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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.)

Abstract: McClean, ZJ, Pasanen, K, Lun, V, Charest, J, Herzog, W, Werthner, P, Black, A, Vleuten, RV, Lacoste, E, and Jordan, MJ. A biopsychosocial model for understanding training load, fatigue, and musculoskeletal sport injury in university athletes: A scoping review. J Strength Cond Res 38(6): 1177-1188, 2024-The impact of musculoskeletal (MSK) injury on athlete health and performance has been studied extensively in youth sport and elite sport. Current research examining the relationship between training load, injury, and fatigue in university athletes is sparse. Furthermore, a range of contextual factors that influence the training load-fatigue-injury relationship exist, necessitating an integrative biopsychosocial model to address primary and secondary injury prevention research. The objectives of this review were (a) to review the scientific literature examining the relationship between training load, fatigue, and MSK injury in university athletes and (b) to use this review in conjunction with a transdisciplinary research team to identify biopsychosocial factors that influence MSK injury and develop an updated, holistic biopsychosocial model to inform injury prevention research and practice in university sport. Ten articles were identified for inclusion in this review. Key findings were an absence of injury surveillance methodology and contextual factors that can influence the training load-fatigue-MSK injury relationship. We highlight the inclusion of academic load, social load, and mental health load as key variables contributing to a multifactorial, gendered environmental, scientific inquiry on sport injury and reinjury in university sport. An integrative biopsychosocial model for MSK injury in university sport is presented that can be used to study the biological, psychological, and social factors that modulate injury and reinjury risk in university athletes. Finally, we provide an example of how causal inference can be used to maximize the utility of longitudinally collected observational data that is characteristic of sport performance research in university sport., (Copyright © 2024 National Strength and Conditioning Association.)

Background: Sleep as a biological phenomenon is effective in the performance and recovery of athletes. Questionnaires can be used as a cost-effective initial assessment tool for sleep. The Athlete Sleep Screening Questionnaire (ASSQ) demonstrated a clinically valid instrument for screening relevant sleep issues in athletic populations. Due to the lack of validated tools for adequate screening for sleep difficulties in the Iranian athlete population, the present study was conducted to evaluate the validity and reliability of the Persian version of the ASSQ., Materials and Methods: The translation process was performed using instructions by Beaton et al . Content validity was assessed by a panel of experts. Exploratory and confirmatory factor analysis was performed for two 5-item sleep difficulty scores (SDS) and a 4-item chronotype score. Internal consistency based on Cronbach's alpha and McDonald's omega and stability reliability were used to evaluate reliability., Results: The ASSQ achieved conceptual and semantic equivalence with the original scale. The item-level content validity index (I-CVI) of each item ranged from 0.87 to 1, and the averaging scale-level CVI/average was 0.95. In factor analysis, one factor for SDS and one factor for chronotype score were identified and confirmed. The internal consistency of the SDS scale (α =0.77, Ω =0.83) and chronotype (α =0.74, Ω =0.77) was acceptable. Stability reliability was confirmed for SDS scale (intra-class correlation [ICC] =0.87) and for chronotype (ICC = 0.83)., Conclusion: Persian ASSQ has acceptable psychometric measurement properties as a screening tool to assess sleep in Iranian athletes., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Research in Medical Sciences.)

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.

Sleep improves the cognitive and physical performance of athletes. A detailed questionnaire that detects sleep disruptions is required to identify sleep-deprived athletes. This study evaluates the translated Athlete Sleep Screening Questionnaire (ASSQ), a tool suggested by the International Olympic Committee, among Arabic-speaking athletes. The ASSQ was translated into Arabic and examined for floor or ceiling effects, internal consistency, and validity among Arabic-speaking athletes. The Arabic Pittsburgh Sleep Quality Index (PSQI) was employed to assess convergent validity. Ninety athletes (28.9% women) participated and completed this study's questionnaires. The Cronbach's alpha for the ASSQ-Sleep Difficulty Score (SDS) was 0.435, and that of the ASSQ-chronotype was 0.632. The SDS and chronotype subset of the ASSQ demonstrated excellent test-retest reliability, with intraclass correlation coefficients of 0.84 and 0.938, respectively. The ASSQ-SDS correlated positively with the PSQI (0.734, p = 0.001). The ASSQ-chronotype was inversely associated with the PSQI ( p = 0.001). This study's findings can assist clinicians in assessing sleep disorders in sports. The Arabic version of the ASSQ has satisfactory psychometric qualities and can identify clinically relevant sleep problems in athletes.

Background: Due to the rising concern of inadequate sleep, critical analysis is needed for the presence of sleep problems in diverse populations. Research has shown that college athletes may be one such population at risk for sleep disturbances. Poor sleep may lead to physiological, psychological, and cognitive deficits that can impact college athletes academically and athletically. This investigation was performed to examine the relationship of age, sex, and history of concussion on sleep disturbance in college athletes., Methods: A total of 191 collegiate athletes between the ages of 18-26 from a single academic NCAA institution in the Rocky Mountain region of the USA, consented to participate in the study. Participants completed a demographic questionnaire and the Athlete Sleep Screening Questionnaire (ASSQ). Results were analyzed using SPSS Version 27., Results: Primary results revealed that female athletes reported higher sleep disturbance scores when compared to males (U=3643.0, P=0.016). Self-reported sleep disturbances when traveling for sport were higher for females (X(1) = 23.800, P<0.001). Males were also less likely to report daytime dysfunction when traveling for sport (X(1) =22.988, P<0.001). Sleep disturbance had a significant association with age (X(1) =4.145, P=0.042), with older participants (20+ years of age) reporting greater sleep disturbance. Concussion history did not associate with sleep disturbance in the present study., Conclusions: Results suggest that sophomore or older female may be at higher risk for sleep disturbances. Clarifying sex-specific sleep health and understanding the role of age and academic class is crucial to enhance and personalize interventions.

Purpose of Review: Sleep is an essential human behavior that plays a key role in proper biopsychosocial development as well as short- and long-term biological, physical, psychological, and cognitive health. Sleep plays a key role in athletic performance, influencing an athlete's ability to train, recover, and perform, as well as their overall wellness. Over the recent decade, the awareness of sleep's import has penetrated just about every professional sport domain. The purpose of the review was to identify and synthesize the literature published within the past 5 years (2018-2022) that relates to sleep and performance in professional athletes. Literature related to nonprofessional, high-level athletes (e.g., collegiate; Olympic) was omitted as well as those associated with non-traditional professional sports (e.g., eSports)., Recent Findings: Results from 38 articles were incorporated into this review, which covered (1) the sleep's role in the training, physical injury prevention and recovery, competitive performance, and mental health of professional athletes, (2) common sleep problems and disorders in professional athletes, and (3) the impact of unique challenges from training, travel, competition, and other factors on sleep health. Additionally, we provide an orientation to utilized strategies and interventions to assist with sleep health in professional athletes, as well as conclude with a commentary on critical steps forward., Summary: Sleep plays a critically important role in the training, recovery, performance, and overall wellness of professional athletes. Professional athletes are vulnerable to a variety of sleep-related problems and disorders, due to unique factors related to training, travel, and competition, among other factors. Improved, standardized research methodology and partnerships between professional athletes, coaches, teams, and organizations and researchers are necessary to advance the knowledge of sleep and performance in professional athletes, including identifying sport-specific differences and variation across individual characteristics, as well as developing individualizable, dynamic, and appropriate interventions for improving sleep health among professional athletes., Competing Interests: Conflict of InterestJesse Cook serves as a consultant to Cerno Health© and Somni© and previously served as a consultant to Bodymatter, Inc., with these affiliations unrelated to the current study. Jonathan Charest serves as a consultant to Apeiron Life and has work funded by Mitacs, with these affiliations unrelated to the current study., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

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.)

Background: Sleep is considered an essential component related to physiological and psychological recovery in athletes and particularly in basketball, given the impact of condensed travel and game schedules on player health and performance., Objective: The aim of this systematic review is to examine studies published to date on sleep and basketball performance., Methodology: All scientific articles that reported a relationship between sleep and its possible impact on performance in basketball are included. The research processes followed the PRISMA criteria, and the relevant articles were extracted (PubMed, WOS, Scopus) as of December 31, 2021., Results: Twenty-eight articles were selected for inclusion and data extraction, with 27 demonstrating that sleep is a vital component in the recovery of basketball players and their corresponding on-court performance. Three central themes that we identified: (1) the quality and extension of sleep (the better quality and more extension of sleep, better performance and lower probability of injury); (2) influence of the players circadian rhythm (travel and game scheduling do not currently facilitate or take this into account); and (3) higher training loads and/or increased stress may jeopardize a subsequent good night's sleep, which should be taken into account when scheduling practices and workouts., Conclusion: The current systematic review regarding sleep and basketball performance and highlights that there is a strong relationship between both variables. Collectively, the evidence supports the critical influence of sleep on player recovery and basketball performance and risk for injury.

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.

Sleep health is an important consideration for athletic performance. Athletes are at high risk of insufficient sleep duration, poor sleep quality, daytime sleepiness and fatigue, suboptimal sleep schedules, irregular sleep schedules, and sleep and circadian disorders. These issues likely have an impact on athletic performance via several domains. Sleep loss and/or poor sleep quality can impair muscular strength, speed, and other aspects of physical performance. Sleep issues can also increase risk of concussions and other injuries and impair recovery after injury. Cognitive performance is also impacted in several domains, including vigilance, learning and memory, decision making, and creativity., Competing Interests: Disclosure Dr M.A. Grandner has received grants from Jazz Pharmaceuticals, National Institutes of Health, Nexalin Technology, and Kemin Foods. He has performed consulting activities for Fitbit, Natrol, Casper, Curaegis, Thrive, Pharmavite, SPV, Nightfood, and Merck. This work was supported by R01MD011600 and an Innovation Grant from the National Collegiate Athletic Association., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Study Objectives: Travel fatigue and circadian disruptions are known factors that can hinder performance in professional athletes. The present study focused on travel distance and direction on back-to-back games over the 2013-2020 seasons in the National Basketball Association (NBA)., Methods: The outcomes were based on winning percentage with additional covariates including the direction of travel (eastward or westward), the distance traveled (0-500 km; 501-1,000 km; 1,001-1,500 km; 1,501 km and more), team quality, and season. If a team played both games of a back-to-back sequence on the road, they were considered Away-Away; if a team played the first game of a back-to-back sequence at home they were considered Home-Away; if a team played the first game of a back-to-back sequence on the road they were considered Away-Home., Results: The sequence Away-Home significantly increases the likelihood of winning compared with the Away-Away and Home-Away sequences: 54.4% (95% confidence interval [CI], 54.4%-54.5%), 39.2% (95% CI, 37.2%-41.2%), and 36.8% (95% CI, 36.7%-36.8%), respectively. When teams travel back home, every additional 500 km reduces the likelihood of winning by approximately 4% ( P = .038). Finally, after withdrawing the Away-Home sequence, traveling eastward significantly increases the chance of winning ( P = .024) compared with westward travel but has no significant impact on the probability of winning compared with neutral time zone travel ( P = .091)., Conclusions: The accumulation of travel fatigue and the chronic circadian desynchronization that occurs over the NBA season can acutely disturb sleep and recovery. It appears that tailored sleep and recovery strategies need to be dynamically developed throughout the season to overcome the different challenges of the NBA schedule., Citation: Charest J, Samuels CH, Bastien CH, Lawson D, Grandner MA. Impacts of travel distance and travel direction on back-to-back games in the National Basketball Association. J Clin Sleep Med . 2021;17(11):2269-2274., (© 2021 American Academy of Sleep Medicine.)

Introduction: Previous studies have shown that student-athletes suffer from sleep difficulties. This study explored the impact of tDCS on sleep parameters among student-athletes., Method: Thirty student-athletes (15 females, 15 males, age 21.1 ± 2.1 years) were recruited. All participants underwent a series of questions to rule out depressive and anxiety disorders or any specific tDCS exclusion criteria. All participants were advised to maintain their usual sleep schedule., Results: Compared polysomnographic and Psychomotor Vigilance Task data analyses did not show any improvement after experimental tDCS. Regardless of groups, PVT mean reaction time was decreased. Regarding the questionnaires, data analyses showed improvement on the PSQI ( p < .001), ISI ( p < .001) and ASSQ ( p < .007) scores after tDCS., Discussion: tDCS appears to increase total sleep time and should be further explored. Improvements in subjective sleep suggest that tDCS bears interesting possibilities into the enhancement of sleep among student-athletes.

Previous research has shown that student athletes are more likely to be involved in a physical altercation or be a victim of verbal, physical and/or sexual abuse than student non-athletes, which can have long-lasting negative effects on mood, behavior and quality of life. In addition, among college students, sleep difficulties are ubiquitous and may deteriorate the unique life experience that university represents. The influences of poor sleep quality, mood and alcohol consumption related to these events are examined here between student athletes and student non-athletes. A series of hierarchical logistic regressions explored the relationship between verbal, physical and sexual assault risk factors. Results suggest that poor sleep, alcohol consumption and mood are all associated with exposure to a physical altercation or episode of abuse, irrespective of athlete status. Results also show that variables targeting self-reported difficulty sleeping and experiences of verbal, physical and sexual assault were positively associated. However, given the cross-sectional nature of the study, it is impossible to establish the direction of these relationships.

None: Frequent air travel and the condensed game schedule typical of a National Basketball Association (NBA) team during the season, often results in accompanying sleep disturbances related to sleep length, sleep quality, and sleep timing (with highly harmful impacts on health, both physical and mental). These issues are not only problematic for NBA players, but also the coaches, training staff, and management support. In this narrative review, we summarize the detrimental effects that this travel and game schedule could have on NBA team members' sleep, as well as their physical and mental health. Multiple peer-reviewed articles address the role of sleep in athletic performance and health; however, to date, the literature focused on sleep-related issues that are unique to the NBA schedule is scarce. Firstly, this review addresses the impact of the NBA schedule, outlining the number of games and the travel involved (number of flights, the timing of flights, timings of arrival at destination and hotel); we also outline a typical daily NBA travel schedule, providing the reader a glimpse of what this encompasses. Secondly, we provide a brief overview of sleep science and discuss specific applications related to the NBA. Finally, we provide comment on the unique current situation of the NBA "bubble". Based on this review, there appears to be considerable scope for further investigation of the acute and chronic effects of sleep disturbances concerning the NBA travel and game schedule. Sleep science recommendations need to inform practice, target sleep interventions, and personalized protocols designed to enhance sleep health that can be incorporated at the organizational level., (© 2021 American Academy of Sleep Medicine.)

Current reconstruction methods of the laryngotracheal segment fail to replace the complex functions of the human larynx. Bioengineering approaches to reconstruction have been limited by the complex tissue compartmentation of the larynx. We attempted to overcome this limitation by bioengineering laryngeal grafts from decellularized canine laryngeal scaffolds recellularized with human primary cells under one uniform culture medium condition. First, we developed laryngeal scaffolds which were generated by detergent perfusion-decellularization over 9 days and preserved their glycosaminoglycan content and biomechanical properties of a native larynx. After subcutaneous implantations in rats for 14 days, the scaffolds did not elicit a CD3 lymphocyte response. We then developed a uniform culture medium that strengthened the endothelial barrier over 5 days after an initial growth phase. Simultaneously, this culture medium supported airway epithelial cell and skeletal myoblast growth while maintaining their full differentiation and maturation potential. We then applied the uniform culture medium composition to whole laryngeal scaffolds seeded with endothelial cells from both carotid arteries and external jugular veins and generated reendothelialized arterial and venous vascular beds. Under the same culture medium, we bioengineered epithelial monolayers onto laryngeal mucosa and repopulated intrinsic laryngeal muscle. We were then able to demonstrate early muscle formation in an intramuscular transplantation model in immunodeficient mice. We supported formation of three humanized laryngeal tissue compartments under one uniform culture condition, possibly a key factor in developing complex, multicellular, ready-to-transplant tissue grafts. Impact Statement For patients undergoing laryngectomy, no reconstruction methods are available to restore the complex functions of the human larynx. The first promising preclinical results have been achieved with the use of biological scaffolds fabricated from decellularized tissue. However, the complexity of laryngeal tissue composition remains a hurdle to create functional viable grafts, since previously each cell type requires tailored culture conditions. In this study, we report the de novo formation of three humanized laryngeal tissue compartments under one uniform culture condition, a possible keystone in creating vital composite tissue grafts for laryngeal regeneration.

Research has characterized the sleep of elite athletes and attempted to identify factors associated with athletic performance, cognition, health, and mental well-being. Sleep is a fundamental component of performance optimization among elite athletes, yet only recently embraced by sport organizations as an important part of training and recovery. Sleep plays a crucial role in physical and cognitive performance and is an important factor in reducing risk of injury. This article aims to highlight the prevalence of poor sleep, describe its impacts, and address the issue of sport culture surrounding healthy sleep., Competing Interests: Disclosure Dr M.A. Grandner has received grants from Jazz Pharmaceuticals, National Institutes of Health, Nexalin Technology, and Kemin Foods. He has performed consulting activities for Fitbit, Natrol, Casper, Curaegis, Thrive, Pharmavite, SPV, NightFood, and Merck. This work was supported by R01MD011600 and an Innovation Grant from the National Collegiate Athletics Association., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Islet transplantation is superior to extrinsic insulin supplementation in the treating severe Type 1 diabetes. However, its efficiency and longevity are limited by substantial islet loss post-transplantation due to lack of engraftment and vascular supply. To overcome these limitations, we developed a novel approach to bio-fabricate functional, vascularized islet organs (VIOs) ex vivo. We endothelialized acellular lung matrixes to provide a biocompatible multicompartment scaffold with an intact hierarchical vascular tree as a backbone for islet engraftment. Over seven days of culture, islets anatomically and functionally integrated into the surrounding bio-engineered vasculature, generating a functional perfusable endocrine organ. When exposed to supra-physiologic arterial glucose levels in vivo and ex vivo, mature VIOs responded with a physiologic insulin release from the vein and provided more efficient reduction of hyperglycemia compared to intraportally transplanted fresh islets. In long-term transplants in diabetic mice, subcutaneously implanted VIOs achieved normoglycemia significantly faster and more efficiently compared to islets that were transplanted in deviceless fashion. We conclude that ex vivo bio-fabrication of VIOs enables islet engraftment and vascularization before transplantation, and thereby helps to overcome limited islet survival and function observed in conventional islet transplantation. Given recent progress in stem cells, this technology may enable assembly of functional personalized endocrine organs., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction: The proportion of university/college students (UCS) consuming alcohol is similar to the number of those reporting poor sleep, at approximately 30%, the proportion being greater in student athletes (SA). What remains to be understood is if poor sleep potentiates risky behaviors., Objective: Our aim was to examine the association among sleep difficulties, insomnia symptoms, and insufficient sleep on the risk of driving under the influence of alcohol in a sample of UCS and whether these associations were more pertinent in SA., Methods: Data from the National University/College Health Assessment was used from the years 2011⁻2014. Questions on number of drinks consumed and behaviors such as driving after drinking alcohol were related to answers to questions pertaining to sleep difficulties, insufficient sleep, and insomnia symptoms., Results: Mean alcohol intake was of about 3 drinks; SA consumed significantly more than student non-athletes (SNA). Binge-drinking episodes were significantly higher among SA than SNA. Difficulty sleeping was associated with an increased likelihood of driving after any drinks and after 5 or more drinks in both groups, effects being stronger among SA. Insomnia was associated with an increased likelihood of driving after any drinks and after 5 or more drinks in SA and after 5 or more drinks in SNA. These effects were stronger among athletes., Conclusion: The present study found that self-reported difficulties sleeping, insomnia symptoms, and insufficient sleep are associated with driving after drinking alcohol. This relationship applied to driving after drinking any alcohol or binge drinking and was again stronger among SA than SNA.

Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high-throughput screen and lead-compound-optimization campaign that delivered a cell-permeable inhibitor, NGI-1. NGI-1 targets oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small-cell lung cancer cells, NGI-1 blocks cell-surface localization and signaling of the epidermal growth factor receptor (EGFR) glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or fibroblast growth factor, FGFR) for survival. In these cell lines, OST inhibition causes cell-cycle arrest accompanied by induction of p21, autofluorescence, and cell morphology changes, all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor-tyrosine-kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells.

Bio-engineered organs for transplantation may ultimately provide a personalized solution for end-stage organ failure, without the risk of rejection. Building upon the process of whole organ perfusion decellularization, we aimed to develop novel, translational methods for the recellularization and regeneration of transplantable lung constructs. We first isolated a proliferative KRT5(+)TP63(+) basal epithelial stem cell population from human lung tissue and demonstrated expansion capacity in conventional 2D culture. We then repopulated acellular rat scaffolds in ex vivo whole organ culture and observed continued cell proliferation, in combination with primary pulmonary endothelial cells. To show clinical scalability, and to test the regenerative capacity of the basal cell population in a human context, we then recellularized and cultured isolated human lung scaffolds under biomimetic conditions. Analysis of the regenerated tissue constructs confirmed cell viability and sustained metabolic activity over 7 days of culture. Tissue analysis revealed extensive recellularization with organized tissue architecture and morphology, and preserved basal epithelial cell phenotype. The recellularized lung constructs displayed dynamic compliance and rudimentary gas exchange capacity. Our results underline the regenerative potential of patient-derived human airway stem cells in lung tissue engineering. We anticipate these advances to have clinically relevant implications for whole lung bioengineering and ex vivo organ repair., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Whole lung extracellular matrix scaffolds can be created by perfusion of cadaveric organs with decellularizing detergents, providing a platform for organ regeneration. Lung epithelial engineering must address both the proximal airway cells that function to metabolize toxins and aid mucociliary clearance and the distal pneumocytes that facilitate gas exchange. Engineered pulmonary vasculature must support in vivo blood perfusion with low resistance and intact barrier function and be antithrombotic. Repopulating the native lung matrix with sufficient cell numbers in appropriate anatomic locations is required to enable organ function., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Rationale: More than 25 million individuals have heart failure worldwide, with ≈4000 patients currently awaiting heart transplantation in the United States. Donor organ shortage and allograft rejection remain major limitations with only ≈2500 hearts transplanted each year. As a theoretical alternative to allotransplantation, patient-derived bioartificial myocardium could provide functional support and ultimately impact the treatment of heart failure., Objective: The objective of this study is to translate previous work to human scale and clinically relevant cells for the bioengineering of functional myocardial tissue based on the combination of human cardiac matrix and human induced pluripotent stem cell-derived cardiomyocytes., Methods and Results: To provide a clinically relevant tissue scaffold, we translated perfusion-decellularization to human scale and obtained biocompatible human acellular cardiac scaffolds with preserved extracellular matrix composition, architecture, and perfusable coronary vasculature. We then repopulated this native human cardiac matrix with cardiomyocytes derived from nontransgenic human induced pluripotent stem cells and generated tissues of increasing 3-dimensional complexity. We maintained such cardiac tissue constructs in culture for 120 days to demonstrate definitive sarcomeric structure, cell and matrix deformation, contractile force, and electrical conduction. To show that functional myocardial tissue of human scale can be built on this platform, we then partially recellularized human whole-heart scaffolds with human induced pluripotent stem cell-derived cardiomyocytes. Under biomimetic culture, the seeded constructs developed force-generating human myocardial tissue and showed electrical conductivity, left ventricular pressure development, and metabolic function., Conclusions: Native cardiac extracellular matrix scaffolds maintain matrix components and structure to support the seeding and engraftment of human induced pluripotent stem cell-derived cardiomyocytes and enable the bioengineering of functional human myocardial-like tissue of multiple complexities., (© 2015 American Heart Association, Inc.)

The primary treatment for end-stage lung disease is lung transplantation. However, donor organ shortage remains a major barrier for many patients. In recent years, techniques for maintaining lungs ex vivo for evaluation and short-term (<12 h) resuscitation have come into more widespread use in an attempt to expand the donor pool. In parallel, progress in whole organ engineering has provided the potential perspective of patient derived grafts grown on demand. As both of these strategies advance to more complex interventions for lung repair and regeneration, the need for a long-term organ culture system becomes apparent. Herein we describe a novel clinical scale bioreactor capable of maintaining functional porcine and human lungs for at least 72 h in isolated lung culture (ILC). The fully automated, computer controlled, sterile, closed circuit system enables physiologic pulsatile perfusion and negative pressure ventilation, while gas exchange function, and metabolism can be evaluated. Creation of this stable, biomimetic long-term culture environment will enable advanced interventions in both donor lungs and engineered grafts of human scale., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Asparagine-linked glycosylation is an endoplasmic reticulum co- and post-translational modification that enables the transit and function of receptor tyrosine kinase (RTK) glycoproteins. To gain insight into the regulatory role of glycosylation enzymes on RTK function, we investigated shRNA and siRNA knockdown of mannose phosphate isomerase (MPI), an enzyme required for mature glycan precursor biosynthesis. Loss of MPI activity reduced phosphorylation of FGFR family receptors in U-251 and SKMG-3 malignant glioma cell lines and also resulted in significant decreases in FRS2, Akt, and MAPK signaling. However, MPI knockdown did not affect ligand-induced activation or signaling of EGFR or MET RTKs, suggesting that FGFRs are more susceptible to MPI inhibition. The reductions in FGFR signaling were not caused by loss of FGF ligands or receptors, but instead were caused by interference with receptor dimerization. Investigations into the cellular consequences of MPI knockdown showed that cellular programs driven by FGFR signaling, and integral to the clinical progression of malignant glioma, were impaired. In addition to a blockade of cellular migration, MPI knockdown also significantly reduced glioma cell clonogenic survival following ionizing radiation. Therefore our results suggest that targeted inhibition of enzymes required for cell surface receptor glycosylation can be manipulated to produce discrete and limited consequences for critical client glycoproteins expressed by tumor cells. Furthermore, this work identifies MPI as a potential enzymatic target for disrupting cell surface receptor-dependent survival signaling and as a novel approach for therapeutic radiosensitization.

The native extracellular matrix (ECM) outlines the architecture of organs and tissues. It provides a unique niche of composition and form, which serves as a foundational scaffold that supports organ-specific cell types and enables normal organ function. Here we describe a standard process for pressure-controlled perfusion decellularization of whole organs for generating acellular 3D scaffolds with preserved ECM protein content, architecture and perfusable vascular conduits. By applying antegrade perfusion of detergents and subsequent washes to arterial vasculature at low physiological pressures, successful decellularization of complex organs (i.e., hearts, lungs and kidneys) can be performed. By using appropriate modifications, pressure-controlled perfusion decellularization can be achieved in small-animal experimental models (rat organs, 4-5 d) and scaled to clinically relevant models (porcine and human organs, 12-14 d). Combining the unique structural and biochemical properties of native acellular scaffolds with subsequent recellularization techniques offers a novel platform for organ engineering and regeneration, for experimentation ex vivo and potential clinical application in vivo.

Activating mutations of the epidermal growth factor receptor (EGFR) occur in multiple tumor types, including non-small cell lung cancer (NSCLC) and malignant glioma, and have become targets for therapeutic intervention. The determination of EGFR mutation status using a noninvasive, molecular imaging approach has the potential for clinical utility. In this study, we investigated [(11)C]-erlotinib positron emission tomography (PET) imaging as a tool to identify activating mutations of EGFR in both glioma and NSCLC xenografts. Radiotracer specific binding was determined for high and low specific activity (SA) [(11)C]-erlotinib PET scans in mice bearing synchronous human cancer xenografts with different EGFR expression profiles (PC9, HCC827, U87, U87 ΔEGFR, and SW620). Although xenograft immunohistochemistry demonstrated constitutive EGFR phosphorylation, PET scan analysis using the Simplified Reference Tissue Model showed that only kinase domain mutant NSCLC (HCC827 and PC9) had significantly greater binding potentials in high versus low SA scans. Xenografts with undetectable EGFR expression (SW620), possessing wild-type EGFR (U87), and expressing an activating extracellular domain mutation (U87 ΔEGFR) were indistinguishable under both high and low SA scan conditions. The results suggest that [(11)C]-erlotinib is a promising radiotracer that could provide a novel clinical methodology for assessing EGFR and erlotinib interactions in patients with tumors that harbor EGFR-activating kinase domain mutations.

The endoplasmic reticulum (ER) provides a specialized environment for the folding and modification of trans-membrane proteins, including receptor tyrosine kinases (RTKs), which are vital for the growth and survival of malignancies. To identify compounds which disrupt the function of the ER and thus could potentially impair cancer cell survival signaling, we adapted a set of glycosylation-sensitive luciferase reporters for the development and optimization of a cell-based high-throughput screen (HTS). Secondary screens for false-positive luciferase activation and tertiary lectin-based and biochemical analyses were also devised for compound triage. Through a pilot screen of 2802 compounds from the National Cancer Institute (NCI) chemical libraries, we identified aclacinomycin (Acm) as a compound that preferentially affects ER function. We report that Acm reduces plasma membrane expression of glycoproteins including epidermal growth factor receptor (EGFR) and Met but does not inhibit N-linked glycosylation or generalized protein translation. Fluorescence microscopy co-localization experiments were also performed and demonstrated Acm accumulation in the ER in further support of the overall HTS design. The consequences of Acm treatment on cell survival were analyzed through clonogenic survival analysis. Consistent with the reduction of EGFR levels, pretreatment with Acm sensitizes the EGFR-mutant non-small cell lung cancer (NSCLC) cell lines HCC827 and HCC2935 to ionizing radiation and did not affect the sensitivity of the RTK-independent and KRAS-mutant A549 NSCLC cell line. Thus, Acm and similar compounds targeting the ER may represent a novel approach for radiosensitizing tumor cells dependent on RTK function.

Both substrate topography and substrate mechanical properties are known to influence cell behavior, but little is known about how they act in concert. Here, a method is presented to introduce topographical features into PA hydrogel substrates that span a wide range of physiological E values. Gel swelling plays a significant role in the fidelity of protruding micromolded features, with the most efficient pattern transfer occurring at a crosslinking concentration equal to or greater than ≈5%. In contrast, swelling does not influence the spacing fidelity of microcontact printed islands of collagen on 2D PA substrates. BAECs cultured on micromolded PA substrates exhibit contact guidance along ridges patterned for all E tested., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)