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Burgeoning interest in marathons necessitates an understanding of performance determinants. Research has highlighted the importance of diet, training and sleep, yet relations of circadian preference and sleep inertia with marathon performance remain largely unexplored. Because marathons generally start early-to-mid morning, these characteristics may have relevant impact. This study investigates relationships of circadian preference, sleep inertia and their interaction with marathon completion time. Consenting participants in a 2016 large mass-participation city marathon completed self-report questionnaires capturing circadian preference and sleep inertia, along with demographics and other characteristics. Circadian preference and sleep inertia were described across subgroups. Analyses examined the associations and interactions of circadian preference and sleep inertia with marathon completion times, with adjusted analyses accounting for age, sex and sleep health. Participants were marathon finishers (n = 936; 64.5% male; 66.3% young-adults), with a majority reporting morningness tendencies (60.8%). Results supported a linear association between increasing eveningness preference with slower marathon times (p = 0.003; p adjusted  = 0.002), while some support was provided for a linear relationship between greater sleep inertia and slower marathon times (p = 0.04; p adjusted  = 0.07). A significant interaction was observed (p = 0.02; p adjusted  = 0.01), with the directionality suggesting that the circadian preference relationship weakened when sleep inertia severity increased, and vice-versa. Our results suggest deleterious associations of increasing eveningness preference and greater sleep inertia with marathon completion time. These features may aid identifying marathoners who could be at a disadvantage, while also serving as modifiable targets for personalized training regimens preceding competition., (© 2024 The Author(s). Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

The first syntheses of the Alpinia officinarum natural products alpinidinoid C and officinine B are reported. These unusual dimeric diarylheptanoids were accessed from a 3-substituted pyridine intermediate via a blue-light-mediated, triple-Minisci-type alkylation. Very few reports utilize N -(acyloxy)phthalimides (NAPs) in the construction of natural products, and the syntheses reported herein highlight the power of this methodology toward the orthogonal construction of highly substituted arenes.

Tianeptine ( 1 ) is an unusual antidepressant in that its mechanism of action appears to be independent from any activity at serotonin receptors or monoamine transporters. In fact, tianeptine has been shown to be a moderately potent agonist for the mu opioid receptor (MOR) and to a lesser extent the delta opioid receptor (DOR). Additionally, tianeptine's efficacy may be related to its action on glutamate-mediated pathways of neuroplasticity. Regardless of which neurotransmitter system is primarily responsible for the observed efficacy, the MOR agonist activity is problematic with respect to abuse liability. Increasing numbers of case reports have demonstrated that tianeptine is indeed being used recreationally at doses far beyond what are considered therapeutically relevant or safe, and scheduling reclassifications or outright bans on tianeptine products are ongoing around the world. It is the aim of this review to discuss the medicinal chemistry and pharmacology of tianeptine and to summarize this intriguing discrepancy between tianeptine's historical use as a safe and effective antidepressant and its emerging potential for abuse.

Herein we report progress toward a backup clinical candidate to the M 1 positive allosteric modulator (PAM) VU319/ACP-319. Scaffold-hopping from the pyrrolo[2,3- b ]pyridine-based M 1 PAM VU6007477 to isomeric pyrrolo[3,2- b ]pyridine and thieno[3,2- b ]pyridine congeners identified several backup contenders. Ultimately, VU6007496, a pyrrolo[3,2- b ]pyridine, advanced into late stage profiling, only to be plagued with unanticipated, species-specific metabolism and active/toxic metabolites which were identified in our phenotypic seizure liability in vivo screen, preventing further development. However, VU6007496 proved to be a highly selective and CNS penetrant M 1 PAM, with minimal agonism, that displayed excellent multispecies IV/PO pharmacokinetics (PK), CNS penetration, no induction of long-term depression (or cholinergic toxicity) and robust efficacy in novel object recognition (minimum effective dose = 3 mg/kg p.o.). Thus, VU6007496 can serve as another valuable in vivo tool compound in rats and nonhuman primates, but not mouse, to study selective M 1 activation.

Prostaglandin E1 (PGE1) is a substance produced by the patent ductus arteriosus that keeps it open. PGE1 can be a lifesaving drug for infants born with ductus-dependent congenital heart disease (CHD) where there is a block of blood flow to the lungs or transposition of great arteries. We present a case of a 36-week, 2-day gestation neonate with CHD who developed bright erythematous annular and polycyclic patches on day 2 of PGE1 administration. When PGE1 dosing was decreased, the rash resolved on its own. Our case demonstrates that PGE1 treatment may not need to be interrupted., (© 2024 Wiley Periodicals LLC.)

Objectives: To assess the sleep characteristics of collegiate soccer and basketball student-athletes and explore the associations between sleep and injury risk., Design: Cohort study., Setting: NCAA D1 and NAIA Tier 1., Participants: One hundred eighty-one collegiate soccer and basketball student-athletes (42% female; mean age: 20.0 ± 1.7 years)., Independent Variables: Questionnaires were administered during the 2020/2021 and 2021/2022 preseason, collecting demographic, injury history, medical history, and sleep information, including sleep difficulty category scores of 0 to 4 (none), 5 to 7 (mild), and ≥8 (moderate/severe) and other sleep disturbance measures derived from the Athlete Sleep Screening Questionnaire (ASSQ), including insufficient sleep duration (<7 hours of sleep) and poor subjective sleep quality., Main Outcome Measures: All-complaint knee and ankle injuries., Results: According to the ASSQ, 25.4% (95% confidence interval [CI], 17.9-34.3) of the student-athletes had mild sleep difficulty and 12.7% (95% CI, 7.3-20.1) had moderate/severe sleep difficulty. 36.1% (95% CI, 29.1-43.6) had insufficient sleep duration. 17.1% (95% CI, 11.7-23.7) were not satisfied with the quality of their sleep (poor sleep quality), and 13.8% (95% CI, 9.1-19.7) had an "eveningness" chronotype. Based on multivariable logistic regression models, student-athletes with poor sleep quality had significantly higher odds for injury (OR: 2.2, 95% CI, 1.04-4.79, P = 0.039)., Conclusions: Clinically relevant dysfunctional sleep patterns are prevalent among collegiate soccer and basketball student-athletes. Poor sleep quality was significantly associated with injury risk among student-athletes. Findings suggest a substantial sleep problem in collegiate soccer and basketball student-athletes and warrant that student-athletes are regularly screened and timely interventions applied., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Understanding sleep patterns and behaviors of athletes is essential for developing targeted sleep-based interventions for implementation in practice. However, more than double the number of sleep studies have examined male athletes compared with female athletes, making the current understanding of sleep patterns, behaviors, and interventions among athletes disproportionately indicative of men. Consequently, this review demonstrates the need for more female-specific sleep data among athlete populations due to research inattention and sex-related differences. Specifically, this review identifies variations in sleep patterns and behaviors between male and female athletes, as well as physiological and lifestyle factors that potentially affect sleep patterns and behaviors across the lifespan, specifically in female athletes. In this regard, evidence suggests some female athletes experience longer sleep durations and better objective sleep quality, but similar or worse subjective sleep quality compared with male athletes. Additionally, scheduling training in the morning or throughout the day may benefit sleep in some female athletes. Considering sleep disorders, women may be at greater risk for insomnia and restless legs syndrome compared with men, which may be attributed to pregnancy, as well as a higher prevalence of anxiety and depressive symptoms, iron deficiency without anemia, and use of psychotropic medication among women. Finally, the menstrual cycle, menstrual disorders, oral contraceptive use, and the postpartum period have been shown to exert detrimental effects on sleep patterns and behaviors and should theoretically be considered when monitoring and managing sleep in female athletes., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Herein, we report the synthesis and characterization of a novel set of substituted indazole-ethanamines and indazole-tetrahydropyridines as potent serotonin receptor subtype 2 (5-HT 2 ) agonists. Specifically, we examine the 5-HT 2 pharmacology of the direct indazole analogs of 5-methoxy- N , N -dimethyltryptamine (5-MeO-DMT) and related serotonergic tryptamines, and highlight the need for rigorous characterization of 5-HT 2 subtype selectivity for these analogs, particularly for the 5-HT 2B receptor subtype. Within this series, the potent analog VU6067416 ( 19d ) was optimized to have suitable preclinical pharmacokinetic properties for in vivo dosing, although potent 5-HT 2B agonist activity precluded further characterization for this series. Additionally, in silico docking studies suggest that the high potency of 19d may be a consequence of a halogen-bonding interaction with Phe234 5.38 in the 5-HT 2A orthosteric pocket., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: As the disorder progresses, patients with depression suffer from decreased emotional stability, cognitive control and motivation. In the present study, we examined the effectiveness of three interventions on emotion dysregulation and insomnia severity: 1) mindfulness; 2) physical activity, and 3) mindfulness plus physical activity., Method: A total of 50 participants (mean age 33.21 ± 5.72 SD, 59% females) with major depression were randomly assigned to one of the three study conditions. Emotional dysregulation and insomnia severity were assessed at baseline, eight weeks later at study completion, and 4 weeks after that at follow-up., Results: Emotion regulation and sleep quality improved over time from baseline to study completion and to follow-up. Compared to the mindfulness and physical activity alone conditions, the mindfulness plus physical activity condition led to higher emotion regulation and sleep quality., Conclusion: The combination of physical activity and mindfulness seems to have a beneficial effect on sleep quality and emotion regulation in those with major depression disorder and could be a valuable treatment strategy.

M 4 muscarinic receptors are highly expressed in the striatum and cortex, brain regions that are involved in diseases such as Parkinson's disease, schizophrenia, and dystonia. Despite potential therapeutic advantages of specifically targeting the M 4 receptor, it has been historically challenging to develop highly selective ligands, resulting in undesired off-target activity at other members of the muscarinic receptor family. Recently, we have reported first-in-class, potent, and selective M 4 receptor antagonists. As an extension of that work, we now report the development and characterization of a radiolabeled M 4 receptor antagonist, [ 3 H]VU6013720, with high affinity (pK d of 9.5 ± 0.2 at rat M 4 , 9.7 at mouse M 4 , and 10 ± 0.1 at human M 4 with atropine to define nonspecific binding) and no significant binding at the other muscarinic subtypes. Binding assays using this radioligand in rodent brain tissues demonstrate loss of specific binding in Chrm4 knockout animals. Dissociation kinetics experiments with various muscarinic ligands show differential effects on the dissociation of [ 3 H]VU6013720 from M 4 receptors, suggesting a binding site that is overlapping but may be distinct from the orthosteric site. Overall, these results demonstrate that [ 3 H]VU6013720 is the first highly selective antagonist radioligand for the M 4 receptor, representing a useful tool for studying the basic biology of M 4 as well for the support of M 4 receptor-based drug discovery. SIGNIFICANCE STATEMENT: This manuscript describes the development and characterization of a novel muscarinic (M) acetylcholine subtype 4 receptor antagonist radioligand, [ 3 H]VU6013720. This ligand binds to or overlaps with the acetylcholine binding site, providing a highly selective radioligand for the M 4 receptor that can be used to quantify M 4 protein expression in vivo and probe the selective interactions of acetylcholine with M 4 versus the other members of the muscarinic receptor family., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

The latent reservoir for HIV-1 in resting CD4 + T cells persists despite antiretroviral therapy (ART) and precludes cure. Reservoir-targeting interventions are evaluated in ART-treated macaques infected with simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV). Efficacy is determined by reservoir measurements before and after the intervention. However, most proviruses persisting in the setting of ART are defective. In addition, intact HIV-1 and SIV genomes undergo complex, multiphasic decay observable when new infection events are blocked by ART. Intervention-induced elimination of latently infected cells must be distinguished from natural decay. Here, we address these issues for SHIV. We describe an intact proviral DNA assay that allows digital counting of SHIV genomes lacking common fatal defects. We show that intact SHIV genomes in circulating CD4 + T cells undergo biphasic decay during the first year of ART, with a rapid first phase (t 1/2 = 30.1 d) and a slower second phase (t 1/2 = 8.1 mo) that is still more rapid that the slow decay observed in people with HIV-1 on long-term ART (t 1/2 = 3.7 y). In SHIV models, most interventions are tested during 2nd phase decay. Natural 2nd phase decay must be considered in evaluating interventions as most infected cells present at this time do not become part of the stable reservoir. In addition, for interventions tested during 2nd phase decay, a caveat is that the intervention may not be equally effective in people with HIV on long-term ART whose reservoirs are dominated by latently infected cells with a slower decay rate.

Despite sleep health being critically important for athlete performance and well-being, sleep health in marathoners is understudied. This foundational study explored relations between sleep health, individual characteristics, lifestyle factors, and marathon completion time. Data were obtained from the 2016 London Marathon participants. Participants completed the Athlete Sleep Screening Questionnaire (ASSQ) along with a brief survey capturing individual characteristics and lifestyle factors. Sleep health focused on the ASSQ sleep difficulty score (SDS) and its components. Linear regression computed relations among sleep, individual, lifestyle, and marathon variables. The analytic sample (N = 943) was mostly male (64.5%) and young adults (66.5%). A total of 23.5% of the sample reported sleep difficulties (SDS ≥ 8) at a severity warranting follow-up with a trained sleep provider. Middle-aged adults generally reported significantly worse sleep health characteristics, relative to young adults, except young adults reported significantly longer sleep onset latency (SOL). Sleep tracker users reported worse sleep satisfaction. Pre-bedtime electronic device use was associated with longer SOL and longer marathon completion time, while increasing SOL was also associated with longer marathon completion. Our results suggest a deleterious influence of pre-bedtime electronic device use and sleep tracker use on sleep health in marathoners. Orthosomnia may be a relevant factor in the relationship between sleep tracking and sleep health for marathoners.

Ligands for the serotonin 2B receptor (5-HT 2B ) have shown potential to treat pulmonary arterial hypertension in preclinical models but cannot be used in humans because of predicted off-target neurological effects. The aim of this study was to develop novel systemically restricted compounds targeting 5-HT 2B . Here, we show that mice treated with VU6047534 had decreased RVSP compared with control treatment in both the prevention and intervention studies using Sugen-hypoxia. VU6047534 is a novel 5-HT 2B partial agonist that is peripherally restricted and able to both prevent and treat Sugen-hypoxia-induced pulmonary arterial hypertension. We have synthesized and characterized a structurally novel series of 5-HT 2B ligands with high potency and selectivity for the 5-HT 2B receptor subtype. Next-generation 5-HT 2B ligands with similar characteristics, and predicted to be systemically restricted in humans, are currently advancing to investigational new drug-enabling studies., Competing Interests: This work was supported by the National Institutes of Health (HL135790, HL095797, and HL087738) and Vanderbilt University Discovery Grant. Research undertaken in the Vanderbilt Mouse Neurobehavior Core was supported by the EKS NICHD of the National Institutes of Health under Award P50HD103537. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

The cardiotoxicity associated with des -ethyl-dexfenfluramine (norDF) and related agonists of the serotonin receptor 2B (5-HT 2B ) has solidified the receptor's place as an "antitarget" in drug discovery. Conversely, a growing body of evidence has highlighted the utility of 5-HT 2B antagonists for the treatment of pulmonary arterial hypertension (PAH), valvular heart disease (VHD), and related cardiopathies. In this Perspective, we summarize the link between the clinical failure of fenfluramine-phentermine (fen-phen) and the subsequent research on the role of 5-HT 2B in disease progression, as well as the development of drug-like and receptor subtype-selective 5-HT 2B antagonists. Such agents represent a promising class for the treatment of PAH and VHD, but their utility has been historically understudied due to the clinical disasters associated with 5-HT 2B . Herein, it is our aim to examine the current state of 5-HT 2B drug discovery, with an emphasis on the receptor's role in the central nervous system (CNS) versus the periphery.

Competing Interests: Conflicts of interests None disclosed.

Previously described approaches for the alkylation of N H-sulfoximines typically rely either on transition metal catalysis, or the use of traditional alkylation reagents and strong bases. Herein, we report a straightforward alkylation of diverse N H-sulfoximines under simple Mitsunobu-type conditions, despite the unusually high p K a of the N H center.

The literature on developing alliance with youth clients has severely lagged behind that of adults. To date, there has been no meta-analytic review and limited qualitative synthesis of clinician variables which may contribute to the alliance with youth clients. Systematic literature search found a total of 49 relevant citations. Of the identified articles, 13 (27.08%) reported quantitative methods. Results of the qualitative review suggested that the majority of this research has focused on developing an emotional bond and a sense of collaboration. Meta-analysis found significant relations between alliance building and reducing variables and alliance (r alliance building  = 0.17; r alliance reducing  = -0.24). This analysis revealed specific behaviors particularly facilitative to youth alliance development, including collaborating with the client, finding common ground, exploring subjective experiences, orienting to treatment, providing praise, and enhancing facilitative conditions. In contrast, clinician lapse and pushing the client to talk were most predictive of a worse alliance. These results indicate certain behaviors which may be particularly important for clinicians to facilitate and not impair youth alliance formation. There is a need for greater youth alliance formation research to better determine how alliance formation may differ across stages of development and treatment modalities., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Antagonists of the serotonin receptor 2B (5-HT 2B ) have shown great promise as therapeutics for the treatment of pulmonary arterial hypertension, valvular heart disease, and related cardiopathies. Herein, we describe a high-throughput screen campaign that led to the identification of highly potent and selective 5-HT 2B antagonists. Furthermore, selected compounds were profiled for their predicted ability to cross the blood-brain barrier. Two exemplary compounds, VU0530244 and VU0631019, were predicted to have very limited potential for brain penetration in human subjects, a critical profile for the development of 5-HT 2B antagonists devoid of centrally-mediated adverse effects.

The decay kinetics of HIV-1-infected cells are critical to understand virus persistence. We evaluated the frequency of simian immunodeficiency virus (SIV)-infected cells for 4 years of antiretroviral therapy (ART). The intact proviral DNA assay (IPDA) and an assay for hypermutated proviruses revealed short- and long-term infected cell dynamics in macaques starting ART ∼1 year after infection. Intact SIV genomes in circulating CD4 + T cells showed triphasic decay with an initial phase slower than the decay of the plasma virus, a second phase faster than the second phase decay of intact HIV-1, and a stable third phase reached after 1.6-2.9 years. Hypermutated proviruses showed bi- or mono-phasic decay, reflecting different selective pressures. Viruses replicating at ART initiation had mutations conferring antibody escape. With time on ART, viruses with fewer mutations became more prominent, reflecting decay of variants replicating at ART initiation. Collectively, these findings confirm ART efficacy and indicate that cells enter the reservoir throughout untreated infection., Competing Interests: Declaration of interests Aspects of HIV-1 IPDA are subject of a patent application PCT/ US16/28822 filed by Johns Hopkins University. R.F.S. is an inventor on this application. Accelevir Diagnostics holds an exclusive license for this patent application. R.F.S. holds no equity interest in Accelevir Diagnostics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: It is well known that there is a socioeconomic gradient in the prevalence of many chronic diseases, including type 2 diabetes (T2DM). We present a simple assessment of the macro-level association between area socioeconomic disadvantage and the area-level prevalence of T2DM in Danish municipalities and the development in this relationship over the last decade., Methods: We used readily available public data on the socioeconomic composition of municipalities and T2DM prevalence to illustrate this association and report the absolute and relative summary measures of socioeconomic inequality over the time period 2008-2018., Results: The results show a persistent relationship between municipality socioeconomic disadvantage and T2DM prevalence across all analyses, with a modelled gap in T2DM prevalence between the most and least disadvantaged municipalities, the slope index of inequality, of 1.23 [0.97;1.49] in 2018., Conclusions: These results may be used to indicate areas with specific needs, to encourage systematic monitoring of socioeconomic gradients in health, and to provide a descriptive backdrop for a discussion of how to tackle these socioeconomic and geographic inequalities, which seem to persist even in the context of the comprehensive welfare systems in Scandinavia.

A substantial body of research supports dialectical behavior therapy (DBT) as an evidence-based treatment for those with borderline personality disorder (BPD); however, there remains a lack of mental health clinicians trained in this modality, resulting in limited clinician competencies and skills. Furthermore, the effectiveness of DBT trainings with mental health clinicians remains understudied. The present study evaluated a comprehensive 5-day DBT-Linehan Board of Certification training program. Informed by the Theory of Planned Behavior, this study assessed changes in clinician knowledge, attitudes, perceived behavioral control (PBC), intentions, and behaviors relevant to DBT at baseline, posttraining, and 6-month follow-up. Results showed large, significant pre-to-post training improvements in clinicians' knowledge, attitudes, PBC, and intentions related to DBT implementation. Large improvements in knowledge, attitudes, and PBC were sustained at follow-up. A significant improvement in actual behaviors was also found at follow-up. Implications of the present study and directions for future research are discussed.

Commonly known as "Quaaludes," methaqualone ( 1 ) is a sedative-hypnotic medication, with effects resembling barbiturates and other downers, that exerts its effects through modulation of γ-aminobutyric acid type A receptors (GABA A R). Following the discovery of the sedative and euphoric effects of methaqualone ( 1 ), it was quickly adopted by pharmaceutical companies and promoted by clinicians around the world as a "safe" sleeping pill option, and for a period it was available over the counter. The popularity of methaqualone ( 1 ) soared worldwide, and many people began to use it recreationally for its sedative-hypnotic-like psychoactive effects. Not long after its introduction, many individuals began to misuse the drug leading to overdoses and drug dependence which brought to light methaqualone's ( 1 ) addictive nature. In this review, the background, synthesis, pharmacology, metabolism, and pharmacokinetics of methaqualone ( 1 ) will be covered along with its discovery, history, and the derivatives that are currently available around the world through manufacture in clandestine laboratories.

Technological advances in sleep monitoring have seen an explosion of devices used to gather important sleep metrics. These devices range from instrumented 'smart pyjamas' through to at-home polysomnography devices. Alongside these developments in sleep technologies, there have been concomitant increases in sleep monitoring in athletic populations, both in the research and in practical settings. The increase in sleep monitoring in sport is likely due to the increased knowledge of the importance of sleep in the recovery process and performance of an athlete, as well as the well-reported challenges that athletes can face with their sleep. This narrative review will discuss: (1) the importance of sleep to athletes; (2) the various wearable tools and technologies being used to monitor sleep in the sport setting; (3) the role that sleep tracking devices may play in gathering information about sleep; (4) the reliability and validity of sleep tracking devices; (5) the limitations and cautions associated with sleep trackers; and, (6) the use of sleep trackers to guide behaviour change in athletes. We also provide some practical recommendations for practitioners working with athletes to ensure that the selection of such devices and technology will meet the goals and requirements of the athlete.

Objectives: Many studies have investigated the role that travel plays in athletic performance. However, these studies lacked a holistic representation of travel. For instance, they do not consider travel distance and uniquely focuses on travel direction., Design: An open source (www.evolving-hockey.com) provided NHL (2013-2020) game data. In total, this resulted in 17,088 regular season games., Methods: Linear and quadratic versions of time zone change (TZΔ) and adjusted jet lag (AJL) were formulated. TZΔ captured circadian delay/advance based on travel for a game, with each TZ going eastward and westward reflected by -1 and +1, respectively. AJL advances TZΔ by allowing TZ acclimation, with each day resulting in a 1-unit change towards circadian neutral. AJL is a season-long rolling summation, which was computed using two different travel approaches: Approach A (AJL&#95;A) assumes travel the day before each game, whereas Approach B (AJL&#95;B) was designed to prioritize being home. A standardized flight tracker determined travel distance for each game. Team ability differences, characterized as difference in total season points, served as an analytic covariate. Outcome variables included goal differential, difference between actual and expected Fenwick save percentage (dFSv%), and goals saved above average (GSAA)., Results: GameDistance (β = -0.14, p = 0.0007), AJL&#95;B 2 (β = -0.15, p = 0.0006), and their interaction (p = 0.0004) associated with GoalDifferential. GameDistance (β = -0.18, p = 0.02) and AJL&#95;B 2 (β = 0.12, p = 0.03) associated with dFSv%, whereas only AJL&#95;B 2 (β = 0.03, p = 0.05) associated with GSAA., Conclusions: Results suggest that circadian change, in both direction, and greater traveled distance can negatively impact NHL athletes., Competing Interests: Declaration of Interest Statement The authors do no have any conflict of interest to disclose., (Copyright © 2022 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Objective: Despite aims of equal access to treatment and care in the Nordic countries, marked socioeconomic inequality in the development of type 2 diabetes (T2D) complications persists. The study purpose was to estimate the associations of individual socioeconomic position and deprivation at the general practitioner (GP) level with referrals to T2D rehabilitation.Research Design and Methods: In 2015-2018, 3390 people affiliated with 432 primary GPs living in the municipality of Copenhagen were identified through registry data as newly diagnosed with T2D. Of these, 656 (19%) individuals were referred to municipal rehabilitation services in 2015-2021. Individual socioeconomic position was measured by education, income, and employment. The Danish Deprivation Index (DADI) was used as a measure of GP-level deprivation., Results: Patients were more likely to be referred to municipal rehabilitation if they had low vs. high income (hazard ratio (HR) 2.87 [women], 1.64 [men]), were not employed vs. employed (HR 1.95 [women], 1.23 [men]) and were affiliated with GPs with a low vs. very high level of deprivation (HR 7.63 [women], 4.30 [men]). The results suggest that GPs practice proportionate universalism by allocating treatment to lower socioeconomic individuals in likely higher need of care. However, the overall HR for referrals was lower among GPs with more deprived patient populations, indicating unequal treatment of all citizens, which conflicts with the aims of general universal health care. Inequality in rehabilitation healthcare services must be further addressed and investigated to prevent exacerbating health disparities., (© 2022 Published by Elsevier Ltd.)

This investigation aimed to clarify the influence of circadian change and travel distance on National Basketball Association (NBA) team performance using a dataset from the 2014-2018 seasons. Data from 9,840 games were acquired from an open-access source. Game point differential and team free-throw percentage served as outcome variables. Time zone change (TZΔ) captured raw circadian delay/advance based on travel for a game and adjusted TZΔ (AdjTZΔ) evolved TZΔ by allowing acclimation to a novel TZ. We also further categorized AdjTZΔ into AdjTZΔ&#95;A, which assumed travel the day before each game and AdjTZΔ&#95;B, which assumed teams spent as many days in their home city as possible. Travel distance for each game was calculated. Linear mixed-effects modeling estimated associations, with games nested within team and year. Adjusted associations accounted for differences in team ability, whether the game was home or away, and whether the game occurred on the second half of a back-to-back game sequence. Greater circadian misalignment, regardless of delay or advance, and increasing travel distance negatively influenced NBA game performance. Yet, results suggest that performance outcomes may be more influenced by travel distance than circadian misalignment. Moreover, circadian misalignment and travel distance interacted to significantly influence game point differential. Furthermore, differences in results across analyses were observed between AdjTZΔ&#95;A and AdjTZΔ&#95;B, which suggests that subtle differences in constructed travel schedules can have notable impact on NBA performance outcomes. Lastly, playing on the second half of a back-to-back sequence emerged as a robust predictor of performance disadvantage, which corroborates the existing literature and provides further support for NBA schedule changes purposed to enhance competitive equity by reducing the number of back-to-back games across a season. These findings can help guide NBA teams on key strategies for reducing travel-related disadvantages and inform schedule makers on critical factors to prioritize across future schedules to attenuate competitive inequity from travel. Furthermore, they can help direct teams towards scenarios that are best to target for load management purposes due to the cumulative disadvantage arising from travel-related factors, opponent quality, game location, and game sequence.

Suicide rates continue to rise, and clinicians and mental health staff play a critical role in keeping suicidal clients safe. Safety planning, including means safety, may help to decrease suicide risk. Unfortunately, availability and evaluation of safety planning training for these providers are scarce. The goal of the present study was to evaluate a safety planning training, LINC to LIFE Safety Planning (L2L SP). L2L SP is a 150-minute, face-to-face training program that teaches providers to engage clients in collaborative safety planning and means safety efforts, facilitate diverse client coping strategies, problem-solve, and involve close others, among other skills. These objectives are achieved through interactive content delivery, role-play, and corrective feedback. L2L SP was administered to 95 participants. Key determinants of behavioral change (e.g., knowledge, attitudes, perceived behavioral control [PBC]) were measured at pre, post, and six-month follow-up. Additionally, participants' behaviors and emotions in working with suicidal clients were measured at pretest and six-month follow-up. Paired sample t -tests, repeated measures MANOVA, and univariate ANOVAs with post-hoc testing using Bonferroni correction were conducted. Results supported significant improvements in knowledge, PBC, and intentions at post-test, and attitudes, PBC, and effective emotional responses at follow-up. Exploratory analyses suggested significant improvements in behaviors among clinicians and mental health staff who saw clients reporting suicidal ideation. The present study provides promising results regarding brief safety planning training. Declines in knowledge and PBC following the training highlight the potential need for booster sessions or more intensive initial training in these areas.HighlightsThe present study evaluated a comprehensive, interactive safety planning training.Knowledge, PBC, and intentions were significantly improved at post-test.Attitudes, PBC, and emotions were significantly improved at follow-up.

Suicidal thoughts and behaviors are highly prevalent among adolescents, and peers are often the first, and sometimes only, people to know about youth suicidality. Since many adolescents do not directly disclose suicidal thoughts, school-based suicide prevention programs aim to train youth to recognize warning signs of suicide in their peers that serve as "cues" to refer at-risk peers to an appropriate adult. However, peer-presented cues vary widely in presentation, and adolescents are more likely to recognize overt (i.e., obvious or explicit) as opposed to covert (i.e., hidden or implied) cues. The type of cue exhibited may, in turn, affect whether adolescents make a referral to an adult. The current study examined whether training suicide prevention influences referral intentions for overt and covert suicide cues. Participants included 244 high school students (54% female; M age = 16.21) in the Southeastern United States who received suicide prevention training (SOS; Signs of Suicide) as part of their health curriculum. Prior to training, students endorsed higher referral intentions for peers exhibiting overt compared to covert cues. Training was associated with increased intentions to refer peers across cue type, but referral intentions for covert cues improved significantly from pre to post-training while those for overt cues remained high and stable. Findings suggest that suicide prevention training might differentially improve students' ability to detect and respond appropriately to less obvious indicators of suicide risk. These findings may inform the adaptation and development of future, more nuanced school-based suicide prevention programming., Competing Interests: Conflict of Interest The authors declare that they have no conflicts of interest to report.

In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR 4 ). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M 4 potency, and further structure-activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M 4 potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The social inequality in mortality is due to differential incidence of several disorders and injury types, as well as differential survival. The resulting clustering and possible interaction in disadvantaged groups of several disorders make multimorbidity a potentially important component in the health divide. This study decomposes the effect of education on mortality into a direct effect, a pure indirect effect mediated by multimorbidity and a mediated interaction between education and multimorbidity., Methods: The study uses the Danish population registers on the total Danish population aged 45-69 years. A multimorbidity index based on all somatic and psychiatric hospital contacts as well as prescribed medicines includes 22 diagnostic groups weighted together by their 5 years mortality risk as weight. The Aalen additive hazard model is used to estimate and decompose the 5 years risk difference in absolute numbers of deaths according to educational status., Results: Most (69%-79%) of the effect is direct not involving multimorbidity, and the mediated effect is for low educated women 155 per 100 000 of which 87 is an effect of mediated interaction. For low educated men, the mediated effect is 250 per 100 000 of which 93 is mediated interaction., Conclusion: Multimorbidity plays an important role in the social inequality in mortality among middle aged in Denmark and mediated interaction represents 5%-17%. As multimorbidity is a growing challenge in specialised health systems, the mediated interaction might be a relevant indicator of inequities in care of multimorbid patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims/hypothesis: High prevalence of coexisting morbidity in people with type 2 diabetes highlights the need to include interactions with education and comorbidity in the assessments of societal consequences of type 2 diabetes. The purpose of this study was to estimate the joint effects of education, type 2 diabetes and six frequent comorbidities., Methods: Nationwide administrative register data on type 2 diabetes diagnosis, hospital admissions, education and disability pension were grouped at the individual level by means of a unique personal identification number. Included were all people (N = 2,281,599) in the age span of 40-59 years living in Denmark in the period 2005 to 2017, covering a total of 17,754,788 person-years. We used both Cox proportional hazards and Aalen additive hazards models to estimate relative and absolute joint effects of type 2 diabetes, educational attainment and six common comorbidities (CVD, cancer and cerebrovascular, respiratory, musculoskeletal and psychiatric diseases). We decomposed the joint effects of educational level, type 2 diabetes and comorbidities into main effects and the interaction effect, measured as extra cases of disability pension., Results: Lower level of educational attainment, type 2 diabetes and comorbidities independently contributed to additional granted disability pensions. The joint number of cases of disability pension exceeded the sum of the three exposures, which is explained by a synergistic effect of lower educational level, type 2 diabetes and comorbidity., Conclusions/interpretation: In this population study, the joint effects of type 2 diabetes, lower education and comorbidity were associated with larger than additive rates of disability pension. An integrated approach that takes into account socioeconomic barriers to type 2 diabetes rehabilitation may slow down disease progression and increase the working ability of socially disadvantaged people., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Athletes are increasingly required to travel domestically and internationally, often resulting in travel fatigue and jet lag. Despite considerable agreement that travel fatigue and jet lag can be a real and impactful issue for athletes regarding performance and risk of illness and injury, evidence on optimal assessment and management is lacking. Therefore 26 researchers and/or clinicians with knowledge in travel fatigue, jet lag and sleep in the sports setting, formed an expert panel to formalise a review and consensus document. This manuscript includes definitions of terminology commonly used in the field of circadian physiology, outlines basic information on the human circadian system and how it is affected by time-givers, discusses the causes and consequences of travel fatigue and jet lag, and provides consensus on recommendations for managing travel fatigue and jet lag in athletes. The lack of evidence restricts the strength of recommendations that are possible but the consensus group identified the fundamental principles and interventions to consider for both the assessment and management of travel fatigue and jet lag. These are summarised in travel toolboxes including strategies for pre-flight, during flight and post-flight. The consensus group also outlined specific steps to advance theory and practice in these areas., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This Letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) of the muscarinic acetylcholine receptor M 1 (mAChR M 1 ). Through the continued optimization of M 1 PAM tool compound VU0453595, with a focus on replacement of the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one with a wide variety of alternative 4,5-dihydropyrrolo-fused heteroaromatics, the generation of M 1 PAMs with structurally novel chemotypes is disclosed. Two compounds from these subseries, 8b (VU6005610) and 20a (VU6005852), show robust selectivity for the M 1 mAChR, and no M 1 agonism. Both compounds have favorable preliminary PK profiles in vitro;8b additionally demonstrates high brain exposure in a rodent IV cassette model., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Herein, we report the SAR leading to the discovery of VU6028418, a potent M 4 mAChR antagonist with high subtype-selectivity and attractive DMPK properties in vitro and in vivo across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered., Competing Interests: The authors declare the following competing financial interest(s): C.M.N., J.W.D., C.W.L., P.J.C., T.M.B., J.M.R., T.R.C., L.A.B., C.H., M.S., J.L.E., D.W.E., and A.M.B. are inventors on applications for composition of matter patents that protect several series of M4 antagonists., (© 2021 American Chemical Society.)

Nonselective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson's disease and dystonia. Despite their efficacy in these and other central nervous system disorders, antimuscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the antiparkinsonian and antidystonic efficacy observed with the use of nonselective antimuscarinic therapeutics. Our recent work has indicated that the M 4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M 4 may recapitulate the efficacy of nonselective antimuscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M 4 . Here, we utilize genetic mAChR knockout animals in combination with nonselective mAChR antagonists to confirm that the M 4 receptor activation is required for the locomotor-stimulating and antiparkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M 4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have antiparkinsonian and antidystonic efficacy in pharmacological and genetic models of movement disorders., Competing Interests: The authors declare the following competing financial interest(s): C.M.N., J.W.D., C.W.L., P.J.C., T.M.B., A.M.B., J.L.E., and J.M.R. are inventors on applications for composition of matter patents that protect several series of M4 antagonists., (© 2021 American Chemical Society.)

Background: The human immunodeficiency virus (HIV)-1 latent reservoir (LR) in resting CD4+ T cells is a barrier to cure. LR measurements are commonly performed on blood samples and therefore may miss latently infected cells residing in tissues, including lymph nodes., Methods: We determined the frequency of intact HIV-1 proviruses and proviral inducibility in matched peripheral blood (PB) and lymph node (LN) samples from 10 HIV-1-infected patients on antiretroviral therapy (ART) using the intact proviral DNA assay and a novel quantitative viral induction assay. Prominent viral sequences from induced viral RNA were characterized using a next-generation sequencing assay., Results: The frequencies of CD4+ T cells with intact proviruses were not significantly different in PB versus LN (61/106 vs 104/106 CD4+ cells), and they were substantially lower than frequencies of CD4+ T cells with defective proviruses. The frequencies of CD4+ T cells induced to produce high levels of viral RNA were not significantly different in PB versus LN (4.3/106 vs 7.9/106), but they were 14-fold lower than the frequencies of cells with intact proviruses. Sequencing of HIV-1 RNA from induced proviruses revealed comparable sequences in paired PB and LN samples., Conclusions: These results further support the use of PB as an appropriate proxy for the HIV-1 LR in secondary lymphoid organs., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Individuals who identify as lesbian, gay, bisexual, transgender, or queer (LGBTQ) are at a higher risk for suicidality compared to the general population. A growing body of research has investigated this risk, particularly with attention to systemic factors such as discrimination and harassment. Unfortunately, research has only examined the impact of direct discrimination on suicidality and has neglected to examine how ambient discrimination (i.e., witnessing or being made aware of discriminatory behaviors directed at someone other than yourself in your group) relates to suicidality. Additionally, although some links exist between discrimination and suicidality, the mechanisms by which these are related are understudied. This study aimed to address these gaps by exploring the effect of ambient discrimination on suicidal ideation and examining psychological pain as a mediator in this relationship. Data were collected from a sample of 200 LGBTQ-identified individuals (M age = 35 years; 53.5% female; 86% White). Results of independent t tests and a one-way multivariate ANOVA revealed greater vulnerability for ambient/direct discrimination and psychache among individuals identifying as transgender, queer, and other. Regression and mediation analyses revealed that while both ambient and direct discrimination predicted suicidal ideation, only direct discrimination accounted for unique variance in the outcome; however, both ambient and direct discrimination contributed unique variance to psychological pain, which fully mediated their relationships to suicidal ideation. Results of this study may begin to provide insight into the pathways of risk and points of intervention for suicidality in the LGBTQ community.

Gatekeeper trainings have been increasingly utilized in response to rising suicide rates in youths. However, the extent to which common factors inherent to gatekeeper trainings impact training outcomes is largely understudied. As such, the present study explored how factors such as training size and trainer engagement abilities influenced trainee participation and outcomes (i.e. changes in attitudes, perceived behavioral control (PBC), and knowledge regarding suicide prevention). All trainees participated in a gatekeeper training; trainers were not randomly assigned. Mediation and moderation analyses were completed using the PROCESS macro for SPSS (Hayes in Introduction to mediation, moderation, and conditional process analysis: a regression-based approach, Guilford Press, New York, 2013). Trainee participation in a training was examined as a mediator of the relationship between the training size and training outcomes, while trainer engagement was examined as a moderator of the relationship between size of training and trainee participation. Size of training was significantly related to lower changes in participant knowledge, along with lower trainee participation in gatekeeper trainings. Trainee participation significantly mediated the relationship between size of training, attitudes, and PBC. Additionally, trainer engagement significantly moderated the association between size of training and trainee participation. The results of this study suggest that general gatekeeper training-related variables may influence participant outcomes, specifically through trainee participation.

Because of its remarkable potency and relative ease of synthesis, carfentanil ( 1 ) has recently emerged as a problematic contaminant in other drugs of abuse. Carfentanil and its close analogues, currently approved only for large animal veterinary medicine, have found use both as illicit additives to the clandestine manufacture of scheduled drugs and as chemical weapons. In this Review, the background, synthesis, manufacture, metabolism, pharmacology, approved indications, dosage, and adverse effects of carfentanil will be discussed along with its emergence as a key player in the ongoing opioid crisis.

Background: In recent years, social differences in overweight and obesity (OWOB) have become more pronounced. Health impact assessments provide population-level scenario evaluations of changes in disease prevalence and risk factors. The objective of this study was to simulate the health effects of reducing the prevalence of overweight and obesity in populations with short and medium education., Methods: The DYNAMO-HIA tool was used to conduct a health inequality impact assessment of the future reduced disease prevalence (ischemic heart disease (IHD), diabetes, stroke, and multi-morbidity) and changes in life expectancy for the 2040-population of Copenhagen, Denmark (n = 742,130). We simulated an equalized weight scenario where the prevalence of OWOB in the population with short and medium education was reduced to the levels of the population with long education., Results: A higher proportion of the population with short and medium education were OWOB relative to the population with long education. They also had a higher prevalence of cardiometabolic diseases. In the equalized weight scenario, the prevalence of diabetes in the population with short education was reduced by 8-10% for men and 12-13% for women. Life expectancy increased by one year among women with short education. Only small changes in prevalence and life expectancy related to stroke and IHD were observed., Conclusion: Reducing the prevalence of OWOB in populations with short and medium education will reduce the future prevalence of cardiometabolic diseases, increase life expectancy, and reduce the social inequality in health. These simulations serve as reference points for public health debates.

Elite athletes are particularly susceptible to sleep inadequacies, characterised by habitual short sleep (<7 hours/night) and poor sleep quality (eg, sleep fragmentation). Athletic performance is reduced by a night or more without sleep, but the influence on performance of partial sleep restriction over 1-3 nights, a more real-world scenario, remains unclear. Studies investigating sleep in athletes often suffer from inadequate experimental control, a lack of females and questions concerning the validity of the chosen sleep assessment tools. Research only scratches the surface on how sleep influences athlete health. Studies in the wider population show that habitually sleeping <7 hours/night increases susceptibility to respiratory infection. Fortunately, much is known about the salient risk factors for sleep inadequacy in athletes, enabling targeted interventions. For example, athlete sleep is influenced by sport-specific factors (relating to training, travel and competition) and non-sport factors (eg, female gender, stress and anxiety). This expert consensus culminates with a sleep toolbox for practitioners (eg, covering sleep education and screening) to mitigate these risk factors and optimise athlete sleep. A one-size-fits-all approach to athlete sleep recommendations (eg, 7-9 hours/night) is unlikely ideal for health and performance. We recommend an individualised approach that should consider the athlete's perceived sleep needs. Research is needed into the benefits of napping and sleep extension (eg, banking sleep)., Competing Interests: Competing interests: AMB and CH have received grant funding from Own the Podium and Mitacs. MAG has received grant funding from Kemin Foods, Nexalin Technology and Jazz Pharmaceuticals; he has performed consulting activities for Fitbit, Natrol, Casper Sleep, Curaegis Technologies, Smartypants, Thrive Global, Pharmavite and Merck., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)