Multiple Contributors Research Articles

The Impact of Endovascular Rescue Therapy on the Clinical and Radiological Outcome After Aneurysmal Subarachnoid Hemorrhage: A Safe and Effective Treatment Option for Hemodynamically Relevant Vasospasm?

ObjectiveCerebral vasospasm (CVS) represents one of the multiple contributors to delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH). Especially the management of CVS, refractory to medical treatment, is a challenging task during the acute phase after aSAH. Endovascular rescue therapies (ERT), such as medical and mechanical dilation, are possible treatment options on an individual basis. However, data about the influence on the patients' functional outcomes are limited. This study aims to assess the impact of ERT on the long-term functional outcome in aSAH-patients with refractory CVS.MethodsWe performed a retrospective analysis of aSAH patients treated between 2012 and 2018. CVS was considered refractory, if it persisted despite oral/intravenous nimodipine application and induced hypertension. The decision to perform ETR was made on an individual basis, according to the detection of “tissue at risk” on computed tomography perfusion (CTP) scans and CVS on computed tomography angiography (CTA) or digital subtraction angiography (DSA). The functional outcome was assessed according to the modified Rankin scale (mRS) 3 months after the ictus, whereas an mRS ≤ 2 was considered as a good outcome.ResultsA total of 268 patients were included. Out of these, 205 patients (76.5%) were treated without ERT (group 1) and 63 patients (23.5%) with ERT (group 2). In 20 patients (31.8%) balloon dilatation was performed, in 23 patients (36.5%) intra-arterial nimodipine injection alone, and in 20 patients (31.8%) both procedures were combined. Considering only the patient group with DCI, the patients who were treated with ERT had a significantly better outcome compared to the patients without ERT (Mann–Whitney test, p = 0.02).ConclusionEndovascular rescue therapies resulted in a significantly better functional outcome in patients with DCI compared to the patient group treated without ETR. CTP and CTA-based identification of “tissue at risk” might be a reliable tool for patient selection for performing ERT.

Targeting Glucose Transport Proteins for Diabetes Management: Regulatory Roles of Food-Derived Compounds.

With the rapid rise in prevalence, diabetes mellitus is one of the leading causes of mortality worldwide. Impaired cellular glucose transport is a major contributor to diabetes progression and, thus, an important target for treatment. Functional foods are a rich source of antidiabetic agents. These compounds target multiple physiological contributors to diabetes with lower risk for side effects. This perspective highlights recent advances in food-derived compounds that regulate the gene expression or activity of glucose transport proteins (SGLT1, SGLT2, GLUT1, GLUT2, and GLUT4) and provides insights for future research on targeting the transporters as a promising antidiabetic mechanism of nutraceutical compounds.

Economics and Engineering: Institutions, Practices, and Cultures ed. by Pedro Garcia Duarte and Yann Giraud

Reviewed by: Economics and Engineering: Institutions, Practices, and Cultures ed. by Pedro Garcia Duarte and Yann Giraud Matthew Wisnioski (bio) Economics and Engineering: Institutions, Practices, and Cultures Edited by Pedro Garcia Duarte and Yann Giraud. Special issue, History of Political Economy 52, no. 6 ( 2020). Pp. 332. As economists' role in managing society has grown, Nobel Prize winners and science studies scholars alike have noted that economics resembles engineering. The association is sometimes pejorative; economists, like engineers, claim objectivity but serve corporate interests. At other times it is triumphant; economists, like engineers, craft intricate and beautiful systems. But it is most often a recognition of pragmatism; economists, like engineers, intervene in complex ever-changing environments. In this essential collection, Pedro Garcia Duarte and Yann Giraud assemble an international team that moves beyond metaphor to historicize the economics-engineering nexus. The volume is the result of a conference at Duke University's Center for the History of Political Economy (HOPE). It is available as a journal special issue and low-cost paperback. Its essays can be accessed individually, but the consistently excellent contributions deserve to be read as a whole. The volume's main focus is the United States, the center of post–World War II "technocratic economics," though a few chapters document European developments. The book's three parts are on engineer-economist relationships in institutions, the exchange of tools, and national contexts. Economics and Engineering does dual work as specialist exploration and accelerated introduction. Its core audience is historians of economics. Most essays investigate the flow of engineering into economics and assume knowledge of economic theory, institutions, and actors. Amy Sue Bix notably studies the reverse flow, showing how Depression-era engineering educators developed "technonomics" curricula to train engineers for management. In some of the best essays, boundaries between economics and engineering disappear and get reconfigured in new ways. Thomas Staple-ford, for instance, follows Malcolm Rorty from engineering student to [End Page 523] AT&T lineman, then "commercial engineer" to creator of the National Bureau of Economic Research (NBER). He shows that on AT&T's path to monopoly, it faced problems of quantification at the intersection of technology, management, regulation, and prediction that defied categories. Once the system stabilized, however, Rorty's innovations became the purview of economics rather than engineering. The volume offers insights into three themes in the history of technology. First, it revisits the formation and tensions of "engineering science" through an economics lens. Beatrice Cherrier and Aurélien Saïdi survey a century of "joint institutional redevelopment" at Stanford University between economics, engineering, and business amid battles over institutional identity. Multiple contributors show how hybrid activity, backed by military-industrial funding, troubled distinctions between academic and applied research. Hybridity fueled organizational innovations like joint-appointments, new fields like operations research, and philosophies such as design science while elevating the giants of technocratic economics, including Kenneth Arrow and Herbert Simon. Meanwhile in the Soviet Union, as Ivan Boldyrev explores, control engineers developed a similar interdisciplinary culture, forwarding general choice theory under state censorship. Second, Economics and Engineering spotlights the profound transformations wrought by computing, which remade both economics and engineering. Judy L. Klein explores how experts identified similarities between Keynesian feedback loops and control engineering, importing cybernetic concepts into economic decision-making. Chung-Tang Cheng similarly follows the career of econometrician Guy H. Orcutt, whose microsimulation techniques for "socioeconomic engineering" expanded alongside computing power from War on Poverty programs to strategic planning today. Third, the volume reiterates how experts used quantification in the coevolution of technical infrastructures and social orders. In electric and communications systems, devices, people, and social processes were abstracted, bringing economists and engineers into common cause. System-building and maintaining served as fertile ground for new concepts and tools. A couple of papers by my colleague Daniel Breslau and Guillaume Yon map how American and French technocrats navigated competing demands between producers and users, operators and businessmen, and socialists and capitalists, serving practical ends that also generated innovations in economic theory. Economics and Engineering emphasizes co-evolution over difference and divergence. It offers few clues as to why economics gained prestige and power while engineers were less successful in their technocratic...

Post-Mortem CT Delivers Fast and Accurate Injury Identification in Trauma Patients.

Accurate and timely injury identification is critical but difficult to achieve in trauma patients who die shortly after arrival to the hospital. Autopsy has historically been used to detect injuries, but few undergo formal autopsy. This study investigates the utility of post-mortem computed tomography (PMCT) for injury identification in a diverse trauma population. Cross-sectional study of adult trauma patients who died within 24 hours of arrival to a Level I trauma center were included. Among patients with PMCT, injury severity score (ISS) and number of injuries (NOI) were calculated either from physical exam alone (pre-PMCT) or exam and imaging (post-PMCT). ISS and NOI before and after PMCT were compared. A cause of death analysis was performed for patients who underwent comprehensive (ie, head, neck, and torso) PMCT. Non-parametric repeated measures tests were used, as appropriate. 7.3% (N = 28) of patients received PMCT. Compared to pre-PMCT, median ISS (21 vs 3.5) and NOI (5 vs 2) were greater post-PMCT (P < .001, respectively). Autopsy rate was 13.2% overall; 82.5% of autopsies were due to a penetrating mechanism, and median time to autopsy reporting was 38.5 days. Among 17 patients who received comprehensive PMCT, 64.7% had a single cause of death identified, and the remaining were classified as either multiple potential contributors or unknown. PMCT is a readily available method to identify injuries in trauma patients who expire shortly upon presentation. Given the low autopsy rate for blunt trauma and delay in reporting, PMCT is an important adjunct for trauma providers.

The Quintessential Quincunx: A model for health care delivery.

Health care delivery is based on teamwork, in which active involvement of multiple contributors is required. The quadruple of Atreya underscores the need for physician, patient, drug and attendant to work in unison with each other. The concept of person centered, or person-centered care reminds us to keep the person living with disease or disability, at the centre of our work. Effective communication is essential for efficient team work. We merge these thoughts to create a Quintessential Quincunx as a model for health care delivery. The rubric keeps the person living with disease or disability at the centre of a square, the four angles of which are the physician, other members of the health care team, drugs/therapeutic modalities, and care givers.

AMALGAMATION OF INDIRECT GAMIFICATION INTO DEVELOPMENT AND OPERATIONS (DEVOPS) COURSE TEACHING

The work investigates the effect of indirect Gamification in Development and Operations (DevOps) Course teaching. The software development team consisting of multiple contributors coordinates in the collaborative work environment to achieve specific predefined goals in a regulated and controlled fashion. In DevOps Course, the Installation and configuration of the various software tools are useful in the context of application development. To teach DevOps Tools precisely to achieve the learning outcome is a skilled task for a trainer. From the perspective of the learner, the learning environment has to be encouraging and exciting. Pedagogical techniques and ICT tools play an essential role during the knowledge transfer process. The motivation and reward to the Student are essential in achieving the learning outcomes of the Course. The author used the third-party Competition as an indirect Gamification technique to achieve the learning outcomes of the Course. The author encouraged the students to participate in the Hacktoberfest Competition to use the practical skills learned in the Course. The Under Graduate (UG) and Post Graduate (PG) Students have gone through the regular sessions of DevOps. For the participation purpose, both groups of students communicated on one platform. The students who succeeded faster during the GitHub Pull Request (PR) submission shared their experiences with other participants. The PG students participated 68.75% higher than UG students. Minimum of four PR submissions on GitHub and acceptance by the repository maintainer are the task completion criteria. The active participation of the small number of UG students became a motivational factor for the PG students. The Gaussian distribution on the marks obtained by the experimental group shows the absence of outliers. The research shows that the effectiveness of indirect Gamification depends on the age group, level, course content, and learning environment. The participation of a faculty member in the Competition during the learning activity boosts the desire of the Student to complete the task. The experimental group of 15 Students has outperformed in terms of the marks obtained compared to the control group of 52 students.

A Comprehensive Review: Computational Models for Obstructive Sleep Apnea Detection in Biomedical Applications.

Obstructive sleep apnea (OSA) is a sleep disorder characterized by periodic episodes of partial or complete upper airway obstruction caused by narrowing or collapse of the pharyngeal airway despite ongoing breathing efforts during sleep. Fall in the blood oxygen saturation and cortical arousals are prompted by this reduction in the airflow which lasts for at least 10 seconds. Impaired labor performance, debilitated quality of life, excessive daytime sleepiness, high snoring, and tiredness even after a whole night's sleep are the primary symptoms of OSA. In due course, the long-standing contributions of OSA culminate in hypertension, arrhythmia, cerebrovascular disease, and heart failure. The traditional diagnostic approach of OSA is the laboratory-based polysomnography (PSG) overnight sleep study, which is a tedious and labor-intensive process that exaggerates the discomfort to the patient. With the advent of computer-aided diagnosis (CAD), automatic detection of OSA has gained increasing interest among researchers in the area of sleep disorders as it influences both diagnostic and therapeutic decisions. The research literature on sleep apnea published during the last decade has been surveyed, focusing on the varied screening approaches accustomed to identifying OSA events and the developmental knowledge offered by multiple contributors from the software perspective. The current study presents an overview of the pathophysiology of OSA, the detection methods, physiological signals related to OSA, the different preprocessing, feature extraction, feature selection, and classification techniques employed for the detection and classification of OSA. Consequently, the research challenges and research gaps in the diagnosis of OSA are identified, critically analyzed, and presented in the best possible light.

Central Nervous System Systemic Lupus Erythematosus: Pathophysiologic, Clinical, and Imaging Features

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiple immunologic abnormalities and has the potential to involve the central nervous system (CNS). The prevalence of SLE seems to be growing, possibly because of earlier diagnosis and improved survival; however, the associated mortality is still high. The mortality is associated with disease-related risk factors such as lupus disease activity, young age, and organ damage or with antiphospholipid syndrome (APS). Neuropsychiatric SLE (NPSLE), which is caused by SLE-related CNS involvement, comprises a broad range of neurologic and psychiatric manifestations with varying severity, which can make this disease indistinguishable from other conditions that are unrelated to SLE. No unifying pathophysiology has been found in the etiology of NPSLE, suggesting that this condition has multiple contributors such as various immune effectors and the brain-intrinsic neuroimmune interfaces that are breached by the immune effectors. The postulated neuroimmune interfaces include the blood-brain barrier, blood-cerebrospinal fluid barrier, meningeal barrier, and glymphatic system. On the basis of the immunologic, pathologic, and imaging features of NPSLE, the underlying pathophysiology can be classified as vasculitis and vasculopathy, APS, demyelinating syndrome, or autoimmune antibody-mediated encephalitis. Each pathophysiology has different imaging characteristics, although the imaging and pathophysiologic features may overlap. Moreover, there are complications due to the immunocompromised status caused by SLE per se or by SLE treatment. Radiologists and clinicians should become familiar with the underlying mechanisms, radiologic findings, and complications of NPSLE, as this information may aid in the diagnosis and treatment of NPSLE. Online supplemental material is available for this article.©RSNA, 2022.

Assigning Credits to Multiple Contributors of a Scholarly Output Using Arithmetic Series

As the academic world is focusing deeply on quantification of contributions brought about by researchers, it becomes imperative to assign true and deserving credits to the individuals. Modern-day databases do not account for the number of contributors or sequence number of a contributor in the contributors’ list while assigning credit of a scholarly output. As such, every contributor of a researcher-studded output gets the same credit as does the sole contributor of a single-author output. The current work presents a mathematical method to assign credits based on the number of contributors, the sequence of the contributor in the contributors list (if so required), and the magnitude of commendation achieved per unit time by the scholarly output. The concept of arithmetic series is utilized to materialize the idea of true assignment of credits. A case study is also provided to elaborate working of the mathematical method.

Relationship building in pediatric research recruitment: Insights from qualitative interviews with research staff.

Clinical research staff play a critical role in recruiting families for pediatric research, but their views are not well described. We aimed to describe how pediatric research staff build trusting research relationships with patients and their families. We interviewed research staff at one pediatric research institution and its affiliated academic medical center between November 2020 and February 2021. Staff were eligible if they conducted participant recruitment, consent, and/or enrollment for clinical research. We developed our semi-structured interview guide based on a framework for trusting researcher-community partnerships. We interviewed 28 research staff, with a median age of 28 years (range 22-50) and a median of 5 years of experience (range 1-29). Interviewees identified factors relevant to relationship building across three levels: the individual staff member, the relational interaction with the family, and the institutional or other structural backdrop. Individual factors included how staff developed recruitment skills, their perceived roles, and their personal motivations. Relational factors spanned four stages of recruitment: before the approach, forming an initial connection with a family, building the connection, and following up. Structural factors were related to access and diversity, clinical interactions, and the COVID-19 pandemic. Research staff discussed tensions and supports with various actors, challenges with the integration of research and clinical care, the importance of voluntariness for building trust, and multiple contributors to inequities in research. These findings reveal the importance of ensuring research staff have a voice in institutional policies and are supported to advocate for patients and families.

The Author and the Authors of the 'Vita Ædwardi Regis:' Women's Literary Culture and Digital Humanities

Commissioned by Queen Edith in the 1060s, the Vita Ædwardi Regis (hereafter VER) has recently received substantial scholarly attention, including focus on identification of the author of this putatively anonymous text; the quest for authorial identification has until now proceeded with the assumption of sole authorship of the text. Lexomics, an open-access vocabulary analysis tool, adds digital strategies to more traditional literary and historical analyses; the Lexomic evidence indicates that the VER is a composite text built by multiple contributors under the direction of the queen. Not only did Edith's patronage cause the VER to be written, but her knowledge, and her personal and political interests, shaped the Life's content. Hers was the active, guiding intellect behind the entire text, and in two passages the VER appears not only to communicate the queen's intentions but also to preserve her voice. If any one person is to be identified as the 'author' of the VER, therefore, it is Edith, guiding a team of writers and scribes to tell her story.

Multi-Level Socioenvironmental Contributors to Childhood Asthma in New York City: a Cluster Analysis

Childhood asthma exacerbation remains the leading cause of pediatric emergency department visits and hospitalizations and disproportionately affects Latinx and Black children, compared to non-Latinx White children in NYC. Environmental exposures and socioeconomic factors may jointly contribute to childhood asthma exacerbations; however, they are often studied separately. To better investigate the multiple contributors to disparities in childhood asthma, we compiled data on various individual and neighborhood level socioeconomic and environmental factors, including education, race/ethnicity, income disparities, gentrification, housing characteristics, built environment, and structural racism, from the NYC Department of Health’s KIDS 2017 survey and the US Census’ American Community Survey. We applied cluster analysis and logistic regression to first identify the predominant patterns of social and environmental factors experienced by children in NYC and then estimate whether children experiencing specific patterns are more likely to experience asthma exacerbations. We found that housing and built environment characteristics, such as density and age of buildings, were the predominant features to differentiate the socio-environmental patterns observed in New York City. Children living in neighborhoods with greater proportions of rental housing, high-density buildings, and older buildings were more likely to experience asthma exacerbations than other children. These findings add to the literature about childhood asthma in urban environments, and can assist efforts to target actionable policies and practices that promote health equity related to childhood asthma.

Unraveling nonlinear and interaction effects of various determinants on bus gaseous emissions

Urban transit buses equipped with large-displacement engines operate on circular routes several times throughout the day, emitting large amounts of environmentally hazardous exhaust. Hence, understanding the intricate associations between bus emissions and multiple contributors is beneficial for creating sustainable transportation systems, while previous studies focusing on statistical methods fail to unravel them. This paper innovatively leverages the bagged decision tree approach to delineate such complex relationships based on the data collected from CNG-fueled and diesel-powered buses. Relative importance indicates that velocity appears to be the primary factor and is therefore selected as the research objective. Results suggest that the effects of different contributors on bus emissions present nonlinear patterns. More specifically, the influence of speed on CO, CO2, and NOx exhaust generally reveals an increasing-stabilizing tendency while that of HC represents a decreasing-stabilizing mode. Besides, the phenomenon of synergies between determinants is also prevalent, for instance, buses within high-speed and large-slope conditions tend to produce more emissions. These findings can provide nuanced guidance for policy-making and bus route planning issues in consideration of environmental protection and pollution mitigation.

The Florentine Codex: An Encyclopedia of the Nahua World in Sixteenth-Century Mexico

The Florentine Codex: An Encyclopedia of the Nahua World in Sixteenth-Century Mexico

Contributors to and consequences of burnout among clinical genetic counselors in the United States.

Prior research has found that many genetic counselors (GCs) experience burnout. Studies of other clinicians have demonstrated that burnout can have significant detrimental consequences for clinicians, patients, and the healthcare system. We sought to explore the prevalence of, contributors to, and consequences of burnout among GCs. We performed a secondary data analysis of baseline data from Me‐GC, a randomized controlled trial of meditation for GCs. We applied a systems model of burnout proposed by the National Academy of Medicine (NAM), which depicts burnout arising from a combination of contributors that include both work system and individual mediating factors, and then leading to consequences. Validated self‐report scales were used to measure burnout and most contributors and consequences. Female and white GCs were over‐represented in our sample. Over half (57.2%) of the 397 participants had Professional Fulfillment Index scores indicative of burnout. Multiple potential contributors were associated with burnout, consistent with its known multifactorial nature. Among work system factors, higher levels of burnout were associated with insufficient administrative support, lack of autonomy, and not feeling valued by non‐GC colleagues. Individual mediating factors associated with greater burnout included higher levels of anxiety, depression, and stress. Participants with lower levels of burnout reported greater mindfulness, resilience, and use of professional self‐care behaviors. Among variables categorized as consequences, higher levels of burnout were associated with lower levels of empathy, counseling alliance, and positive unconditional regard, as well as higher reactive distress, and a greater desire to reduce the amount of time spent on clinical care. Given the prevalence and potential consequences of burnout observed here, it is imperative that the field take steps to mitigate burnout risk.

Neurocognitive Impairment After Hematopoietic Stem Cell Transplant for Hematologic Malignancies: Phenotype and Mechanisms

Hematopoietic stem cell transplant (HSCT) plays a central role in the treatment of hematologic cancers. With the increasing survival of patients after HSCT, survivorship issues experienced by this population have become an important outcome. Cognitive impairment is an established sequela of HSCT, with studies to date establishing its presence, associated risk factors, and clinical phenotype. There are multiple potential contributors to cognitive impairment after HSCT. Efforts are ongoing to further characterize its clinical phenotype, associated biomarkers, and biologic underpinnings. A fundamental knowledge of post-HSCT cognitive impairment is of value for all clinicians who interface with this population, and further academic efforts are needed to more fully understand the impact of this cancer treatment on brain health. IMPLICATIONS FOR PRACTICE: As survival outcomes after hematopoietic stem cell transplant (HSCT) improve, an awareness of the post-treatment challenges faced by this population has become central to its care. HSCT can have a sustained and broad impact on brain health, causing cognitive dysfunction, fatigue, disturbed mood, and sleep. In affected patients, autonomy, return to work, relationships, and quality of life may all be affected. A fundamental fluency in this area is important for clinicians interfacing with HSCT survivors, facilitating the identification and management of cognitive dysfunction and concurrent symptom clusters, and stimulating interest in these sequelae as areas for future clinical research.

Conclusion: Strategic Policy in the Indian Ocean Region

Conclusion:Strategic Policy in the Indian Ocean Region Arzan Tarapore (bio) As the United States and China compete for primacy in the Indo-Pacific, the Indian Ocean remains largely free of heavily militarized disputes comparable to those in the western Pacific Ocean that could flare into war. As a result, policymakers in Washington, Canberra, and other like-minded capitals have pursued approaches to an Indian Ocean defined by relatively low strategic risk. They expect that over the long term a steadily rising India, supported by an engaged United States and other partners, will be able to manage the challenge posed by China's growing influence. In other words, these states assume stable strategic preferences among the major powers and a largely favorable balance of power in the Indian Ocean. As this alternative futures project has illustrated, however, those assumptions are contestable, and plausible disruptive scenarios would carry enormous security implications for all concerned actors. If existing assumptions are disputable, how can strategic policy hedge against them? The various contributions to this roundtable have revealed a wide range of policy concerns arising from the future scenarios—but several common themes have also emerged. For example, the prospect of a closer U.S.-India partnership in the Indian Ocean may be a key driver of a more assertive Chinese presence, but it may also be an important bulwark against Chinese influence. Either way, multiple contributors regarded such strategic partnerships as a particularly consequential variable in future policy settings. This concluding essay outlines five key findings of this alternative futures project, synthesized from the scenarios and the roundtable discussion of policy implications. Together, they represent a checklist of sorts—considerations that policymakers in Washington, Canberra, and like-minded capitals should deliberately and explicitly weigh to maximize the effectiveness and resilience of strategic policy toward the Indian Ocean region. [End Page 51] Understand the Relative—and the Absolute—Importance of the Indian Ocean For all the major security actors in the Indian Ocean region, the ocean has traditionally been of secondary importance, as they face greater or more urgent threats elsewhere. As the scenarios showed, this is certainly true of India, which has always devoted a far greater share of defense resources to managing continental threats from Pakistan and China. It is also true of Australia, which traditionally prioritizes the adjacent areas of Southeast Asia and the South Pacific, although its 2020 Defence Strategic Update did reconceptualize the country's immediate region to include the "northeast Indian Ocean."1 As Zack Cooper argues in this roundtable, this is also true of the United States, which—despite its newfound focus on the expanded contiguous region of the Indo-Pacific—recognizes that the first and second island chains in the western Pacific must dominate its military planning. And as Hu Bo argues in this roundtable, this is true of China, which similarly regards its adjacent waters as its area of primary strategic interest. This recognition carries several policy implications. First, secondary importance is not the same as negligible importance. For all these states, the Indian Ocean is home to critical energy and trade routes. The security of sea lanes, if nothing else, demands a certain minimum level of strategic attention. Second, given those interests, regional states should creatively search for cost-effective policy instruments to build and maintain influence, rather than basing plans on unrealistic expectations of lavish future resource allocations. Third, the relative importance of the Indian Ocean may rise if there is a sudden shift in the balance of power—especially if the United States sharply reduces its presence or China accelerates its expansion. In that case, the Indian Ocean will assume added strategic salience. Regional states such as India, Australia, and their partners will accordingly face a sharper dilemma between competing strategic priorities. If history is any guide, they will only reluctantly and belatedly adjust their policies in the wake of reduced U.S. commitments. Manage Ongoing Uncertainty about Chinese Plans The rapid expansion of Chinese military interests and capabilities has brought with it uncertainty over China's future plans. In just a decade, China went from having a negligible expeditionary capability to maintaining a [End Page 52] permanent naval task force and...

Systematic Review on Healthcare and Societal Costs of Tinnitus.

Tinnitus disability is a heterogeneous and complex condition, affecting more than 10% and compromising the quality of life of 2% of the population, with multiple contributors, often unknown, and enigmatic pathophysiology. The available treatment options are unsatisfactory, as they can, at best, reduce tinnitus severity, but not eliminate its perception. Given the spread of tinnitus and the lack of a standardized treatment, it is crucial to understand the economic burden of this condition. We conducted a systematic review of the literature on PubMed/MEDLINE, Embase, the Cochrane Database of Systematic Reviews (CDSR) and Google Scholar, in order to identify all the articles published on the economic burden of tinnitus before 1 April 2021 (PROSPERO—International prospective register of systematic reviews—No: CRD42020180438). Out of 273 articles identified through our search strategy, only five articles from studies conducted in the United States of America (USA), the Netherlands and the United Kingdom (UK) provided data on tinnitus’s economic costs. Three studies provided mean annual estimates per patient ranging between EUR 1544 and EUR 3429 for healthcare costs, between EUR 69 and EUR 115 for patient and family costs and between EUR 2565 and EUR 3702 for indirect costs, including productivity loss. The other two studies reported an annual mean cost of EUR 564 per patient for tinnitus-related clinical visits, and total costs of EUR 1388 and EUR 3725 for patients treated with a sound generator and Neuromonics Tinnitus Treatment, respectively. Our comprehensive review shows a gap in the knowledge about the economic burden of tinnitus on healthcare systems, patients and society. The few available studies show considerable expenses due to healthcare and indirect costs, while out-of-pocket costs appear to be less financially burdensome. Comprehensive health economic evaluations are needed to fill the gaps in current knowledge, using a unified method with reliable and standardized tools.

Identification of Functional Determinants of Response and Resistance to CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy of Chronic Lymphocytic Leukemia

The adoptive transfer of autologous T cells genetically modified to express a chimeric antigen receptor (CAR) targeting CD19 has shown remarkable activity for patients with B cell malignancies. Using a second- generation CAR signaling through 4-1BB/CD3ζ, (CTL019), over 90% of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) will achieve complete remission (Maude, S.L. et. al. New England Journal of Medicine, 2014). Similar therapy can induce long-term remissions for R/R chronic lymphocytic leukemia (CLL), but only in a subset of patients (Porter, D.L. et. al. Science Transl. Medicine, 2015). The ability to identify individuals most likely to respond will have a dramatic impact on patient selection and provide critical information that may allow immune modification to enhance responses using this approach. We here present updated analyses and functional validation of our previously reported biomarker profiles of CTL019 cells in CLL (Fraietta, J.A. et. al., Blood, 2016). Retrospective samples of clinically manufactured CAR T cells from forty-one patients with advanced, heavily pre-treated and high-risk CLL were evaluated for functional determinants of potency. Transcriptomic analysis of CTL019 cells from subjects who had complete responses (CR) to this therapy revealed enrichment in early memory T cells and IL-6/STAT3 gene signatures, while T cells from non-responding (NR) patients were enriched in genes belonging to known pathways of terminal differentiation, exhaustion, apoptosis and glycolysis. Accordingly, CAR-stimulated T cells from NR relative to CR patents demonstrated an increased uptake of a glucose analog; inhibition of glycolysis using 2-deoxy-D-glucose resulted in the generation of early memory CAR T cells in culture. Furthermore, CTL019 cells that were highly functional in CLL patients had increased levels of phosphorylated STAT3 (pSTAT3) upon activation compared to CAR T cells from NR patients with poor anti-tumor activity. These data were concordant with the highly significant direct correlation between serum IL-6 and the degree of CTL019 proliferative capacity in patients. Increasing pSTAT3 activity by addition of exogenous IL-6 to culture media elevated the absolute numbers of CAR T cells following repeated stimulation with CD19-expressing tumor targets, while pSTAT3 inhibition diminished CTL019 cell growth.Single-cell proteomic analysis of CAR-stimulated CTL019 cells from CLL patients revealed marked heterogeneity in cytokine secretions and enhanced polyfunctional strength in CAR T cells from responding over non-responding patients. There were multiple contributors to CTL019 cell polyfunctional strength, including granzyme B, MIP-1α, IFNg, TNFα, IL-5, IL-8, MIP-1β and perforin. We next performed deep immunophenotyping on the above pre-infusion CAR T cells and, through unbiased computational analysis of the flow cytometry data, defined a single subset (CD8+CD27-PD1-) that segregated CRs from NRs. Importantly, we noted a highly significant association between the likelihood of having a response to CTL019 therapy and the infusion of CTL019 products containing a high dose of CD8+PD1-CD27+ CAR T cells. To confirm that this cell population drives the response to CTL019 therapy, we depleted it from CR patient CTL019 cells and observed loss of tumor control and decreased survival in leukemia-bearing NOD scid gamma (NSG) mice compared to animals treated with subject-matched unmanipulated cellular products. These findings, coupled with our previous results, reveal a functionally relevant T lymphocyte population that can serve as a novel predictive biomarker and a framework for future mechanistic dissection to enhance the efficacy of CAR T cell therapies. DisclosuresFraietta:Novartis: Patents & Royalties: patents, Research Funding. Lacey:Novartis: Research Funding; Genentech: Honoraria. Orlando:Novartis: Employment. Pruteanu:Novartis Pharmaceuticals Corporation: Employment. OConnor:Novartis: Research Funding. Chen:Novartis: Research Funding. Davis:Novartis: Research Funding. Young:Novartis: Research Funding. Levine:Brammer Bio: Consultancy; Tmunity Therapeutics: Equity Ownership, Research Funding; GE Healthcare: Consultancy; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding. Siegel:Novartis: Research Funding. Zhou:IsoPlexis: Employment, Equity Ownership. Paczkowski:IsoPlexis: Employment, Equity Ownership. Mackay:IsoPlexis: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Speakers Bureau. Brogdon:Novartis: Employment. Bitter:Novartis: Employment. Porter:Incyte: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Servier: Honoraria, Other: Travel reimbursement; Genentech/Roche: Employment, Other: Family member employment, stock ownship - family member; Immunovative Therapies: Other: Member DSMB. June:Tmunity Therapeutics: Equity Ownership, Research Funding; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Patents & Royalties, Research Funding. Melenhorst:Novartis: Research Funding.

Pathology of the Bearded Dragon (Pogona vitticeps): a Retrospective Analysis of 36 Cases

The bearded dragon (Pogona vitticeps) is a common species in the pet reptile trade and in zoological collections. Despite this, only a few reviews detailing common causes of mortality have been published. The goal of this retrospective study was to compile information related to the presence and prevalence of various diseases in bearded dragons in several private and one zoological collection. Findings from 36 animals, necropsied over a 20-year period were categorized on the basis of the cause of death or euthanasia and the organ system affected. Multiple contributors to death were identified in a subset of animals (n=12; 33.33%) and were counted in more than one category. The most common contributors to death by category were inflammatory (infectious or non-infectious) diseases (n=25; 69.44%), followed by chronic/degenerative diseases (n=17; 47.22%). Diseases or conditions that were systemic, or affected the hepatobiliary system, were the most commonly implicated in death. The most frequent histological findings included hepatic fatty change, renal tubular epithelial pigmentation and the presence of faveolar hyaline-like material. Although Chi square testing did not reveal an association between these common findings and comorbidities, a statistically significant association was found between chronic/degenerative causes of death and renal tubular epithelial pigment. Chi square testing of categorical variables, including contributors to death, primary organ(s) affected, sex, age class and institution, identified statistically significant associations between males and chronic/degenerative disease (P=0.043) and inflammatory contributors to death and private collection animals (P=0.039). Death due to inflammatory contributors was significantly higher in the 1-5-year-old and >5-year-old age classes (P=0.02).