In-Q-Tel

Estimates of the worldwide incidence and mortality from 27 cancers in 2008 have been prepared for 182 countries as part of the GLOBOCAN series published by the International Agency for Research on Cancer. In this article, we present the results for 20 world regions, summarizing the global patterns for the eight most common cancers. Overall, an estimated 12.7 million new cancer cases and 7.6 million cancer deaths occur in 2008, with 56% of new cancer cases and 63% of the cancer deaths occurring in the less developed regions of the world. The most commonly diagnosed cancers worldwide are lung (1.61 million, 12.7% of the total), breast (1.38 million, 10.9%) and colorectal cancers (1.23 million, 9.7%). The most common causes of cancer death are lung cancer (1.38 million, 18.2% of the total), stomach cancer (738,000 deaths, 9.7%) and liver cancer (696,000 deaths, 9.2%). Cancer is neither rare anywhere in the world, nor mainly confined to high-resource countries. Striking differences in the patterns of cancer from region to region are observed.

OBJECTIVE: Although general definitions of the sepsis continuum have been published for adults, no such work has been done for the pediatric population. Physiologic and laboratory variables used to define the systemic inflammatory response syndrome (SIRS) and organ dysfunction require modification for the developmental stages of children. An international panel of 20 experts in sepsis and clinical research from five countries (Canada, France, Netherlands, United Kingdom, and United States) was convened to modify the published adult consensus definitions of infection, sepsis, severe sepsis, septic shock, and organ dysfunction for children. DESIGN: Consensus conference. METHODS: This document describes the issues surrounding consensus on four major questions addressed at the meeting: a) How should the pediatric age groups affected by sepsis be delineated? b) What are the specific definitions of pediatric SIRS, infection, sepsis, severe sepsis, and septic shock? c) What are the specific definitions of pediatric organ failure and the validity of pediatric organ failure scores? d) What are the appropriate study populations and study end points required to successfully conduct clinical trials in pediatric sepsis? Five subgroups first met separately and then together to evaluate the following areas: signs and symptoms of sepsis, cell markers, cytokines, microbiological data, and coagulation variables. All conference participants approved the final draft of the proceedings of the meeting. RESULTS: Conference attendees modified the current criteria used to define SIRS and sepsis in adults to incorporate pediatric physiologic variables appropriate for the following subcategories of children: newborn, neonate, infant, child, and adolescent. In addition, the SIRS definition was modified so that either criteria for fever or white blood count had to be met. We also defined various organ dysfunction categories, severe sepsis, and septic shock specifically for children. Although no firm conclusion was made regarding a single appropriate study end point, a novel nonmortality end point, organ failure-free days, was considered optimal for pediatric clinical trials given the relatively low incidence of mortality in pediatric sepsis compared with adult populations. CONCLUSION: We modified the adult SIRS criteria for children. In addition, we revised definitions of severe sepsis and septic shock for the pediatric population. Our goal is for these first-generation pediatric definitions and criteria to facilitate the performance of successful clinical studies in children with sepsis.

Abstract This study extends the developing body of literature on supply chain integration (SCI), which is the degree to which a manufacturer strategically collaborates with its supply chain partners and collaboratively manages intra‐ and inter‐organizational processes, in order to achieve effective and efficient flows of products and services, information, money and decisions, to provide maximum value to the customer. The previous research is inconsistent in its findings about the relationship between SCI and performance. We attribute this inconsistency to incomplete definitions of SCI, in particular, the tendency to focus on customer and supplier integration only, excluding the important central link of internal integration. We study the relationship between three dimensions of SCI, operational and business performance, from both a contingency and a configuration perspective. In applying the contingency approach, hierarchical regression was used to determine the impact of individual SCI dimensions (customer, supplier and internal integration) and their interactions on performance. In the configuration approach, cluster analysis was used to develop patterns of SCI, which were analyzed in terms of SCI strength and balance. Analysis of variance was used to examine the relationship between SCI pattern and performance. The findings of both the contingency and configuration approach indicated that SCI was related to both operational and business performance. Furthermore, the results indicated that internal and customer integration were more strongly related to improving performance than supplier integration.

Abstract Globalization results in both pressure and drivers for Chinese enterprises to improve their environmental performance. As a developing country, China has to balance economic and environmental performance. Green supply chain management (GSCM) is emerging to be an important approach for Chinese enterprises to improve performance, possibly on both these dimensions. Using empirical results from 186 respondents on GSCM practice in Chinese manufacturing enterprises, we examine the relationships between GSCM practice and environmental and economic performance. Using moderated hierarchical regression analysis, we evaluate the general relationships between specific GSCM practices and performance. We then investigate how two primary types of management operations philosophies, quality management and just‐in‐time (or lean) manufacturing principles, influence the relationship between GSCM practices and performance. Significant findings were determined for a number of relationships. Managerial implications are also identified.

Abstract Rising international cooperation, vertical disintegration, along with a focus on core activities have led to the notion that firms are links in a networked supply chain. This novel perspective has created the challenge of designing and managing a network of interdependent relationships developed and fostered through strategic collaboration. Although research interests in supply chain management (SCM) are growing, no research has been directed towards a systematic development of SCM instruments. This study identifies and consolidates various supply chain initiatives and factors to develop key SCM constructs conducive to advancing the field. To this end, we analyzed over 400 articles and synthesized the large, fragmented body of work dispersed across many disciplines. The result of this study, through successive stages of measurement analysis and refinement, is a set of reliable, valid, and unidimensional measurements that can be subsequently used in different contexts to refine or extend conceptualization and measurements or to test various theoretical models, paving the way for theory building in SCM.

Abstract Our research addresses the confusion and inconsistency associated with “lean production.” We attempt to clarify the semantic confusion surrounding lean production by conducting an extensive literature review using a historical evolutionary perspective in tracing its main components. We identify a key set of measurement items by charting the linkages between measurement instruments that have been used to measure its various components from the past literature, and using a rigorous, two‐stage empirical method and data from a large set of manufacturing firms, we narrow the list of items selected to represent lean production to 48 items, empirically identifying 10 underlying components. In doing so, we map the operational space corresponding to conceptual space surrounding lean production. Configuration theory provides the theoretical underpinnings and helps to explain the synergistic relationships among its underlying components.

Abstract. Assembly rules provide one possible unifying framework for community ecology. Given a species pool, and measured traits for each species, the objective is to specify which traits (and therefore which subset of species) will occur in a particular environment. Because the problem primarily involves traits and environments, answers should be generalizable to systems with very different taxonomic composition. In this context, the environment functions like a filter (or sieve) removing all species lacking specified combinations of traits. In this way, assembly rules are a community level analogue of natural selection. Response rules follow a similar process except that they transform a vector of species abundances to a new vector using the same information. Examples already exist from a range of habitats, scales, and kinds of organisms.

Abstract In much of the current literature on supply chain management, supply networks are recognized as a system. In this paper, we take this observation to the next level by arguing the need to recognize supply networks as a complex adaptive system (CAS). We propose that many supply networks emerge rather than result from purposeful design by a singular entity. Most supply chain management literature emphasizes negative feedback for purposes of control; however, the emergent patterns in a supply network can much better be managed through positive feedback, which allows for autonomous action. Imposing too much control detracts from innovation and flexibility; conversely, allowing too much emergence can undermine managerial predictability and work routines. Therefore, when managing supply networks, managers must appropriately balance how much to control and how much to let emerge.

UNLABELLED: Periprosthetic joint infection is one of the most challenging complications of joint arthroplasty. We identified current risk factors of periprosthetic joint infection after modern joint arthroplasty, and determined the incidence and timing of periprosthetic joint infection. We reviewed prospectively collected data from our database on 9245 patients undergoing primary hip or knee arthroplasty between January 2001 and April 2006. Periprosthetic joint infections developed in 63 patients (0.7%). Sixty-five percent of periprosthetic joint infections developed within the first year of the index arthroplasty. The infecting organism was isolated in 57 of 63 cases (91%). The most common organisms identified were Staphylococcus aureus and Staphylococcus epidermidis. We identified the following independent predictors for periprosthetic joint infection: higher American Society of Anesthesiologists score, morbid obesity, bilateral arthroplasty, knee arthroplasty, allogenic transfusion, postoperative atrial fibrillation, myocardial infarction, urinary tract infection, and longer hospitalization. This study confirmed some previously implicated factors and identified new variables that predispose patients to periprosthetic joint infection. LEVEL OF EVIDENCE: Level II, prognostic study.

Abstract There has been an increase in interest towards corporate activities aimed at reducing or eliminating the waste created during the production, use and/or disposal of the firm’s products. Prior research has focused on the need for such activities, while current research tries to identify those components that encourage or discourage such activities. As a result of the introduction of ISO 14001, attention has turned to corporate environmental management systems (EMS). The underlying assumption is that such a system is critical to a firm’s ability to reduce waste and pollution while simultaneously improving overall performance. This study evaluates this assumption. Drawing on data provided by a survey of North American managers, their attitudes toward EMS and ISO 14001, this study assesses the relative effects of having a formal but uncertified EMS compared to having a formal, certified system. The results strongly demonstrate that firms in possession of a formal EMS perceive impacts well beyond pollution abatement and see a critical positive impact on many dimensions of operations performance. The results also show that firms having gone through EMS certification experience a greater impact on performance than do firms that have not certified their EMS. Additionally, experience with these systems over time has a greater impact on the selection and use of environmental options. These results demonstrate the need for further investigation into EMS, the environmental options a firm chooses, and the direct and indirect relationships between these systems and performance.

New studies of the treatment of neuropathic pain have increased the need for an updated review of randomized, double-blind, placebo-controlled trials to support an evidence based algorithm to treat neuropathic pain conditions. Available studies were identified using a MEDLINE and EMBASE search. One hundred and five studies were included. Numbers needed to treat (NNT) and numbers needed to harm (NNH) were used to compare efficacy and safety of the treatments in different neuropathic pain syndromes. The quality of each trial was assessed. Tricyclic antidepressants and the anticonvulsants gabapentin and pregabalin were the most frequently studied drug classes. In peripheral neuropathic pain, the lowest NNT was for tricyclic antidepressants, followed by opioids and the anticonvulsants gabapentin and pregabalin. For central neuropathic pain there is limited data. NNT and NNH are currently the best way to assess relative efficacy and safety, but the need for dichotomous data, which may have to be estimated retrospectively for old trials, and the methodological complexity of pooling data from small cross-over and large parallel group trials, remain as limitations.

Angiogenesis, a critical driver of tumor development, is controlled by interconnected signaling pathways. Vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature. Regorafenib (BAY 73-4506), a novel oral multikinase inhibitor, potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays. Furthermore, regorafenib inhibits additional angiogenic kinases (VEGFR1/3, platelet-derived growth factor receptor-β and fibroblast growth factor receptor 1) and the mutant oncogenic kinases KIT, RET and B-RAF. The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast-enhanced magnetic resonance imaging. Regorafenib administered once orally at 10 mg/kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts. In a daily (qd)×4 dosing study, the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition (TGI). A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd×5 dosing at 10 and 30 mg/kg. Regorafenib exhibited potent dose-dependent TGI in various preclinical human xenograft models in mice, with tumor shrinkages observed in breast MDA-MB-231 and renal 786-O carcinoma models. Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki-67 and phosphorylated extracellular regulated kinases 1/2. These data demonstrate that regorafenib is a well-tolerated, orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies.

Abstract This study investigates the relationships between U.S. buying firms’ supplier development efforts, commitment, social capital accumulation with key suppliers, and buying firm performance. We identify linkages between supply chain management research on supplier development and organization theory research on social capital to consider how buying firm commitment to a long‐term relationship, cognitive capital (goals and values), structural capital (information sharing, supplier evaluation, supplier development), and relational capital (length of relationship, buyer dependency, supplier dependency) are related to buying firm performance improvements (cost improvements, and quality, delivery, flexibility improvements). Analysis of buying firms from the U.S. automotive and electronics industries provides support for the theory that buyer commitment and social capital accumulation with key suppliers can improve buying company performance. Moreover, the findings suggest that the relationships of structural and relational capital vary depending on the type of performance improvement considered.

Abstract In many industries, firms are seeking to cut concept to customer development time, improve quality, reduce the cost of new products and facilitate the smooth launch of new products. Prior research has indicated that the integration of material suppliers into the new product development (NPD) cycle can provide substantial benefits towards achieving these goals. This involvement may range from simple consultation with suppliers on design ideas to making suppliers fully responsible for the design of components or systems they will supply. Moreover, suppliers may be involved at different stages of the new product development process. Early supplier involvement is a key coordinating process in supply chain design, product design and process design. Several important questions regarding supplier involvement in new product development remain unanswered. Specifically, we look at the issue of what managerial practices affect new product development team effectiveness when suppliers are to be involved. We also consider whether these factors differ depending on when the supplier is to be involved and what level of responsibility is to be given to the supplier. Finally, we examine whether supplier involvement in new product development can produce significant improvements in financial returns and/or product design performance. We test these proposed relationships using survey data collected from a group of global organizations and find support for the relationships based on the results of a multiple regression analysis.

Abstract Today’s marketplace is characterized by intense competitive pressures as well as high levels of turbulence and uncertainty. Organizations require agility in their supply chains to provide superior value as well as to manage disruption risks and ensure uninterrupted service to customers. Thus the cultivation of agility is approached as a risk management initiative that enables a firm to respond rapidly to marketplace changes, as well as anticipated and actual disruptions in the supply chain. Agility is of value for both risk mitigation and response. This research investigates the impact of two cultural antecedents, market orientation and learning orientation, and three organizational practices, all aimed at augmenting the supply chain agility of a firm. A firm’s supply chain agility (FSCA) is defined as the capability of the firm, both internally and in conjunction with its key suppliers and customers, to adapt or respond in a speedy manner to marketplace changes as well as to potential and actual disruptions, contributing to the agility of the extended supply chain. The two cultural antecedents of market and learning orientations are posited to affect the organizational practices of internal integration, external integration with key suppliers and customers, and external flexibility, and eventually impact the firm’s supply chain agility. The external flexibility elements considered are volume and mix flexibility. In addition, the specific organizational characteristics and practices exhibited by firms with high levels of supply chain agility are also investigated. Through the use of the structural equation modeling technique, partial least squares (PLS), it is shown that strong linkages exist among the cultural antecedents, the three organizational practices considered, and the firm’s supply chain agility. All three organizational practices, internal integration, external integration with key suppliers and customers, and external flexibility are shown to have significant positive impact on the firm’s supply chain agility. Market orientation is shown to significantly impact both internal and external supply chain integration, along with the two elements of external flexibility. Learning orientation, on the other hand, is shown to have a strong and direct influence only on the level of internal integration. Firms with high levels of external integration are also shown to have high levels of internal integration, consistent with past research. Internal and external integration efforts are also seen to be unrelated to the levels of external flexibility present. The results serve to establish a set of key drivers for augmenting supply chain agility as a risk management initiative.

This study describes the development and validation of a novel tool for identifying patients in whom neuropathic mechanisms dominate their pain experience. The Leeds assessment of neuropathic symptoms and signs (LANSS) Pain Scale is based on analysis of sensory description and bedside examination of sensory dysfunction, and provides immediate information in clinical settings. It was developed in two populations of chronic pain patients. In the first (n = 60), the use of sensory descriptors and questions were compared in patients with nociceptive and neuropathic pain, combined with an assessment of sensory function. This data was used to derive a seven item pain scale, consisting of grouped sensory description and sensory examination with a simple scoring system. The LANSS Pain Scale was validated in a second group of patients (n = 40) by assessing discriminant ability, internal consistency and agreement by independent raters. Clinical and research applications of the LANSS Pain Scale are discussed.

Abstract This paper estimates the shareholder wealth affects of supply chain glitches that resulted in production or shipment delays. The results are based on a sample of 519 glitches announcements made during 1989–2000. Shareholder wealth affects are estimated by computing the abnormal stock returns (actual returns adjusted for industry and market‐wide influences) around the date when information about glitches is publicly announced. Supply chain glitch announcements are associated with an abnormal decrease in shareholder value of 10.28%. Regression analysis is used to identify factors that influence the direction and magnitude of the change in the stock market’s reaction to glitches. We find that larger firms experience a less negative market reaction, and firms with higher growth prospects experience a more negative reaction. There is no difference between the stock market’s reaction to pre‐1995 and post‐1995 glitches, suggesting that the market has always viewed glitches unfavorably. Capital structure (debt–equity ratio) has little impact on the stock market’s reaction to glitches. We also provide descriptive results on how sources of responsibility and reasons for glitches affect shareholder wealth.

Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the number of infiltrating tumor-activated macrophages, which was highest in the more aggressive tumor subtypes. These findings indicate that human breast cancer progression and aggression, collagen linearization and stromal stiffening are linked and implicate tissue inflammation and TGF beta.

Pooled data on human papillomavirus (HPV) type distribution in invasive cervical cancer (ICC) can help to predict the potential impact of HPV type-specific vaccines and screening tests, and to understand the carcinogenicity of HPV types. We performed a meta-analysis of HPV type-specific prevalence data published from 1990 to 2010, including a total of 243 studies and 30,848 ICC. The proportion of ICC associated with HPV16 and/or 18 (HPV16/18) was between 70 and 76% in all world regions except Asia. In Western/Central Asia, 82% of ICC was HPV16/18-associated compared to only 68% in Eastern Asia. The 12 most common HPV types identified, in order of decreasing prevalence, were HPV16 (57%), 18 (16%), 58, 33, 45, 31, 52, 35, 59, 39, 51 and 56. The prevalence of other types, phylogenetically related to those above, ranged from <0.1% for HPV85 to 0.6% for HPV68. Overall HPV prevalence increased significantly from 85.9% in studies published from 1990 to 1999 to 92.9% in studies published from 2006 to 2010. Prevalence increases were large for multiple infections (from 4.0 to 15.7%) and for HPV16 (from 51.8 to 60.0%, including HPV16 alone or in multiple infections). Smaller but significant increases in prevalence were also seen for HPV39, 53 and 58. A large amount of recently published data has improved the understanding of the contribution of a broad range of HPV types to ICC in different world regions. However, estimating the fraction of ICC attributable to different types is increasingly complicated by the detection of multiple HPV infections in ICC.

Autism is a severe developmental disorder marked by a triad of deficits, including impairments in reciprocal social interaction, delays in early language and communication, and the presence of restrictive, repetitive and stereotyped behaviors. In this review, it is argued that the search for the neurobiological bases of the autism spectrum disorders should focus on the social deficits, as they alone are specific to autism and they are likely to be most informative with respect to modeling the pathophysiology of the disorder. Many recent studies have documented the difficulties persons with an autism spectrum disorder have accurately perceiving facial identity and facial expressions. This behavioral literature on face perception abnormalities in autism is reviewed and integrated with the functional magnetic resonance imaging (fMRI) literature in this area, and a heuristic model of the pathophysiology of autism is presented. This model posits an early developmental failure in autism involving the amygdala, with a cascading influence on the development of cortical areas that mediate social perception in the visual domain, specifically the fusiform "face area" of the ventral temporal lobe. Moreover, there are now some provocative data to suggest that visual perceptual areas of the ventral temporal pathway are also involved in important ways in representations of the semantic attributes of people, social knowledge and social cognition. Social perception and social cognition are postulated as normally linked during development such that growth in social perceptual skills during childhood provides important scaffolding for social skill development. It is argued that the development of face perception and social cognitive skills are supported by the amygdala-fusiform system, and that deficits in this network are instrumental in causing autism.