Reprint of: Exploring tourists' motivations, constraints, and negotiations regarding outdoor recreation trips during COVID-19 through a focus group study.

The current COVID-19 outbreak has duly influenced tourists' psychology and subsequently their behavior and decision making to participate in outdoor activities. The purpose of this paper is to illuminate tourists' motivations, perceived constraints, and negotiation strategies to participate in outdoor recreation trips, within the current COVID-19 context. To explore and categorize motivating factors, constraints, and negotiation strategies, we employed a qualitative approach via semi-structured online focus group discussion with 16 tourists (mostly residents of Utah, United States) during late summer 2020. First, COVID-19 related restrictions and fewer opportunities to go outdoors were found to encourage outdoor recreation, for novelty-seeking and experiencing normalcy. Through content analysis, we found that tourists experience a blend of personal, social, practical, and ethical constraints. Additionally, we identified how tourists negotiate their constraints through different ways: by extensive planning and information searching, avoiding crowds, and changing leisure aspirations. Finally, we discuss theoretical and managerial implications of the study, followed by recommendations for future research. Management implications: Understanding of tourists' motivations, constraints, and negotiation strategies-relevant to outdoor recreation trips-provides several managerial implications to destination managers and marketers, as outlined below:•Lack of centralized and reliable information was frequently cited as a constraint in the focus group discussions. In order to provide adequate and timely information to potential participations, we proposed a novel website template including details about information to be presented.•As our study sheds light on tourists' companionship preferences, activity choice, and evaluation of a destination's COVID-related operational practices, we propose several advertising strategies and destination operational guidelines to attract tourists.

Impacts of the COVID-19 Pandemic on Pedestrian Push-Button Utilization and Pedestrian Volume Model Accuracy in Utah.

This work investigated the impacts of COVID-19 on pedestrian behavior, answering two research questions using pedestrian push-button data from Utah traffic signals: How did push-button utilization change during the early pandemic, owing to concerns over disease spread through high-touch surfaces? How did the accuracy of pedestrian volume estimation models (developed pre-COVID based on push-button traffic signal data) change during the early pandemic? To answer these questions, we first recorded videos, counted pedestrians, and collected push-button data from traffic signal controllers at 11 intersections in Utah in 2019 and 2020. We then compared changes in push-button presses per pedestrian (to measure utilization), as well as model prediction errors (to measure accuracy), between the two years. Our first hypothesis of decreased push-button utilization was partially supported. The changes in utilization at most (seven) signals were not statistically significant; yet, the aggregate results (using 10 of 11 signals) saw a decrease from 2.1 to 1.5 presses per person. Our second hypothesis of no degradation of model accuracy was supported. There was no statistically significant change in accuracy when aggregating across nine signals, and the models were actually more accurate in 2020 for the other two signals. Overall, we concluded that COVID-19 did not significantly deter people from using push-buttons at most signals in Utah, and that the pedestrian volume estimation methods developed in 2019 probably do not need to be recalibrated to work for COVID conditions. This information may be useful for public health actions, signal operations, and pedestrian planning.

Impact of COVID-19 on Traffic Signal Systems: Survey of Agency Interventions and Observed Changes in Pedestrian Activity.

The COVID-19 pandemic, the most significant public health crisis since the 1918-1919 influenza epidemic, is the first such event to occur since the development of modern transportation systems in the twentieth century. Many states across the U.S. imposed lockdowns in early spring 2020, which reduced demand for trips of various types and affected transportation systems. In urban areas, the shift resulted in a reduction in traffic volumes and an increase in bicycling and walking in certain land use contexts. This paper seeks to understand the changes occurring at signalized intersections as a result of the lockdown and the ongoing pandemic, as well as the actions taken in response to these impacts. The results of a survey of agency reactions to COVID-19 with respect to traffic signal operations and changes in pedestrian activity during the spring 2020 lockdown using two case study examples in Utah are presented. First, the effects of placing intersections on pedestrian recall (with signage) to stop pedestrians from pushing the pedestrian button are examined. Next, the changes in pedestrian activity at Utah signalized intersections between the first 6 months of both 2019 and 2020 are analyzed and the impact of land use characteristics is explored. Survey results reveal the importance of using technologies such as adaptive systems and automated traffic signal performance measures to drive decisions. While pedestrian pushbutton actuations decreased in response to the implementation of pedestrian recalls, many pedestrians continued to use the pushbutton. Pedestrian activity changes were also largely driven by surrounding land uses.

Pedestrians and the Built Environment during the COVID-19 Pandemic: Changing Relationships by the Pandemic Phases in Salt Lake County, Utah, U.S.A.

The COVID-19 pandemic has dramatically altered people's travel behavior, in particular outdoor activities, including walking. Their behavior changes may have prolonged effects after the pandemic, and such changes vary by the context and are related to the characteristics of the built environment. But empirical studies about the relationships between pedestrians and the built environment during the pandemic are lacking. This study explores how COVID-19 and related travel restrictions have affected the relationship between pedestrian traffic volume and the built environment. We estimate daily pedestrian volumes for all signalized intersections in Salt Lake County, Utah, U.S.A., from pedestrian push-button log data between January 2019 and October 2020. Multilevel spatial filtering models show that the COVID-19 pandemic has altered the relationship between pedestrian traffic volume and the built environment. During the pandemic, the higher the number of COVID-19 cases, the less (or more negative) the effects of density, street connectivity, and destination accessibility on pedestrian volume being observed. The exception is access to urban parks, as it became more significant in increasing pedestrian activities during the pandemic. The models also highlight the negative impacts of the pandemic in economically disadvantaged areas. Our findings could help urban and transportation planners find effective interventions to promote active transportation and physical activity amid the global pandemic.

Shedding light on the pedestrian safety crisis: An analysis across the injury severity spectrum by lighting condition.

OBJECTIVE: Pedestrian fatalities in the United States increased 51% from 2009 to 2019. During that time, pedestrian fatalities occurring at night increased by 63.7%, compared to a 17.6% increase for pedestrian fatalities occurring during daylight conditions. Have there also been increases in serious, minor, and possible pedestrian injuries (i.e., have all pedestrian collisions been occurring more frequently)? Have pedestrian collisions been getting more severe (i.e., are there now higher proportions of more severe injuries)? Have trends differed between night and day? What role does street lighting play in the nighttime trends? METHODS: We analyzed pedestrian fatalities, serious injuries, minor injuries, and possible injuries that occurred in California, North Carolina, and Texas from 2010 to 2019 using linear regressions to explore the strength and statistical significance of trends. We then parsed these trends by lighting condition, exploring outcomes during the day and night and with and without street lighting. RESULTS: Findings suggest that increases in daytime minor (7.9%) and possible (7.5%) injuries closely mirrored increases in population (9.8%). Increases in daytime fatal/serious injuries were significantly higher (43.1% and 35.1%, respectively), suggesting worsening severities during the day. Increases in nighttime minor/possible injuries (31.9% and 27.6%, respectively) were significantly larger than those during the day, suggesting that pedestrian collisions are occurring more frequently at night. Substantial increases in nighttime fatal/serious injuries (78.0% and 74.7%, respectively) likely reflect a combination of worsening severity (seen throughout the day) and increasing frequency (seen particularly at night). A pedestrian injured in the dark was found to be 5.0 times more likely to be killed than a pedestrian injured during the day. While a lack of street lighting does not seem to be the cause of the disproportionate increase in pedestrian injuries at night, pedestrians struck without a street light were 2.4 times more likely to be killed than those struck in the presence of a street light. CONCLUSIONS: As we find ourselves in the midst of a pedestrian safety crisis, understanding that severities have increased throughout the entire day and frequencies have increased particularly at night helps illuminate a path forward.

Joint position statement of the International Federation of Sports Medicine (FIMS) and European Federation of Sports Medicine Associations (EFSMA) on the IOC framework on fairness, inclusion and non-discrimination based on gender identity and sex variations.

The IOC recently published its framework on fairness, inclusion and non-discrimination based on gender identity and sex variations. This framework is drafted mainly from a human rights perspective, with less consideration for medical/scientific issues. The framework places the onus for gender eligibility and classification entirely on the International Federations (IFs), even though most will not have the capacity to implement the framework. The position of no presumption of advantage is contrary to the 2015 IOC consensus. Implementation of the 2021 framework will be a major challenge for IFs that have already recognised the inclusion of trans and women athletes with differences of sexual development (DSD) using a scientific/medical solution. The potential consequences for sports that need to prioritise fairness or safety could be one of two extremes (1) exclusion of all transgender or DSD athletes on the grounds of advantage or (2) self-identification that essentially equates to no eligibility rules. Exclusion of all transgender or DSD athletes is contrary to the Olympic charter and unlawful in many countries. While having no gender eligibility rules, sport loses its meaning and near-universal support. Athletes should not be under pressure to undergo medical procedures or treatment to meet eligibility criteria. However, if an athlete is fully informed and consents, then it is their free choice to undergo carefully considered or necessary interventions for gender classification for sport to compete fairly and safely in their chosen gender. Free choice is a fundamental human right, but so is the right to fair and safe competition.

Recommendations for Face Coverings While Exercising During the COVID-19 Pandemic.

In an effort to reduce transmission and number of infections of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) virus, governments and official bodies around the world have produced guidelines on the use of face masks and face coverings. While there is a growing body of recommendations for healthcare professionals and the wider population to use facial protection in "enclosed spaces" where minimal distancing from other individuals is not possible, there is a dearth of clear guidelines for individuals undertaking exercise and sporting activity. The present viewpoint aims to propose recommendations for face coverings while exercising during the COVID-19 pandemic that consider physical distancing, the environment, the density of active cases associated with the specific sports activity, and the practical use of face coverings in order to reduce potential viral transmission. Recommendations are provided on the basis of very limited available evidence in conjunction with the extensive collective clinical experience of the authors and acknowledging the need to consider the likelihood of the presence of the SARS-CoV-2 in the general population. We recommend that face coverings should be used in any environment considered to be of a high or moderate transmission risk, where tolerated and after individual risk assessment. In addition, as national caseloads fluctuate, individual sporting bodies should consider up to date guidance on the use of face coverings during sport and exercise, alongside other preventative measures.

Exploring tourists' motivations, constraints, and negotiations regarding outdoor recreation trips during COVID-19 through a focus group study.

The current COVID-19 outbreak has duly influenced tourists' psychology and subsequently their behavior and decision making to participate in outdoor activities. The purpose of this paper is to illuminate tourists' motivations, perceived constraints, and negotiation strategies to participate in outdoor recreation trips, within the current COVID-19 context. To explore and categorize motivating factors, constraints, and negotiation strategies, we employed a qualitative approach via semi-structured online focus group discussion with 16 tourists (mostly residents of Utah, United States) during late summer 2020. First, COVID-19 related restrictions and fewer opportunities to go outdoors were found to encourage outdoor recreation, for novelty-seeking and experiencing normalcy. Through content analysis, we found that tourists experience a blend of personal, social, practical, and ethical constraints. Additionally, we identified how tourists negotiate their constraints through different ways: by extensive planning and information searching, avoiding crowds, and changing leisure aspirations. Finally, we discuss theoretical and managerial implications of the study, followed by recommendations for future research. Management implications: Understanding of tourists' motivations, constraints, and negotiation strategies-relevant to outdoor recreation trips-provides several managerial implications to destination managers and marketers, as outlined below:•Lack of centralized and reliable information was frequently cited as a constraint in the focus group discussions. In order to provide adequate and timely information to potential participations, we proposed a novel website template including details about information to be presented.•As our study sheds light on tourists' companionship preferences, activity choice, and evaluation of a destination's COVID-related operational practices, we propose several advertising strategies and destination operational guidelines to attract tourists.

Recommendations for return to sport during the SARS-CoV-2 pandemic.

In this viewpoint we make specific recommendations that can assist and make the return to sport/exercise as safe as possible for all those impacted - from the recreational athlete to the elite athlete. We acknowledge that there are varying rules and regulations around the world, not to mention the varying philosophies and numerous schools of thought as it relates to return to sport/exercise and we have been cognisant of this in our recommendations. Despite the varying rules and circumstances around the world, we believe it is essential to provide some helpful and consistent guidance for return to training and sport for sport and exercise physicians around the world at this most difficult time. The present viewpoint provides practical and medical recommendations on the resumption to sport process.

Novel Mechanism for Nicotinamide Phosphoribosyltransferase Inhibition of TNF-α-mediated Apoptosis in Human Lung Endothelial Cells.

Nicotinamide phosphoribosyltransferase (NAMPT) exists as both intracellular NAMPT and extracellular NAMPT (eNAMPT) proteins. eNAMPT is secreted into the blood and functions as a cytokine/enzyme (cytozyme) that activates NF-κB signaling via ligation of Toll-like receptor 4 (TLR4), further serving as a biomarker for inflammatory lung disorders such as acute respiratory distress syndrome. In contrast, intracellular NAMPT is involved in nicotinamide mononucleotide synthesis and has been implicated in the regulation of cellular apoptosis, although the exact mechanisms for this regulation are poorly understood. We examined the role of NAMPT in TNF-α-induced human lung endothelial cell (EC) apoptosis and demonstrated that reduced NAMPT expression (siRNA) increases EC susceptibility to TNF-α-induced apoptosis as reflected by PARP-1 cleavage and caspase-3 activation. In contrast, overexpression of NAMPT served to reduce degrees of TNF-α-induced EC apoptosis. Inhibition of nicotinamide mononucleotide synthesis by FK866 (a selective NAMPT enzymatic inhibitor) failed to alter TNF-α-induced human lung EC apoptosis, suggesting that NAMPT-dependent NAD+ generation is unlikely to be involved in regulation of TNF-α-induced EC apoptosis. We next confirmed that TNF-α-induced EC apoptosis is attributable to NAMPT secretion into the EC culture media and subsequent eNAMPT ligation of TLR4 on the EC membrane surface. Silencing of NAMPT expression, direct neutralization of secreted eNAMPT by an NAMPT-specific polyclonal antibody (preventing TLR4 ligation), or direct TLR4 antagonism all served to significantly increase EC susceptibility to TNF-α-induced EC apoptosis. Together, these studies provide novel insights into NAMPT contributions to lung inflammatory events and to novel mechanisms of EC apoptosis regulation.

Regulation of Thrombin-Induced Lung Endothelial Cell Barrier Disruption by Protein Kinase C Delta.

Protein Kinase C (PKC) plays a significant role in thrombin-induced loss of endothelial cell (EC) barrier integrity; however, the existence of more than 10 isozymes of PKC and tissue-specific isoform expression has limited our understanding of this important second messenger in vascular homeostasis. In this study, we show that PKCδ isoform promotes thrombin-induced loss of human pulmonary artery EC barrier integrity, findings substantiated by PKCδ inhibitory studies (rottlerin), dominant negative PKCδ construct and PKCδ silencing (siRNA). In addition, we identified PKCδ as a signaling mediator upstream of both thrombin-induced MLC phosphorylation and Rho GTPase activation affecting stress fiber formation, cell contraction and loss of EC barrier integrity. Our inhibitor-based studies indicate that thrombin-induced PKCδ activation exerts a positive feedback on Rho GTPase activation and contributes to Rac1 GTPase inhibition. Moreover, PKD (or PKCµ) and CPI-17, two known PKCδ targets, were found to be activated by PKCδ in EC and served as modulators of cytoskeleton rearrangement. These studies clarify the role of PKCδ in EC cytoskeleton regulation, and highlight PKCδ as a therapeutic target in inflammatory lung disorders, characterized by the loss of barrier integrity, such as acute lung injury and sepsis.

Extracellular Vesicles from Caveolin-Enriched Microdomains Regulate Hyaluronan-Mediated Sustained Vascular Integrity.

Defects in vascular integrity are an initiating factor in several disease processes. We have previously reported that high molecular weight hyaluronan (HMW-HA), a major glycosaminoglycan in the body, promotes rapid signal transduction in human pulmonary microvascular endothelial cells (HPMVEC) leading to barrier enhancement. In contrast, low molecular weight hyaluronan (LMW-HA), produced in disease states by hyaluronidases and reactive oxygen species (ROS), induces HPMVEC barrier disruption. However, the mechanism(s) of sustained barrier regulation by HA are poorly defined. Our results indicate that long-term (6-24 hours) exposure of HMW-HA induced release of a novel type of extracellular vesicle from HLMVEC called enlargeosomes (characterized by AHNAK expression) while LMW-HA long-term exposure promoted release of exosomes (characterized by CD9, CD63, and CD81 expression). These effects were blocked by inhibiting caveolin-enriched microdomain (CEM) formation. Further, inhibiting enlargeosome release by annexin II siRNA attenuated the sustained barrier enhancing effects of HMW-HA. Finally, exposure of isolated enlargeosomes to HPMVEC monolayers generated barrier enhancement while exosomes led to barrier disruption. Taken together, these results suggest that differential release of extracellular vesicles from CEM modulate the sustained HPMVEC barrier regulation by HMW-HA and LMW-HA. HMW-HA-induced specialized enlargeosomes can be a potential therapeutic strategy for diseases involving impaired vascular integrity.

HABP2 is a Novel Regulator of Hyaluronan-Mediated Human Lung Cancer Progression.

BACKGROUND: Lung cancer is a devastating disease with limited treatment options. Many lung cancers have changes in their microenvironment including upregulation of the extracellular matrix glycosaminoglycan, hyaluronan (HA), which we have previously demonstrated can regulate the activity of the extracellular serine protease, hyaluronan binding protein 2 (HABP2). This study examined the functional role of HABP2 on HA-mediated human lung cancer dynamics. METHODS: Immunohistochemical analysis was performed on lung cancer patient samples using anti-HABP2 antibody. Stable control, shRNA, and HABP2 overexpressing human lung adenocarcinoma cells were evaluated using immunoblot analysis, migration, extravasation, and urokinase plasminogen activator (uPA) activation assays with or without high-molecular weight HA or low-molecular weight HA (LMW-HA). In human lung cancer xenograft models, primary tumor growth rates and lung metastasis were analyzed using consecutive tumor volume measurements and nestin immunoreactivity in nude mouse lungs. RESULTS: We provide evidence that HABP2 is an important regulator of lung cancer progression. HABP2 expression was increased in several subtypes of patient non-small cell lung cancer samples. Further, HABP2 overexpression increased LMW-HA-induced uPA activation, migration, and extravasation in human lung adenocarcinoma cells. In vivo, overexpression of HABP2 in human lung adenocarcinoma cells increased primary tumor growth rates in nude mice by ~2-fold and lung metastasis by ~10-fold compared to vector control cells (n = 5/condition). CONCLUSION: Our data suggest a possible direct effect of HABP2 on uPA activation and lung cancer progression. Our observations suggest that exploration of HABP2 in non-small cell lung carcinoma merits further study both as a diagnostic and therapeutic option.

The mu opioid receptor: A new target for cancer therapy?

Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as in the perioperative period. Several retrospective studies have suggested that opioid use might promote tumor progression and as a result negatively impact survival in patients with advanced cancer; however, in the absence of appropriate prospective validation, any changes in recommendations for opioid use are not warranted. In this review, the authors present preclinical and clinical data that support their hypothesis that the mu opioid receptor is a potential target for cancer therapy because of its plausible role in tumor progression. The authors also propose the hypothesis that peripheral opioid antagonists such as methylnaltrexone, which reverses the peripheral effects of mu opioids but maintains centrally mediated analgesia and is approved by the US Food and Drug Administration for the treatment of opioid-induced constipation, can be used to target the mu opioid receptor.

Hyaluronan regulation of endothelial barrier function in cancer.

Vascular integrity or the maintenance of blood vessel continuity is a fundamental process regulated by endothelial cell-cell junctions. Defects in endothelial barrier function are an initiating factor in several disease processes including tumor angiogenesis and metastasis. The glycosaminoglycan, hyaluronan (HA), maintains vascular integrity through specific mechanisms including HA-binding protein signaling in caveolin-enriched microdomains, a subset of lipid rafts. Certain disease states, including cancer, increase enzymatic hyaluronidase activity and reactive oxygen species generation, which break down high molecular weight HA (HMW-HA) to low molecular weight fragments (LMW-HA). LMW-HA can activate specific HA-binding proteins during tumor progression to promote disruption of endothelial cell-cell contacts. In contrast, exogenous administration of HMW-HA promotes enhancement of vascular integrity. This review focuses on the roles of HA in regulating angiogenic and metastatic processes based on its size and the HA-binding proteins present. Further, potential therapeutic applications of HMW-HA in treating cancer are discussed.

Transactivation of the receptor-tyrosine kinase ephrin receptor A2 is required for the low molecular weight hyaluronan-mediated angiogenesis that is implicated in tumor progression.

Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, understanding the mechanism(s) by which angiogenesis occurs can have important therapeutic implications in numerous malignancies. We and others have demonstrated that low molecular weight hyaluronan (LMW-HA, ∼2500 Da) promotes endothelial cell (EC) barrier disruption and angiogenesis. However, the mechanism(s) by which this occurs is poorly defined. Our data indicate that treatment of human EC with LMW-HA induced CD44v10 association with the receptor-tyrosine kinase, EphA2, transactivation (tyrosine phosphorylation) of EphA2, and recruitment of the PDZ domain scaffolding protein, PATJ, to the cell periphery. Silencing (siRNA) CD44, EphA2, PATJ, or Dbs (RhoGEF) expression blocked LMW-HA-mediated angiogenesis (EC proliferation, migration, and tubule formation). In addition, silencing EphA2, PATJ, Src, or Dbs expression blocked LMW-HA-mediated RhoA activation. To translate our in vitro findings, we utilized a novel anginex/liposomal targeting of murine angiogenic endothelium with either CD44 or EphA2 siRNA and observed inhibition of LMW-HA-induced angiogenesis in implanted Matrigel plugs. Taken together, these results indicate LMW-HA-mediated transactivation of EphA2 is required for PATJ and Dbs membrane recruitment and subsequent RhoA activation required for angiogenesis. These results suggest that targeting downstream effectors of LMW-HA could be a useful therapeutic intervention for angiogenesis-associated diseases including tumor progression.

GRP78 is a novel receptor initiating a vascular barrier protective response to oxidized phospholipids.

Vascular integrity and the maintenance of blood vessel continuity are fundamental features of the circulatory system maintained through endothelial cell-cell junctions. Defects in the endothelial barrier become an initiating factor in several pathologies, including ischemia/reperfusion, tumor angiogenesis, pulmonary edema, sepsis, and acute lung injury. Better understanding of mechanisms stimulating endothelial barrier enhancement may provide novel therapeutic strategies. We previously reported that oxidized phospholipids (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine [OxPAPC]) promote endothelial cell (EC) barrier enhancement both in vitro and in vivo. This study examines the initiating mechanistic events triggered by OxPAPC to increase vascular integrity. Our data demonstrate that OxPAPC directly binds the cell membrane-localized chaperone protein, GRP78, associated with its cofactor, HTJ-1. OxPAPC binding to plasma membrane-localized GRP78 leads to GRP78 trafficking to caveolin-enriched microdomains (CEMs) on the cell surface and consequent activation of sphingosine 1-phosphate receptor 1, Src and Fyn tyrosine kinases, and Rac1 GTPase, processes essential for cytoskeletal reorganization and EC barrier enhancement. Using animal models of acute lung injury with vascular hyperpermeability, we observed that HTJ-1 knockdown blocked OxPAPC protection from interleukin-6 and ventilator-induced lung injury. Our data indicate for the first time an essential role of GRP78 and HTJ-1 in OxPAPC-mediated CEM dynamics and enhancement of vascular integrity.