Showing papers by "Dartmouth College published in 2016"

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

SQUIRE 2.0 (Standards for QUality Improvement Reporting Excellence): revised publication guidelines from a detailed consensus process

Abstract: Since the publication of Standards for QUality Improvement Reporting Excellence (SQUIRE 1.0) guidelines in 2008, the science of the field has advanced considerably. In this manuscript, we describe the development of SQUIRE 2.0 and its key components. We undertook the revision between 2012 and 2015 using (1) semistructured interviews and focus groups to evaluate SQUIRE 1.0 plus feedback from an international steering group, (2) two face-to-face consensus meetings to develop interim drafts and (3) pilot testing with authors and a public comment period. SQUIRE 2.0 emphasises the reporting of three key components of systematic efforts to improve the quality, value and safety of healthcare: the use of formal and informal theory in planning, implementing and evaluating improvement work; the context in which the work is done and the study of the intervention(s). SQUIRE 2.0 is intended for reporting the range of methods used to improve healthcare, recognising that they can be complex and multidimensional. It provides common ground to share these discoveries in the scholarly literature (http://www.squire-statement.org).

Generation and Evaluation of a Cortical Area Parcellation from Resting-State Correlations

Abstract: The cortical surface is organized into a large number of cortical areas; however, these areas have not been comprehensively mapped in the human. Abrupt transitions in resting-state functional connectivity (RSFC) patterns can noninvasively identify locations of putative borders between cortical areas (RSFC-boundary mapping; Cohen et al. 2008). Here we describe a technique for using RSFC-boundary maps to define parcels that represent putative cortical areas. These parcels had highly homogenous RSFC patterns, indicating that they contained one unique RSFC signal; furthermore, the parcels were much more homogenous than a null model matched for parcel size when tested in two separate datasets. Several alternative parcellation schemes were tested this way, and no other parcellation was as homogenous as or had as large a difference compared with its null model. The boundary map-derived parcellation contained parcels that overlapped with architectonic mapping of areas 17, 2, 3, and 4. These parcels had a network structure similar to the known network structure of the brain, and their connectivity patterns were reliable across individual subjects. These observations suggest that RSFC-boundary map-derived parcels provide information about the location and extent of human cortical areas. A parcellation generated using this method is available at http://www.nil.wustl.edu/labs/petersen/Resources.html.

The brain imaging data structure, a format for organizing and describing outputs of neuroimaging experiments.

Abstract: The development of magnetic resonance imaging (MRI) techniques has defined modern neuroimaging. Since its inception, tens of thousands of studies using techniques such as functional MRI and diffusion weighted imaging have allowed for the non-invasive study of the brain. Despite the fact that MRI is routinely used to obtain data for neuroscience research, there has been no widely adopted standard for organizing and describing the data collected in an imaging experiment. This renders sharing and reusing data (within or between labs) difficult if not impossible and unnecessarily complicates the application of automatic pipelines and quality assurance protocols. To solve this problem, we have developed the Brain Imaging Data Structure (BIDS), a standard for organizing and describing MRI datasets. The BIDS standard uses file formats compatible with existing software, unifies the majority of practices already common in the field, and captures the metadata necessary for most common data processing operations.

Dynamic capabilities and organizational agility: Risk, uncertainty, and strategy in the innovation economy

Abstract: “Organizational agility” is often treated as an immutable quality, implying that firms need to be in a constant state of transformation. However, this ignores that such transformations, while often essential, come at a cost. They are not always necessary, and may not even be possible. This article explores agility at a more fundamental level and relates it more specifically to dynamic capabilities. It demonstrates that it is first essential to understand deep uncertainty, which is ubiquitous in the innovation economy. Uncertainty is very different from risk, which can be managed using traditional tools and approaches. Strong dynamic capabilities are necessary for fostering the organizational agility necessary to address deep uncertainty, such as that generated by innovation and the associated dynamic competition. This article explores the mechanisms by which managers may calibrate the required level of organizational agility, deliver it cost effectively, and relate it to strategy.

Allocation of Physician Time in Ambulatory Practice: A Time and Motion Study in 4 Specialties

Abstract: Over the past decade, ambulatory care in the United States has been subject to dramatic pressures to cut costs, meet regulations, and transition to electronic health records. Many physicians expres...

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Abstract: Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013

Abstract: Objective To quantify the dose-response associations between total physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events. Design Systematic review and Bayesian dose-response meta-analysis. Data sources PubMed and Embase from 1980 to 27 February 2016, and references from relevant systematic reviews. Data from the Study on Global AGEing and Adult Health conducted in China, Ghana, India, Mexico, Russia, and South Africa from 2007 to 2010 and the US National Health and Nutrition Examination Surveys from 1999 to 2011 were used to map domain specific physical activity (reported in included studies) to total activity. Eligibility criteria for selecting studies Prospective cohort studies examining the associations between physical activity (any domain) and at least one of the five diseases studied. Results 174 articles were identified: 35 for breast cancer, 19 for colon cancer, 55 for diabetes, 43 for ischemic heart disease, and 26 for ischemic stroke (some articles included multiple outcomes). Although higher levels of total physical activity were significantly associated with lower risk for all outcomes, major gains occurred at lower levels of activity (up to 3000-4000 metabolic equivalent (MET) minutes/week). For example, individuals with a total activity level of 600 MET minutes/week (the minimum recommended level) had a 2% lower risk of diabetes compared with those reporting no physical activity. An increase from 600 to 3600 MET minutes/week reduced the risk by an additional 19%. The same amount of increase yielded much smaller returns at higher levels of activity: an increase of total activity from 9000 to 12 000 MET minutes/week reduced the risk of diabetes by only 0.6%. Compared with insufficiently active individuals (total activity <600 MET minutes/week), the risk reduction for those in the highly active category (≥8000 MET minutes/week) was 14% (relative risk 0.863, 95% uncertainty interval 0.829 to 0.900) for breast cancer; 21% (0.789, 0.735 to 0.850) for colon cancer; 28% (0.722, 0.678 to 0.768) for diabetes; 25% (0.754, 0.704 to 0.809) for ischemic heart disease; and 26% (0.736, 0.659 to 0.811) for ischemic stroke. Conclusions People who achieve total physical activity levels several times higher than the current recommended minimum level have a significant reduction in the risk of the five diseases studied. More studies with detailed quantification of total physical activity will help to find more precise relative risk estimates for different levels of activity.

Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis

Abstract: Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

The Primary Care PTSD Screen for DSM-5 (PC-PTSD-5): Development and Evaluation Within a Veteran Primary Care Sample

Abstract: BACKGROUND Posttraumatic Stress Disorder (PTSD) is associated with increased health care utilization, medical morbidity, and tobacco and alcohol use. Consequently, screening for PTSD has become increasingly common in primary care clinics, especially in Veteran healthcare settings where trauma exposure among patients is common.

Pre-fusion structure of a human coronavirus spike protein

Abstract: A 4.0 A resolution cryo-electron microscopy structure of the pre-fusion form of the trimeric spike from the human coronavirus HKU1 provides insight into how the spike protein mediates host-cell attachment and membrane fusion. Coronaviruses are responsible for respiratory infections worldwide, many of them mild, but also including severe pneumonia and the recent SARS and MERS outbreaks. The entry of coronaviruses into cells is mediated by the virus glycoprotein spike trimer, which contains the receptor-binding domain, as well as membrane fusion domains. Two papers published in this issue of Nature provide high-resolution (4A) cryo-electron microscopy structures of pre-fusion coronavirus spike trimers. David Veesler and colleagues studied the trimer from murine hepatitis virus; Andrew Ward and colleagues used the human betacoronavirus HKU1, a cause of mild respiratory disease. The structures reveal mechanistic insights into the viral fusion process and architectural similarities to paramyxovirus F proteins, suggesting that these fusion proteins may have evolved from a distant common ancestor. HKU1 is a human betacoronavirus that causes mild yet prevalent respiratory disease1, and is related to the zoonotic SARS2 and MERS3 betacoronaviruses, which have high fatality rates and pandemic potential. Cell tropism and host range is determined in part by the coronavirus spike (S) protein4, which binds cellular receptors and mediates membrane fusion. As the largest known class I fusion protein, its size and extensive glycosylation have hindered structural studies of the full ectodomain, thus preventing a molecular understanding of its function and limiting development of effective interventions. Here we present the 4.0 A resolution structure of the trimeric HKU1 S protein determined using single-particle cryo-electron microscopy. In the pre-fusion conformation, the receptor-binding subunits, S1, rest above the fusion-mediating subunits, S2, preventing their conformational rearrangement. Surprisingly, the S1 C-terminal domains are interdigitated and form extensive quaternary interactions that occlude surfaces known in other coronaviruses to bind protein receptors. These features, along with the location of the two protease sites known to be important for coronavirus entry, provide a structural basis to support a model of membrane fusion mediated by progressive S protein destabilization through receptor binding and proteolytic cleavage. These studies should also serve as a foundation for the structure-based design of betacoronavirus vaccine immunogens.

The future of mental health care: peer-to-peer support and social media

Abstract: Aims: People with serious mental illness are increasingly turning to popular social media, including Facebook, Twitter or YouTube, to share their illness experiences or seek advice from others with similar health conditions. This emerging form of unsolicited communication among self-forming online communities of patients and individuals with diverse health concerns is referred to as peer-to-peer support. We offer a perspective on how online peer-to-peer connections among people with serious mental illness could advance efforts to promote mental and physical wellbeing in this group. Methods: In this commentary, we take the perspective that when an individual with serious mental illness decides to connect with similar others online it represents a critical point in their illness experience. We propose a conceptual model to illustrate how online peer-to-peer connections may afford opportunities for individuals with serious mental illness to challenge stigma, increase consumer activation and access online interventions for mental and physical wellbeing. Results: People with serious mental illness report benefits from interacting with peers online from greater social connectedness, feelings of group belonging and by sharing personal stories and strategies for coping with day-to-day challenges of living with a mental illness. Within online communities, individuals with serious mental illness could challenge stigma through personal empowerment and providing hope. By learning from peers online, these individuals may gain insight about important health care decisions, which could promote mental health care seeking behaviours. These individuals could also access interventions for mental and physical wellbeing delivered through social media that could incorporate mutual support between peers, help promote treatment engagement and reach a wider demographic. Unforeseen risks may include exposure to misleading information, facing hostile or derogatory comments from others, or feeling more uncertain about one's health condition. However, given the evidence to date, the benefits of online peer-to-peer support appear to outweigh the potential risks. Conclusion: Future research must explore these opportunities to support and empower people with serious mental illness through online peer networks while carefully considering potential risks that may arise from online peer-to-peer interactions. Efforts will also need to address methodological challenges in the form of evaluating interventions delivered through social media and collecting objective mental and physical health outcome measures online. A key challenge will be to determine whether skills learned from peers in online networks translate into tangible and meaningful improvements in recovery, employment, or mental and physical wellbeing in the offline world.

Stein Variational Gradient Descent: A General Purpose Bayesian Inference Algorithm

Abstract: We propose a general purpose variational inference algorithm that forms a natural counterpart of gradient descent for optimization. Our method iteratively transports a set of particles to match the target distribution, by applying a form of functional gradient descent that minimizes the KL divergence. Empirical studies are performed on various real world models and datasets, on which our method is competitive with existing state-of-the-art methods. The derivation of our method is based on a new theoretical result that connects the derivative of KL divergence under smooth transforms with Stein's identity and a recently proposed kernelized Stein discrepancy, which is of independent interest.

Potentiating the antitumour response of CD8 + T cells by modulating cholesterol metabolism

Abstract: CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

Prices, Markups and Trade Reform

Abstract: This paper examines how prices, markups and marginal costs respond to trade liberalizaƟon. We develop a framework to esƟmate markups from producƟon data with mulƟ-product firms. This approach does not require assumpƟons on the market structure or demand curves faced by firms, nor assumpƟons on how firms allocate their inputs across products. We exploit quanƟty and price informaƟon to disentangle markups from quanƟty-based producƟvity, and then compute marginal costs by dividing observed prices by the esƟmated markups. We use India’s trade liberalizaƟon episode to examine how firms adjust these performance measures. Not surprisingly, we find that trade liberalizaƟon lowers factory-gate prices and that output tariff declines have the expected pro-compeƟƟve effects. However, the price declines are small relaƟve to the declines in marginal costs, which fall predominantly because of the input tariff liberalizaƟon. The reason is that firms offset their reducƟons in marginal costs by raising markups. Our results demonstrate substanƟal heterogeneity and variability in markups across firms and Ɵme and suggest that producers benefited relaƟve to consumers, at least immediately aŌer the reforms. Long-term gains to consumers may be higher to the extent that higher firm profits lead to new product introducƟons and growth. Indeed, firms with larger increases in markups had a higher propensity to introduce new products during this period.

Dissecting Anomalies with a Five-Factor Model

Abstract: A five-factor model that adds profitability (RMW) and investment (CMA) factors to the three-factor model of Fama and French (1993) suggests a shared story for several average-return anomalies. Specifically, positive exposures to RMW and CMA (stock returns that behave like those of profitable firms that invest conservatively) capture the high average returns associated with low market β, share repurchases, and low stock return volatility. Conversely, negative RMW and CMA slopes (like those of relatively unprofitable firms that invest aggressively) help explain the low average stock returns associated with high β, large share issues, and highly volatile returns.

Persister formation in Staphylococcus aureus is associated with ATP depletion.

Abstract: Persisters are dormant phenotypic variants of bacterial cells that are tolerant to killing by antibiotics(1). Persisters are associated with chronic infections and antibiotic treatment failure(1-3). In Escherichia coli, toxin-antitoxin modules have been linked to persister formation(4-6). The mechanism of persister formation in Gram-positive bacteria is unknown. Staphylococcus aureus is a major human pathogen, responsible for a variety of chronic and relapsing infections such as osteomyelitis, endocarditis and infections of implanted devices. Deleting toxin-antitoxin modules in S. aureus did not affect the level of persisters. Here, we show that S. aureus persisters are produced due to a stochastic entrance into the stationary phase accompanied by a drop in intracellular adenosine triphosphate. Cells expressing stationary-state markers are present throughout the growth phase, and increase in frequency with cell density. Cell sorting revealed that the expression of stationary markers is associated with a 100-1,000-fold increase in the likelihood of survival to antibiotic challenge. The adenosine triphosphate level of the cell is predictive of bactericidal antibiotic efficacy and explains bacterial tolerance to antibiotics.

Barriers to healthcare for transgender individuals.

Abstract: Purpose of reviewTransgender persons suffer significant health disparities and may require medical intervention as part of their care. The purpose of this manuscript is to briefly review the literature characterizing barriers to healthcare for transgender individuals and to propose research prioriti

CoSMoMVPA: Multi-Modal Multivariate Pattern Analysis of Neuroimaging Data in Matlab/GNU Octave.

Abstract: Recent years have seen an increase in the popularity of multivariate pattern (MVP) analysis of functional magnetic resonance (fMRI) data, and, to a much lesser extent, magneto- and electro-encephalography (M/EEG) data. We present CoSMoMVPA, a lightweight MVPA (MVP analysis) toolbox implemented in the intersection of the Matlab and GNU Octave languages, that treats both fMRI and M/EEG data as first-class citizens. CoSMoMVPA supports all state-of-the-art MVP analysis techniques, including searchlight analyses, classification, correlations, representational similarity analysis, and the time generalization method. These can be used to address both data-driven and hypothesis-driven questions about neural organization and representations, both within and across: space, time, frequency bands, neuroimaging modalities, individuals, and species. It uses a uniform data representation of fMRI data in the volume or on the surface, and of M/EEG data at the sensor and source level. Through various external toolboxes, it directly supports reading and writing a variety of fMRI and M/EEG neuroimaging formats, and, where applicable, can convert between them. As a result, it can be integrated readily in existing pipelines and used with existing preprocessed datasets. CoSMoMVPA overloads the traditional volumetric searchlight concept to support neighborhoods for M/EEG and surface-based fMRI data, which supports localization of multivariate effects of interest across space, time, and frequency dimensions. CoSMoMVPA also provides a generalized approach to multiple comparison correction across these dimensions using Threshold-Free Cluster Enhancement with state-of-the-art clustering and permutation techniques. CoSMoMVPA is highly modular and uses abstractions to provide a uniform interface for a variety of MVP measures. Typical analyses require a few lines of code, making it accessible to beginner users. At the same time, expert programmers can easily extend its functionality. CoSMoMVPA comes with extensive documentation, including a variety of runnable demonstration scripts and analysis exercises (with example data and solutions). It uses best software engineering practices including version control, distributed development, an automated test suite, and continuous integration testing. It can be used with the proprietary Matlab and the free GNU Octave software, and it complies with open source distribution platforms such as NeuroDebian. CoSMoMVPA is Free/Open Source Software under the permissive MIT license. Website: cosmomvpa.org

Getting to the Top of Mind: How Reminders Increase Saving

Abstract: We provide evidence from field experiments with three different banks that reminder messages increase commitment attainment for clients who recently opened commitment savings accounts. Messages that mention both savings goals and financial incentives are particularly effective, whereas other content variations such as gain versus loss framing do not have significantly different effects. Nor do we find evidence that receiving additional late reminders has an additive effect. These empirical results do not map neatly into existing models, so we provide a simple model where limited attention to exceptional expenses can generate undersaving that is in turn mitigated by reminders. Data, as supplemental material, are available at http://dx.doi.org/10.1287/mnsc.2015.2296. This paper was accepted by Teck-Hua Ho, behavioral economics.

Comparison of Site of Death, Health Care Utilization, and Hospital Expenditures for Patients Dying With Cancer in 7 Developed Countries

Abstract: Importance Differences in utilization and costs of end-of-life care among developed countries are of considerable policy interest. Objective To compare site of death, health care utilization, and hospital expenditures in 7 countries: Belgium, Canada, England, Germany, the Netherlands, Norway, and the United States. Design, Setting, and Participants Retrospective cohort study using administrative and registry data from 2010. Participants were decedents older than 65 years who died with cancer. Secondary analyses included decedents of any age, decedents older than 65 years with lung cancer, and decedents older than 65 years in the United States and Germany from 2012. Main Outcomes and Measures Deaths in acute care hospitals, 3 inpatient measures (hospitalizations in acute care hospitals, admissions to intensive care units, and emergency department visits), 1 outpatient measure (chemotherapy episodes), and hospital expenditures paid by insurers (commercial or governmental) during the 180-day and 30-day periods before death. Expenditures were derived from country-specific methods for costing inpatient services. Results The United States (cohort of decedents aged >65 years, N = 211 816) and the Netherlands (N = 7216) had the lowest proportion of decedents die in acute care hospitals (22.2.% and 29.4%, respectively). A higher proportion of decedents died in acute care hospitals in Belgium (N = 21 054; 51.2%), Canada (N = 20 818; 52.1%), England (N = 97 099; 41.7%), Germany (N = 24 434; 38.3%), and Norway (N = 6636; 44.7%). In the last 180 days of life, 40.3% of US decedents had an intensive care unit admission compared with less than 18% in other reporting nations. In the last 180 days of life, mean per capita hospital expenditures were higher in Canada (US $21 840), Norway (US $19 783), and the United States (US $18 500), intermediate in Germany (US $16 221) and Belgium (US $15 699), and lower in the Netherlands (US $10 936) and England (US $9342). Secondary analyses showed similar results. Conclusions and Relevance Among patients older than 65 years who died with cancer in 7 developed countries in 2010, end-of-life care was more hospital-centric in Belgium, Canada, England, Germany, and Norway than in the Netherlands or the United States. Hospital expenditures near the end of life were higher in the United States, Norway, and Canada, intermediate in Germany and Belgium, and lower in the Netherlands and England. However, intensive care unit admissions were more than twice as common in the United States as in other countries.

Innovation ecosystems and the pace of substitution: Re‐examining technology S‐curves

Abstract: Why do some new technologies emerge and quickly supplant incumbent technologies while others take years or decades to take off? We explore this question by presenting a framework that considers both the focal competing technologies as well as the ecosystems in which they are embedded. Within our framework, each episode of technology transition is characterized by the ecosystem emergence challenge that confronts the new technology and the ecosystem extension opportunity that is available to the old technology. We identify four qualitatively distinct regimes with clear predictions for the pace of substitution. Evidence from 10 episodes of technology transitions in the semiconductor lithography equipment industry from 1972 to 2009 offers strong support for our framework. We discuss the implication of our approach for firm strategy. Copyright © 2015 John Wiley & Sons, Ltd.

In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer.

Abstract: Nanotechnology has tremendous potential to contribute to cancer immunotherapy. The 'in situ vaccination' immunotherapy strategy directly manipulates identified tumours to overcome local tumour-mediated immunosuppression and subsequently stimulates systemic antitumour immunity to treat metastases. We show that inhalation of self-assembling virus-like nanoparticles from cowpea mosaic virus (CPMV) reduces established B16F10 lung melanoma and simultaneously generates potent systemic antitumour immunity against poorly immunogenic B16F10 in the skin. Full efficacy required Il-12, Ifn-γ, adaptive immunity and neutrophils. Inhaled CPMV nanoparticles were rapidly taken up by and activated neutrophils in the tumour microenvironment as an important part of the antitumour immune response. CPMV also exhibited clear treatment efficacy and systemic antitumour immunity in ovarian, colon, and breast tumour models in multiple anatomic locations. CPMV nanoparticles are stable, nontoxic, modifiable with drugs and antigens, and their nanomanufacture is highly scalable. These properties, combined with their inherent immunogenicity and demonstrated efficacy against a poorly immunogenic tumour, make CPMV an attractive and novel immunotherapy against metastatic cancer.

US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis

Abstract: Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease, such as cystic fibrosis (CF). Pulmonary disease (PD) caused by NTM has emerged as a major threat to the health of individuals with CF, but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened a panel of 19 experts to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM-PD in individuals with CF. PICO (population, intervention, comparison, outcome) methodology and systematic literature reviews were employed to inform draft recommendations, which were then modified to achieve consensus and subsequently circulated for public consultation within the USA and European CF communities. We have thus generated a series of pragmatic, evidence-based recommendations as an initial step in optimising management for this challenging condition.

Integrating Marketing Communications: New Findings, New Lessons, and New Ideas

Abstract: With the challenges presented by new media, shifting media patterns, and divided consumer attention, the optimal integration of marketing communications takes on increasing importance. Drawing on a review of relevant academic research and guided by managerial priorities, the authors offer insights and advice as to how traditional and new media such as search, display, mobile, TV, and social media interact to affect consumer decision making. With an enhanced understanding of the consumer decision journey and how consumers process communications, the authors outline a comprehensive framework featuring two models designed to improve the effectiveness and efficiency of integrated marketing communication programs: a “bottom-up” communications matching model and a “top-down” communications optimization model. The authors conclude by suggesting important future research priorities.

Using Smartphones to Collect Behavioral Data in Psychological Science: Opportunities, Practical Considerations, and Challenges.

Abstract: Smartphones now offer the promise of collecting behavioral data unobtrusively, in situ, as it unfolds in the course of daily life. Data can be collected from the onboard sensors and other phone logs embedded in today's off-the-shelf smartphone devices. These data permit fine-grained, continuous collection of people's social interactions (e.g., speaking rates in conversation, size of social groups, calls, and text messages), daily activities (e.g., physical activity and sleep), and mobility patterns (e.g., frequency and duration of time spent at various locations). In this article, we have drawn on the lessons from the first wave of smartphone-sensing research to highlight areas of opportunity for psychological research, present practical considerations for designing smartphone studies, and discuss the ongoing methodological and ethical challenges associated with research in this domain. It is our hope that these practical guidelines will facilitate the use of smartphones as a behavioral observation tool in psychological science.