5] in omnivores, p = 0.8). We observed no significant difference between vegetarians and omnivores before surgery regarding comorbidities and nutritional status. CONCLUSION: It seems that, after bariatric surgery, vegetarian patients taking a standard vitamin supplementation do not show an increased risk of nutritional deficiencies compared to omnivores. However, a larger study with a longer follow-up is needed to confirm these data, including an evaluation of different types of vegetarianism such as veganism.

Heteroaryl urea inhibitors of fatty acid amide hydrolase: structure-mutagenicity relationships for arylamine metabolites.

The structure-activity relationships for a series of heteroaryl urea inhibitors of fatty acid amide hydrolase (FAAH) are described. Members of this class of inhibitors have been shown to inactivate FAAH by covalent modification of an active site serine with subsequent release of an aromatic amine from the urea electrophile. Systematic Ames II testing guided the optimization of urea substituents by defining the structure-mutagenicity relationships for the released aromatic amine metabolites. Potent FAAH inhibitors were identified having heteroaryl amine leaving groups that were non-mutagenic in the Ames II assay.

A preliminary test of a brief intervention to lessen young adults' cannabis use: Episode-level smartphone data highlights the role of protective behavioral strategies and exercise.

Brief interventions are increasingly being used to help young adults to moderate their cannabis use. We conducted a randomized clinical trial of a brief (4 weekly sessions), in-person intervention that included a smartphone application that reinforced the use of protective behavioral strategies (PBSs) to lessen cannabis use. Young adults (N = 37; 24 men) who regularly used cannabis were randomized to 2 intervention conditions rooted in cognitive-behavioral therapy (CBT) and motivational enhancement therapy (MET). Along with learning CBT + MET strategies, participants in 1 of the conditions were instructed to engage in exercise. All participants used smartphone-based ecological momentary assessment to provide episode-level reports about use of cannabis and PBSs. Two multilevel structural equation models were run to test the study hypotheses that (a) cannabis use would be reduced over the course of the 6-month study, (b) reductions would be moderated by intervention condition, and (c) episode-level PBS use would predict episode-level cannabis use. Participants reduced their cannabis use by approximately 1 half of a standard joint per time point. The MET + CBT + Exercise condition reduced cannabis use to a greater degree than did the MET + CBT condition. With episode-level PBS use in the model, reductions in cannabis use were independent of intervention condition. Our findings suggest that young adults will engage with a smartphone app that serves as a component of an in-person intervention to moderate their cannabis use. Intervention content that promotes the use of PBSs and exercise facilitates reductions in cannabis use. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Novel imidazole-based histamine H3 antagonists.

A novel series of imidazole containing histamine H(3) receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22.

Biochemical and biological properties of 4-(3-phenyl-[1,2,4] thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide, a mechanism-based inhibitor of fatty acid amide hydrolase.

Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme within the amidase-signature family. It catalyzes the hydrolysis of several endogenous biologically active lipids, including anandamide (arachidonoyl ethanolamide), oleoyl ethanolamide, and palmitoyl ethanolamide. These endogenous FAAH substrates have been shown to be involved in a variety of physiological and pathological processes, including synaptic regulation, regulation of sleep and feeding, locomotor activity, pain and inflammation. Here we describe the biochemical and biological properties of a potent and selective FAAH inhibitor, 4-(3-phenyl-[1,2,4]thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide (JNJ-1661010). The time-dependence of apparent IC(50) values at rat and human recombinant FAAH, dialysis and mass spectrometry data indicate that the acyl piperazinyl fragment of JNJ-1661010 forms a covalent bond with the enzyme. This bond is slowly hydrolyzed, with release of the piperazinyl fragment and recovery of enzyme activity. The lack of inhibition observed in a rat liver esterase assay suggests that JNJ-1661010 is not a general esterase inhibitor. JNJ-1661010 is >100-fold preferentially selective for FAAH-1 when compared to FAAH-2. JNJ-1661010 dose-dependently increases arachidonoyl ethanolamide, oleoyl ethanolamide, and palmitoyl ethanolamide in the rat brain. The compound attenuates tactile allodynia in the rat mild thermal injury model of acute tissue damage and in the rat spinal nerve ligation (Chung) model of neuropathic pain. JNJ-1661010 also diminishes thermal hyperalgesia in the inflammatory rat carrageenan paw model. These data suggest that FAAH inhibitors with modes of action similar to JNJ-1661010 may be useful clinically as broad-spectrum analgesics.

In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor.

Triple reuptake inhibitors, which block the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT) in the central nervous system have been described as therapeutic alternatives for classical selective serotonin reuptake inhibitors, with advantages due to their multiple mechanisms of action. JNJ-7925476 (trans-6-(4-ethynylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline) is a selective and potent inhibitor of the SERT, NET, and DAT (K(i)=0.9, 17 and 5.2 nM, respectively). Following subcutaneous dosing in rat, JNJ-7925476 was rapidly absorbed into the plasma, and drug concentrations in the brain tracked with those in the plasma but were 7-fold higher. The ED(50) values for JNJ-7925476 occupancy of the SERT, NET, and DAT in rat brain were 0.18, 0.09 and 2.4 mg/kg, respectively. JNJ-7925476 (0.1-10 mg/kg, s.c.) rapidly induced a robust, dose-dependent increase in extracellular serotonin, dopamine, and norepinephrine levels in rat cerebral cortex. The compound also showed potent antidepressant-like activity in the mouse tail suspension test (ED(50)=0.3 mg/kg, i.p.). These results demonstrate that JNJ-7925476 is a triple reuptake inhibitor with in-vivo efficacy in biochemical and behavioral models of depression.

Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase.

A series of thiadiazolopiperazinyl aryl urea fatty acid amide hydrolase (FAAH) inhibitors is described. The molecules were found to inhibit the enzyme by acting as mechanism-based substrates, forming a covalent bond with Ser241. SAR and PK properties are presented.

Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors.

The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H3 ligands and serotonin reuptake inhibitors.

Effects of exercise on experimentally manipulated craving for cannabis: A preliminary study.

Cannabis is the most commonly used illicit drug in the United States, and craving for cannabis is related to cannabis use. Exercise has been demonstrated to reduce craving for substances. To examine the effects of exercise on cannabis craving, we conducted a 3-week within-subject crossover experiment. Young-adult men (n = 35) and women (n = 11), age 18-25 years (M = 20.76, SD = 1.68), who regularly (≥3 times per week) used cannabis participated in a cue exposure paradigm to stimulate craving. After each of three separate craving inductions, they completed a 10-min bout of exercise that varied in intensity (rest, moderate, vigorous). Craving was assessed before and after the induction, immediately following the exercise, and at three 10-min intervals (total of 30 min). Results of condition-specific, repeated measures analyses of variance showed nonsignificant reductions in immediate postexercise craving for the moderate and vigorous conditions. We used latent growth modeling to examine the trajectory of craving rebound during the 30 min following exercise and explored the effect of baseline weekly cannabis use in predicting craving rebound. Within 30 min postexercise, craving rebounded for both the moderate, F(3, 135) = 9.10, p < .01, and vigorous, F(3, 135) = 3.48, p < .05, conditions. We found that among cannabis users reporting larger quantities of typical weekly cannabis use, craving rebounded more quickly following vigorous than moderate exercise, b = 0.02, SE = 0.02, 95% confidence interval [0.00, 0.06]. The findings suggest that moderate exercise may be useful for reducing craving, particularly among those who use larger quantities of cannabis. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Pharmacological characterization of JNJ-28583867, a histamine H(3) receptor antagonist and serotonin reuptake inhibitor.

Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. The wake-promoting action of histamine H(3) receptor antagonists has been evidenced in numerous animal studies. They may therefore be a viable strategy for use as an antidepressant therapy in conjunction with selective serotonin reuptake inhibitors. JNJ-28583867 (2-Methyl-4-(4-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H(3) receptor antagonist (K(i)=10.6 nM) and inhibitor of the serotonin transporter (SERT) (K(i)=3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H(3) receptor and the SERT in rat brain at low doses (<1 mg/kg). JNJ-28583867 blocked imetit-induced drinking (3-10 mg/kg i.p.), confirming in vivo functional activity at the histamine H(3) receptor and also significantly increased cortical extracellular levels of serotonin at doses of 0.3 mg/kg (s.c.) and higher. Smaller increases in cortical extracellular levels of norepinephrine and dopamine were also observed. JNJ-28583867 (3-30 mg/kg p.o.) showed antidepressant-like activity in the mouse tail suspension test. JNJ-28583867 (1-3 mg/kg s.c.) caused a dose-dependent increase in the time spent awake mirrored by a decrease in NREM. Concomitantly, JNJ-28583867 produced a potent suppression of REM sleep from the dose of 1 mg/kg onwards. JNJ-28583867 has good oral bioavailability in the rat (32%), a half-life of 6.9 h and a C(max) of 260 ng/ml after 10 mg/kg p.o. In summary, JNJ-28583867 is a combined histamine H(3) receptor antagonist-SERT inhibitor with in vivo efficacy in biochemical and behavioral models of depression and wakefulness.

Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms.

1 The reversible fatty acid amide hydrolase (FAAH) inhibitor OL135 reverses mechanical allodynia in the spinal nerve ligation (SNL) and mild thermal injury (MTI) models in the rat. The purpose of this study was to investigate the role of the cannabinoid and opioid systems in mediating this analgesic effect. 2 Elevated brain concentrations of anandamide (350 pmol g(-1) of tissue vs 60 pmol g(-1) in vehicle-treated controls) were found in brains of rats given OL135 (20 mg kg(-1)) i.p. 15 min prior to 20 mg kg(-1) i.p. anandamide. 3 Predosing rats with OL135 (2-60 mg kg(-1) i.p.) 30 min before administration of an irreversible FAAH inhibitor (URB597: 0.3 mg kg(-1) intracardiac) was found to protect brain FAAH from irreversible inactivation. The level of enzyme protection was correlated with the OL135 concentrations in the same brains. 4 OL135 (100 mg kg(-1) i.p.) reduced by 50% of the maximum possible efficacy (MPE) mechanical allodynia induced by MTI in FAAH(+/+)mice (von Frey filament measurement) 30 min after dosing, but was without effect in FAAH(-/-) mice. 5 OL135 given i.p. resulted in a dose-responsive reversal of mechanical allodynia in both MTI and SNL models in the rat with an ED(50) between 6 and 9 mg kg(-1). The plasma concentration at the ED(50) in both models was 0.7 microM (240 ng ml(-1)). 6 In the rat SNL model, coadministration of the selective CB(2) receptor antagonist SR144528 (5 mg kg(-1) i.p.), with 20 mg kg(-1) OL135 blocked the OL135-induced reversal of mechanical allodynia, but the selective CB(1) antagonist SR141716A (5 mg kg(-1) i.p.) was without effect. 7 In the rat MTI model neither SR141716A or SR144528 (both at 5 mg kg(-1) i.p.), or a combination of both antagonists coadministered with OL135 (20 mg kg(-1)) blocked reversal of mechanical allodynia assessed 30 min after dosing. 8 In both the MTI model and SNL models in rats, naloxone (1 mg kg(-1), i.p. 30 min after OL135) reversed the analgesia (to 15% of control levels in the MTI model, to zero in the SNL) produced by OL135.

4-phenoxypiperidines: potent, conformationally restricted, non-imidazole histamine H3 antagonists.

Two new series of 4-(1-alkyl-piperidin-4-yloxy)-benzonitriles and 4-(1-isopropyl-piperidin-4-yloxy)-benzylamines have been prepared. In vitro activity was determined at the recombinant human H(3) receptor and several members of these new series were found to be potent H(3) antagonists. The present compounds contain a 4-phenoxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole histamine H(3) ligands. One selected member of the new series, 4-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-morpholine (13g), was found to be a potent, highly selective H(3) receptor antagonist with in vivo efficacy in a rat EEG model of wakefulness at doses as low as 1 mg/kg sc.