Showing papers by "Temple University published in 2015"

Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke

Abstract: Among patients with a proximal vessel occlusion in the anterior circulation, 60 to 80% of patients die within 90 days after stroke onset or do not regain functional independence despite alteplase treatment. We evaluated rapid endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core, a proximal intracranial arterial occlusion, and moderate-to-good collateral circulation. Methods We randomly assigned participants to receive standard care (control group) or standard care plus endovascular treatment with the use of available thrombectomy devices (intervention group). Patients with a proximal intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients with a large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography were excluded. Workflow times were measured against predetermined targets. The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. A proportional odds model was used to calculate the common odds ratio as a measure of the likelihood that the intervention would lead to lower scores on the modified Rankin scale than would control care (shift analysis). Results The trial was stopped early because of efficacy. At 22 centers worldwide, 316 participants were enrolled, of whom 238 received intravenous alteplase (120 in the intervention group and 118 in the control group). In the intervention group, the median time from study CT of the head to first reperfusion was 84 minutes. The rate of functional independence (90-day modified Rankin score of 0 to 2) was increased with the intervention (53.0%, vs. 29.3% in the control group; P<0.001). The primary outcome favored the intervention (common odds ratio, 2.6; 95% confidence interval, 1.7 to 3.8; P<0.001), and the intervention was associated with reduced mortality (10.4%, vs. 19.0% in the control group; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 3.6% of participants in intervention group and 2.7% of participants in control group (P = 0.75). Conclusions Among patients with acute ischemic stroke with a proximal vessel occlusion, a small infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality. (Funded by Covidien and others; ESCAPE ClinicalTrials.gov number, NCT01778335.)

Strongly Constrained and Appropriately Normed Semilocal Density Functional.

Abstract: The ground-state energy, electron density, and related properties of ordinary matter can be computed efficiently when the exchange-correlation energy as a functional of the density is approximated semilocally. We propose the first meta-generalized-gradient approximation (meta-GGA) that is fully constrained, obeying all 17 known exact constraints that a meta-GGA can. It is also exact or nearly exact for a set of "appropriate norms," including rare-gas atoms and nonbonded interactions. This strongly constrained and appropriately normed meta-GGA achieves remarkable accuracy for systems where the exact exchange-correlation hole is localized near its electron, and especially for lattice constants and weak interactions.

Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer

Abstract: BACKGROUND Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. METHODS We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. RESULTS A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. CONCLUSIONS Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.)

Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma

Abstract: Purpose Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1‐derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial. Patients and Methods Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. The primary end point was durable response rate (DRR; objective response lasting continuously 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate. Results Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in 2% of T-VEC‐treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred.

Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial

Abstract: Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. Methods We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF V600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0–1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF V600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. Findings Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45–0·73; p Interpretation These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.

Annual Report to the Nation on the Status of Cancer, 1975-2011, Featuring Incidence of Breast Cancer Subtypes by Race/Ethnicity, Poverty, and State

Abstract: Background: The American Cancer Society (ACS), Centers for Disease Control and Prevention (CDC), National Cancer Institute (NCI), and North American Association of Central Cancer Registries (NAACCR) collaborate annually to produce updated, national cancer statistics. This Annual Report includes a focus on breast cancer incidence by subtype using new, national-level data. Methods: Population-based cancer trends and breast cancer incidence by molecular subtype were calculated. Breast cancer subtypes were classified using tumor biomarkers for hormone receptor (HR) and human growth factor-neu receptor (HER2) expression. Results: Overall cancer incidence decreased for men by 1.8% annually from 2007 to 2011. Rates for women were stable from 1998 to 2011. Within these trends there was racial/ethnic variation, and some sites have increasing rates. Among children, incidence rates continued to increase by 0.8% per year over the past decade while, like adults, mortality declined. Overall mortality has been declining for both men and women since the early 1990’s and for children since the 1970’s. HR+/HER2breast cancers, the subtype with the best prognosis, were the most common for all races/ethnicities with highest rates among non-Hispanic white women, local stage cases, and low poverty areas (92.7, 63.51, and 98.69 per 100 non-Hispanic white women, respectively). HR+/HER2- breast cancer incidence rates were strongly, positively correlated with mammography use, particularly for non-Hispanic white women (Pearson 0.57, two-sided P < .001). Triple-negative breast cancers, the subtype with the worst prognosis, were highest among non-Hispanic black women (27.2 per 100 000 non-Hispanic black women), which is reflected in high rates in southeastern states. Conclusions: Progress continues in reducing the burden of cancer in the United States. There are unique racial/ethnicspecific incidence patterns for breast cancer subtypes; likely because of both biologic and social risk factors, including variation in mammography use. Breast cancer subtype analysis confirms the capacity of cancer registries to adjust national collection standards to produce clinically relevant data based on evolving medical knowledge.

Diffusion of Innovation

Abstract: Diffusion of innovation is the process by which an innovative product spreads within a market. Several models have been proposed to describe this process. According to Rogers' model, the diffusion rate is influenced by product characteristics and diffusion progresses by word of mouth. Moore's crossing-the-chasm model focuses on differences between customer segments, and notes that word-of-mouth may not necessarily flow from early to later adopters. Both Rogers' and Moore's models offer managerial insights and implications. Diffusion models, such as Bass's model of durable goods sales, are often used to predict the rate of diffusion of innovative products into the market. Intriguing questions still remain regarding global diffusion of products. Keywords: diffusion of innovation; product diffusion; barriers to diffusion; diffusion models; crossing the chasm; Bass model; product life cycle

Strongly Constrained and Appropriately Normed Semilocal Density Functional

Abstract: The ground-state energy, electron density, and related properties of ordinary matter can be computed efficiently when the exchange-correlation energy as a functional of the density is approximated semilocally. We propose the first meta-GGA (meta-generalized gradient approximation) that is fully constrained, obeying all 17 known exact constraints that a meta-GGA can. It is also exact or nearly exact for a set of appropriate norms, including rare-gas atoms and nonbonded interactions. This SCAN (strongly constrained and appropriately normed) meta-GGA achieves remarkable accuracy for systems where the exact exchange-correlation hole is localized near its electron, and especially for lattice constants and weak interactions.

The validity of the multi-informant approach to assessing child and adolescent mental health.

Abstract: Child and adolescent patients may display mental health concerns within some contexts and not others (e.g., home vs. school). Thus, understanding the specific contexts in which patients display concerns may assist mental health professionals in tailoring treatments to patients' needs. Consequently, clinical assessments often include reports from multiple informants who vary in the contexts in which they observe patients' behavior (e.g., patients, parents, teachers). Previous meta-analyses indicate that informants' reports correlate at low-to-moderate magnitudes. However, is it valid to interpret low correspondence among reports as indicating that patients display concerns in some contexts and not others? We meta-analyzed 341 studies published between 1989 and 2014 that reported cross-informant correspondence estimates, and observed low-to-moderate correspondence (mean internalizing: r = .25; mean externalizing: r = .30; mean overall: r = .28). Informant pair, mental health domain, and measurement method moderated magnitudes of correspondence. These robust findings have informed the development of concepts for interpreting multi-informant assessments, allowing researchers to draw specific predictions about the incremental and construct validity of these assessments. In turn, we critically evaluated research on the incremental and construct validity of the multi-informant approach to clinical child and adolescent assessment. In so doing, we identify crucial gaps in knowledge for future research, and provide recommendations for "best practices" in using and interpreting multi-informant assessments in clinical work and research. This article has important implications for developing personalized approaches to clinical assessment, with the goal of informing techniques for tailoring treatments to target the specific contexts where patients display concerns. (PsycINFO Database Record

The Validity of the Multi-Informant Approach to Assessing Child and Adolescent Mental Health

Abstract: Child and adolescent patients may display mental health concerns within some contexts and not others (e.g., home vs. school). Thus, understanding the specific contexts in which patients display concerns may assist mental health professionals in tailoring treatments to patients’ needs. Consequently, clinical assessments often include reports from multiple informants who vary in the contexts in which they observe patients’ behavior (e.g., patients, parents, teachers). Previous meta-analyses indicate that informants’ reports correlate at low-to-moderate magnitudes. However, is it valid to interpret low correspondence among reports as indicating that patients display concerns in some contexts and not others? We meta-analyzed 341 studies published between 1989 and 2014 that reported cross-informant correspondence estimates, and observed low-to-moderate correspondence (mean internalizing: r = .25; mean externalizing: r = .30; mean overall: r = .28). Informant pair, mental health domain, and measurement method moderated magnitudes of correspondence. These robust findings have informed the development of concepts for interpreting multi-informant assessments, allowing researchers to draw specific predictions about the incremental and construct validity of these assessments. In turn, we critically evaluated research on the incremental and construct validity of the multi-informant approach to clinical child and adolescent assessment. In so doing, we identify crucial gaps in knowledge for future research, and provide recommendations for “best practices” in using and interpreting multi-informant assessments in clinical work and research. This article has important implications for developing personalized approaches to clinical assessment, with the goal of informing techniques for tailoring treatments to target the specific contexts where patients display concerns.

Tree of Life Reveals Clock-Like Speciation and Diversification

Abstract: Genomic data are rapidly resolving the tree of living species calibrated to time, the timetree of life, which will provide a framework for research in diverse fields of science. Previous analyses of taxonomically restricted timetrees have found a decline in the rate of diversification in many groups of organisms, often attributed to ecological interactions among species. Here, we have synthesized a global timetree of life from 2,274 studies representing 50,632 species and examined the pattern and rate of diversification as well as the timing of speciation. We found that species diversity has been mostly expanding overall and in many smaller groups of species, and that the rate of diversification in eukaryotes has been mostly constant. We also identified, and avoided, potential biases that may have influenced previous analyses of diversification including low levels of taxon sampling, small clade size, and the inclusion of stem branches in clade analyses. We found consistency in time-to-speciation among plants and animals, ∼2 My, as measured by intervals of crown and stem species times. Together, this clock-like change at different levels suggests that speciation and diversification are processes dominated by random events and that adaptive change is largely a separate process.

Encoding Color Information for Visual Tracking: Algorithms and Benchmark

Abstract: While color information is known to provide rich discriminative clues for visual inference, most modern visual trackers limit themselves to the grayscale realm. Despite recent efforts to integrate color in tracking, there is a lack of comprehensive understanding of the role color information can play. In this paper, we attack this problem by conducting a systematic study from both the algorithm and benchmark perspectives. On the algorithm side, we comprehensively encode 10 chromatic models into 16 carefully selected state-of-the-art visual trackers. On the benchmark side, we compile a large set of 128 color sequences with ground truth and challenge factor annotations (e.g., occlusion). A thorough evaluation is conducted by running all the color-encoded trackers, together with two recently proposed color trackers. A further validation is conducted on an RGBD tracking benchmark. The results clearly show the benefit of encoding color information for tracking. We also perform detailed analysis on several issues, including the behavior of various combinations between color model and visual tracker, the degree of difficulty of each sequence for tracking, and how different challenge factors affect the tracking performance. We expect the study to provide the guidance, motivation, and benchmark for future work on encoding color in visual tracking.

Putting Education in “Educational” Apps Lessons From the Science of Learning

Abstract: Children are in the midst of a vast, unplanned experiment, surrounded by digital technologies that were not available but 5 years ago. At the apex of this boom is the introduction of applications ("apps") for tablets and smartphones. However, there is simply not the time, money, or resources available to evaluate each app as it enters the market. Thus, "educational" apps-the number of which, as of January 2015, stood at 80,000 in Apple's App Store (Apple, 2015)-are largely unregulated and untested. This article offers a way to define the potential educational impact of current and future apps. We build upon decades of work on the Science of Learning, which has examined how children learn best. From this work, we abstract a set of principles for two ultimate goals. First, we aim to guide researchers, educators, and designers in evidence-based app development. Second, by creating an evidence-based guide, we hope to set a new standard for evaluating and selecting the most effective existing children's apps. In short, we will show how the design and use of educational apps aligns with known processes of children's learning and development and offer a framework that can be used by parents and designers alike. Apps designed to promote active, engaged, meaningful, and socially interactive learning-four "pillars" of learning-within the context of a supported learning goal are considered educational.

The Challenges of Defining and Measuring Student Engagement in Science

Abstract: Engagement is one of the hottest research topics in the field of educational psychology. Research shows that multifarious benefits occur when students are engaged in their own learning, including increased motivation and achievement. However, there is little agreement on a concrete definition and effective measurement of engagement. This special issue serves to discuss and work toward addressing conceptual and instrumentation issues related to engagement, with particular interest in engagement in the domain of science learning. We start by describing the dimensional perspective of engagement (behavioral, cognitive, emotional, agentic) and suggest a complementary approach that places engagement instrumentation on a continuum. Specifically, we recommend that instrumentation be considered on a “grain-size” continuum that ranges from a person-centered to a context-centered orientation to clarify measurement issues. We then provide a synopsis of the articles included in this special issue and conclude with sug...

Embryonic Stem Cell-Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction

Abstract: Rationale:Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are susceptible to various concerns. Recently, salutary effects of stem cells have been connected to exosome secretion. ESCs have the ability to produce exosomes, however, their effect in the context of the heart is unknown. Objective:Determine the effect of ESC-derived exosome for the repair of ischemic myocardium and whether c-kit+ cardiac progenitor cells (CPCs) function can be enhanced with ESC exosomes. Methods and Results:This study demonstrates that mouse ESC-derived exosomes (mES Ex) possess ability to augment function in infarcted hearts. mES Ex enhanced neovascularization, cardiomyocyte survival, and reduced fibrosis post infarction consistent with resurgence of cardiac proliferative response. Importantly, mES Ex augmented CPC survival, proliferation, and cardiac commitment concurrent with increased c-kit+ CPCs in vivo 8 weeks after in vivo transfer along with formation of bonafide new cardiomyocytes in the isc...

Inside the "Black Box" of sell-side financial analysts

Abstract: Our objective is to penetrate the “black box” of sell-side financial analysts by providing new insights into the inputs analysts use and the incentives they face. We survey 365 analysts and conduct 18 follow-up interviews covering a wide range of topics, including the inputs to analysts’ earnings forecasts and stock recommendations, the value of their industry knowledge, the determinants of their compensation, the career benefits of Institutional Investor All-Star status, and the factors they consider indicative of high-quality earnings. One important finding is that private communication with management is a more useful input to analysts’ earnings forecasts and stock recommendations than their own primary research, recent earnings performance, and recent 10-K and 10-Q reports. Another notable finding is that issuing earnings forecasts and stock recommendations that are well below the consensus often leads to an increase in analysts’ credibility with their investing clients. We conduct cross-sectional analyses that highlight the impact of analyst and brokerage characteristics on analysts’ inputs and incentives. Our findings are relevant to investors, managers, analysts, and academic researchers.

Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer.

Abstract: Purpose BRAF V600E mutation is seen in 5% to 8% of patients with metastatic colorectal cancer (CRC) and is associated with poor prognosis. Vemurafenib, an oral BRAF V600 inhibitor, has pronounced activity in patients with metastatic melanoma, but its activity in patients with BRAF V600E–positive metastatic CRC was unknown. Patients and Methods In this multi-institutional, open-label study, patients with metastatic CRC with BRAF V600 mutations were recruited to an expansion cohort at the previously determined maximum-tolerated dose of 960 mg orally twice a day. Results Twenty-one patients were enrolled, of whom 20 had received at least one prior metastatic chemotherapy regimen. Grade 3 toxicities included keratoacanthomas, rash, fatigue, and arthralgia. Of the 21 patients treated, one patient had a confirmed partial response (5%; 95% CI, 1% to 24%) and seven other patients had stable disease by RECIST criteria. Median progression-free survival was 2.1 months. Patterns of concurrent mutations, microsatellit...

The Contribution of Early Communication Quality to Low-Income Children’s Language Success

Abstract: The disparity in the amount and quality of language that low-income children hear relative to their more-affluent peers is often referred to as the 30-million-word gap. Here, we expand the literature about this disparity by reporting the relative contributions of the quality of early parent-child communication and the quantity of language input in 60 low-income families. Including both successful and struggling language learners from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development, we noted wide variation in the quality of nonverbal and verbal interactions (symbol-infused joint engagement, routines and rituals, fluent and connected communication) at 24 months, which accounted for 27% of the variance in expressive language 1 year later. These indicators of quality were considerably more potent predictors of later language ability than was the quantity of mothers’ words during the interaction or sensitive parenting. Bridging the word gap requires ...

The 'Actually Existing Smart City'

Abstract: This paper grounds the critique of the ‘smart city’ in its historical and geographical context. Adapting Brenner and Theodore’s notion of ‘actually existing neoliberalism’, we suggest a greater attention be paid to the ‘actually existing smart city’, rather than the exceptional or paradigmatic smart cities of Songdo, Masdar and Living PlanIT Valley. Through a closer analysis of cases in Louisville and Philadelphia, we demonstrate the utility of understanding the material effects of these policies in actual cities around the world, with a particular focus on how and from where these policies have arisen, and how they have unevenly impacted the places that have adopted them.

Highly evolvable malaria vectors: The genomes of 16 Anopheles mosquitoes

Abstract: Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts

Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.

Abstract: Aicardi-Goutieres syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutieres syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.

Data and Statistics

Abstract: Statistics is the field of study whose objective is the transformation of data (usually sets of numbers along with identifying characteristics) into information (usually in the form of tables, graphs, and written and verbal summaries) that can inform sound policy decisions. We give examples of applications of statistics to many fields in Chapter 1 Here we focus on the general concepts describing the collection and arrangement of the numbers themselves.

Quaternary Ammonium Compounds: An Antimicrobial Mainstay and Platform for Innovation to Address Bacterial Resistance

Abstract: Quaternary ammonium compounds (QACs) have represented one of the most visible and effective classes of disinfectants for nearly a century. With simple preparation, wide structural variety, and versatile incorporation into consumer products, there have been manifold developments and applications of these structures. Generally operating via disruption of one of the most fundamental structures in bacteria-the cell membrane-leading to cell lysis and bacterial death, the QACs were once thought to be impervious to resistance. Developments over the past decades, however, have shown this to be far from the truth. It is now known that a large family of bacterial genes (generally termed qac genes) encode efflux pumps capable of expelling many QAC structures from bacterial cells, leading to a decrease in susceptibility to QACs; methods of regulation of qac transcription are also understood. Importantly, qac genes can be horizontally transferred via plasmids to other bacteria and are often transmitted alongside other antibiotic-resistant genes; this dual threat represents a significant danger to human health. In this review, both QAC development and QAC resistance are documented, and possible strategies for addressing and overcoming QAC-resistant bacteria are discussed.

Distributed tuning of boundary resources: the case of Apple's iOS service system

Abstract: The digital age has seen the rise of service systems involving highly distributed, heterogeneous, and resource-integrating actors whose relationships are governed by shared institutional logics, standards, and digital technology The cocreation of service within these service systems takes place in the context of a paradoxical tension between the logic of generative and democratic innovations and the logic of infrastructural control Boundary resources play a critical role in managing the tension as a firm that owns the infrastructure can secure its control over the service system while independent firms can participate in the service system In this study, we explore the evolution of boundary resources Drawing on Pickering's (1993) and Barrett et al's (2012) conceptualizations of tuning, the paper seeks to forward our understanding of how heterogeneous actors engage in the tuning of boundary resources within Apple's iOS service system We conduct an embedded case study of Apple's iOS service system with an in-depth analysis of 4,664 blog articles concerned with 30 boundary resources covering 6 distinct themes Our analysis reveals that boundary resources of service systems enabled by digital technology are shaped and reshaped through distributed tuning, which involves cascading actions of accommodations and rejections of a network of heterogeneous actors and artifacts Our study also shows the dualistic role of power in the distributed tuning process

Corporate social performance, analyst stock recommendations, and firm future returns

Abstract: This study posits that security analysts heed corporate social performance information and factor it into their recommendations to general investors. In particular, as corporate social performance is often uncertain and ambiguous to general investors, analysts may serve as the informational pathway connecting corporate social performance to firm stock returns. Thus, we argue that analyst recommendations mediate the relationship between corporate social performance and firm stock returns. On the basis of not only a qualitative study with literature searches and interviews of stock analysts but also a quantitative study with two longitudinal samples of large firms, we find support for these arguments. Our findings uncover an information-based underlying mechanism for the link between corporate social performance and financial performance.

Association Between Bariatric Surgery and Long-term Survival

Abstract: hazard ratio [HR], 1.28 [95% CI, 0.98-1.68]), but significantly lower mortality after 1 to 5 years (HR, 0.45 [95% CI, 0.36-0.56]) and 5 to 14 years (HR, 0.47 [95% CI, 0.39-0.58]). The midterm (>1-5 years) and long-term (>5 years) relationships between surgery and survival were not significantly different across subgroups defined by diabetes diagnosis, sex, and period of surgery. CONCLUSIONS AND RELEVANCE Among obese patients receiving care in the VA health system, those who underwent bariatric surgery compared with matched control patients who did not have surgery had lower all-cause mortality at 5 years and up to 10 years following the procedure. These results provide further evidence for the beneficial relationship between surgery and survival that has been demonstrated in younger, predominantly female populations.

Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury

Abstract: Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase σ (PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.

Predicting Advertising success beyond Traditional Measures: New Insights from Neurophysiological Methods and Market Response Modeling:

Abstract: In the past decade, there has been a tremendous increase in the use of neurophysiological methods to better understand marketing phenomena among academics and practitioners. However, the value of these methods in predicting advertising success remains underresearched. Using a unique experimental protocol to assess responses to 30-second television ads, the authors capture many measures of advertising effectiveness across six commonly used methods (traditional self-reports, implicit measures, eye tracking, biometrics, electroencephalography, and functional magnetic resonance imaging). These measures have been shown to reliably tap into higher-level constructs commonly used in advertising research: attention, affect, memory, and desirability. Using time-series data on sales and gross rating points, the authors attempt to relate individual-level response to television ads in the lab to the ads' aggregate, market-level elasticities. The authors show that functional magnetic resonance imaging measures explain ...

Clinical and Radiologic Disease in Smokers With Normal Spirometry

Abstract: Importance Airflow obstruction on spirometry is universally used to define chronic obstructive pulmonary disease (COPD), and current or former smokers without airflow obstruction may assume that they are disease free. Objective To identify clinical and radiologic evidence of smoking-related disease in a cohort of current and former smokers who did not meet spirometric criteria for COPD, for whom we adopted the discarded label of Global Initiative for Obstructive Lung Disease (GOLD) 0. Design, Setting, and Participants Individuals from the Genetic Epidemiology of COPD (COPDGene) cross-sectional observational study completed spirometry, chest computed tomography (CT) scans, a 6-minute walk, and questionnaires. Participants were recruited from local communities at 21 sites across the United States. The GOLD 0 group (n = 4388) (ratio of forced expiratory volume in the first second of expiration [FEV 1 ] to forced vital capacity >0.7 and FEV 1 ≥80% predicted) from the COPDGene study was compared with a GOLD 1 group (n = 794), COPD groups (n = 3690), and a group of never smokers (n = 108). Recruitment began in January 2008 and ended in July 2011. Main Outcomes and Measures Physical function impairments, respiratory symptoms, CT abnormalities, use of respiratory medications, and reduced respiratory-specific quality of life. Results One or more respiratory-related impairments were found in 54.1% (2375 of 4388) of the GOLD 0 group. The GOLD 0 group had worse quality of life (mean [SD] St George’s Respiratory Questionnaire total score, 17.0 [18.0] vs 3.8 [6.8] for the never smokers; P 1 percent predicted distribution and mean for the GOLD 0 group were lower but still within the normal range for the population. Current smoking was associated with more respiratory symptoms, but former smokers had greater emphysema and gas trapping. Advancing age was associated with smoking cessation and with more CT findings of disease. Individuals with respiratory impairments were more likely to use respiratory medications, and the use of these medications was associated with worse disease. Conclusions and Relevance Lung disease and impairments were common in smokers without spirometric COPD. Based on these results, we project that there are 35 million current and former smokers older than 55 years in the United States who may have unrecognized disease or impairment. The effect of chronic smoking on the lungs and the individual is substantially underestimated when using spirometry alone.