Assessing the Contribution Antiretroviral Therapy to Neuronal Damage and Death as a Mediator of Cognitive Decline in HIV-Associated Neurocognitive Disorders

The advent of combination antiretroviral therapy (ART) in 1996 revolutionized the treatment of HIV/AIDS and significantly decreased the incidence of HIV-associated neurocognitive disorders (HAND), a spectrum of HIV-related CNS dysfunctions ranging from mild cognitive deficits to severe dementia. Although the long-term prognosis for ART-treated, HIV-positive individuals continues to improve, the life-expectancy for this population remains 10-30 years less than that of uninfected individuals. Additionally, the clinical and pathologic presentation of HAND has evolved from a subacute, subcortical encephalitic condition, to a prolonged, cortical, neurodegenerative disease with pathological features that resemble those found in Alzheimer Disease (AD). The specific mechanisms driving these pathological changes remain unknown, although emerging evidence suggests that antiretroviral neurotoxicity may be a significant contributing factor. Here, we examined mechanisms by which antiretroviral drugs induce stress in neurons leading to changes in amyloid precursor protein (APP) processing. Utilizing in vitro models of acute ART exposure, we observed that HIV protease inhibitor (PI)-class ART drugs robustly active the unfolded protein response in primary neurons leading to translational de-repression of beta-site cleaving enzyme 1 (BACE1) by phosphorylated eIF2alpha; and augmented amyloidogenic cleave of APP. These results were corroborated in ART-treated, SIV-infected macaques were we saw increased hippocampal expression of BACE1 AND IN HAND patients where we also found similar increases in BACE1 expression in CA1 and CA3 hippocampal regions accompanied by accumulation of intraneuronal oligomeric Abeta;. Finally, we demonstrate that inhibition of neuronal BACE1 activity in vitro protects cells from hydrogen peroxide and antiretroviral drug-mediated toxicity. From this body of work, we conclude that PI-class antiretroviral drugs play a prominent role in stress activation of CNS neurons leading to aberrant changes in APP processing and potentially contributing to neuronal damage and death in HAND. Lastly, we have identified BACE1 as an important adjunctive therapeutic target in the treatment of chronic cognitive decline in ART-medicated, HIV-positive individuals

On-Orbit Validation of a Framework for Spacecraft-Initiated Communication Service Requests with NASA's SCaN Testbed

We design, analyze, and experimentally validate a framework for demand-based allocation of high-performance space communication service in which the user spacecraft itself initiates a request for service. Leveraging machine-to-machine communications, the automated process has potential to improve the responsiveness and efficiency of space network operations. We propose an augmented ground station architecture in which a hemispherical-pattern antenna allows for reception of service requests sent from any user spacecraft within view. A suite of ground-based automation software acts upon these direct-to-Earth requests and allocates access to high-performance service through a ground station or relay satellite in response to immediate user demand. A software-defined radio transceiver, optimized for reception of weak signals from the helical antenna, is presented. Design and testing of signal processing equipment and a software framework to handle service requests is discussed. Preliminary results from on-orbit demonstrations with a testbed onboard the International Space Station are presented to verify feasibility of the concept

Over and over : consumer engagement and turning sports tourists into fans

Travel to consume sport is an increasingly popular and prevalent leisure pursuit (Fourie & Santana-Gallego, 2011; Fredline, 2005). From those who follow Formula 1 across the globe (Henderson et al., 2010), to Tennis’ most ardent fans (Fredline, 2005), consumers probe further afield in order to satisfy their desires for memorable and gratifying travel couched within the domain of their favourite sporting activities. Football consumption, although traditionally aligned along geographical or demographic boundaries (Jones, 2000; Porat, 2010, Conner, 2014), is no different with 800,000 overseas tourists travelling to the UK to experience matches every year (Magowan, 2015). The extent of this travel provides opportunities tangentially for service providers geographically proximate to major finals and international tournament destinations (Daniels, 2005; Prayag et al., 2013), but also at a granular level for football clubs who seek to attract, engage, and maintain access to this lucrative market of affluent consumers who spend over £680m annually (Magowan, 2015). Extant research is focused on the impact of this economic influx (Daniels, 2007; Smith, 2005, Allan et al., 2007), with little consideration given to the tourists themselves, nor the potential to engage with these one-off visitors in order to transform them into more regular sources of income. Therefore, engagement is crucial and, from an operational perspective, the football ‘industry’ has recognised this. The increasing prevalence of social media transfer announcements (Lang, 2017), innovations such as Manchester City’s newly developed glass-tunnel (Hyde 2017), and ‘city-takeover’ events aimed at bridging the gap between player-and-fan, demonstrate how football clubs are adopting unusual strategies in order to encourage consumers to believe that they have ‘behind-the-scenes’ access to the machinations of the clubs that they love. However, these attempts typically focus on local fans, neglecting those who travel to consumer sport on a regular basis. As such, the question remains, how can football clubs engage these tourists and encourage them to become ‘fans’ (through repeat visits and recommendations to friends) and thus benefit financially from their considerable spending power

Negotiation, bargaining, and discounts:generating WoM and local tourism development at the Tabriz bazaar, Iran

This paper examines the effects of negotiation intention, bargaining propensity, and discount satisfaction on word-of-mouth (WoM) behaviours for tourists visiting Tabriz bazaar, Iran. Data from 615-survey respondents highlight that tourists are motivated to conduct WoM behaviour when they are experientially satisfied with the opportunity to negotiate and bargain, and when they are satisfied with the discount they receive. This paper makes theoretical contributions to social exchange theory and presents managerial implications for policy-makers to generate tourism development

Orthopaedic In-Training Examination (OITE) Preparation and Study Habits of Orthopaedic Residents: Revisited

Introduction: The Orthopaedic In-Training Examination (OITE) is well-established as the cornerstone for educational evaluation of orthopaedic surgery residents. Great significance has been placed on the OITE, particularly as it has been found to correlate closely with successful completion of the American Board of Orthopaedic Surgery Part I Exam (ABOS I). Our study correlated different aspects of OITE study preparation, including resources and habits, with OITE performance. Methods: An online survey was created to assess these different aspects and distributed to 163 programs across the United States for distribution to orthopedic residents in each program. Results: Data analysis showed a positive correlation between OITE ranking and greater total hours devoted to studying (r = 0.26, p= 0.0003), earlier start time for exam preparation (r = 0.25, p = 0.0005), orthopaedic journal review (including Journal of Bone and Joint Surgery[r = 0.17, p=0.02] and American Academy of Orthopaedic Surgeons [r = 0.15, p = 0.0475]), review of prior OITE examinations (r = 0.20, p = 0.0054), and use of Orthobullets (r = 0.31, p \u3c 0.0001). 58% of respondents changed their study habits significantly over the course of residency. Most respondents stated they were able to study most effectively on primarily outpatient rotations, as well as pediatrics, sports, and hand orthopaedic rotations. Conclusion: The results of this study may assist residents and residency directors to develop their curriculum and individual study plans to ensure success on the OITE, ABOS I, and, ultimately, their careers as orthopaedic surgeons

The Penicillin for the Emergency Department Outpatient treatment of CELLulitis (PEDOCELL) trial: update to the study protocol and detailed statistical analysis plan (SAP)

Background: Cellulitis is a painful, potentially serious, infectious process of the dermal and subdermal tissues and represents a significant disease burden. The statistical analysis plan (SAP) for the Penicillin for the Emergency Department Outpatient treatment of CELLulitis (PEDOCELL) trial is described here. The PEDOCELL trial is a multicentre, randomised, parallel-arm, double-blinded, non-inferiority clinical trial comparing the efficacy of flucloxacillin (monotherapy) with combination flucloxacillin/phenoxymethylpenicillin (dual therapy) for the outpatient treatment of cellulitis in the emergency department (ED) setting. To prevent outcome reporting bias, selective reporting and data-driven results, the a priori-defined, detailed SAP is presented here. Methods/design: Patients will be randomised to either orally administered flucloxacillin 500 mg four times daily and placebo or orally administered 500 mg of flucloxacillin four times daily and phenoxymethylpenicillin 500 mg four times daily. The trial consists of a 7-day intervention period and a 2-week follow-up period. Study measurements will be taken at four specific time points: at patient enrolment, day 2-3 after enrolment and commencing treatment (early clinical response (ECR) visit), day 8-10 after enrolment (end-of-treatment (EOT) visit) and day 14-21 after enrolment (test-of-cure (TOC) visit). The primary outcome measure is investigator-determined clinical response measured at the TOC visit. The secondary outcomes are as follows: lesion size at ECR, clinical treatment failure at each follow-up visit, adherence and persistence of trial patients with orally administered antibiotic therapy at EOT, health-related quality of life (HRQoL) and pharmacoeconomic assessments. The plan for the presentation and comparison of baseline characteristics and outcomes is described in this paper. Discussion: This trial aims to establish the non-inferiority of orally administered flucloxacillin monotherapy with orally administered flucloxacillin/phenoxymethylpenicillin dual therapy for the ED-directed outpatient treatment of cellulitis. In doing so, this trial will bridge a knowledge gap in this understudied and common condition and will be relevant to clinicians across several different disciplines. The SAP for the PEDOCELL trial was developed a priori in order to minimise analysis bias