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Multidisciplinary tumor boards have evolved to address the increasing complexity of cancer care management. Given that hepatocellular carcinoma (HCC) often arises in the setting of underlying cirrhosis, expert input from hepatologists alongside hepatobiliary and transplant surgeons, radiation oncologists, interventional and body radiologists, and medical oncologists has become increasingly important in order to offer patients appropriate cancer treatments. The MDLTB structure has evolved since the early 2000s to bring these specialists together at regularly scheduled meetings to develop a therapeutic treatment plan for HCC management. MDLTBs have reduced the time to treatment and improved patient satisfaction. Standardized documentation with common data elements has been recommended to ensure adequate communication from MDLTB to referring healthcare providers. Retrospective studies consistently highlight the frequency of changes in treatment plans after MDLTB review to better adhere to guideline recommended care. Despite several decades of MDLTBs implementation, few studies describe clinical outcomes associated with MDLTBs such as patient survival and cost benefits. More research is needed in this area to further justify the heavy use of resources that are needed to maintain MDLTBs. Development and use of a centralized database to store such information may assist with future studies of clinical outcomes and inform quality improvement projects. [ABSTRACT FROM AUTHOR]

Background: As the era of interferon-alpha (IFN)-based therapy for hepatitis C ends, long-term treatment outcomes are now being evaluated.Aim: To more fully understand the natural history of hepatitis C infection by following a multisite cohort of patients.Methods: Patients with chronic HCV were prospectively enrolled in 1999-2000 from 11 VA medical centers and followed through retrospective medical record review.Results: A total of 2211 patients were followed for an average of 8.5 years after enrollment. Thirty-one percent of patients received HCV antiviral therapy, 15 % with standard IFN/ribavirin only, 16 % with pegylated IFN/ribavirin, and 26.7 % of treated patients achieved sustained virologic response (SVR). Cirrhosis developed in 25.8 % of patients. Treatment nonresponders had a greater than twofold increase in the hazard of cirrhosis and hepatocellular carcinoma, compared to untreated patients, whereas SVR patients were only marginally protected from cirrhosis. Nearly 6 % developed hepatocellular carcinoma, and 27.1 % died during the follow-up period. Treated patients, regardless of response, had a significant survival benefit compared to untreated patients (HR 0.58, CI 0.46-0.72). Improved survival was also associated with college education, younger age, lower levels of alcohol consumption, and longer duration of medical service follow-up-factors typically associated with treatment eligibility.Conclusions: As more hepatitis C patients are now being assessed for all-oral combination therapy, these results highlight that patient compliance and limiting harmful behaviors contribute a significant proportion of the survival benefit in treated patients and that the long-term clinical benefits of SVR may be less profound than previously reported. [ABSTRACT FROM AUTHOR]

Considering that causal mechanisms unfold over time, it is important to investigate the mechanisms over time, taking into account the time-varying features of treatments and mediators. However, identification of the average causal mediation effect in the presence of time-varying treatments and mediators is often complicated by time-varying confounding. This article aims to provide a novel approach to uncovering causal mechanisms in time-varying treatments and mediators in the presence of time-varying confounding. We provide different strategies for identification and sensitivity analysis under homogeneous and heterogeneous effects. Homogeneous effects are those in which each individual experiences the same effect, and heterogeneous effects are those in which the effects vary over individuals. Most importantly, we provide an alternative definition of average causal mediation effects that evaluates a partial mediation effect; the effect that is mediated by paths other than through an intermediate confounding variable. We argue that this alternative definition allows us to better assess at least a part of the mediated effect and provides meaningful and unique interpretations. A case study using ECLS-K data that evaluates kindergarten retention policy is offered to illustrate our proposed approach. [ABSTRACT FROM AUTHOR]

The β-sheet is the key structure underlying the excellent mechanical properties of spider silk. However, the comprehensive mechanism underlying β-sheet formation from soluble silk proteins during the transition into insoluble stable fibers has not been elucidated. Notably, the assembly of repetitive domains that dominate the length of the protein chains and structural features within the spun fibers has not been clarified. Here we determine the conformation and dynamics of the soluble precursor of the repetitive domain of spider silk using solution-state NMR, far-UV circular dichroism and vibrational circular dichroism. The soluble repetitive domain contains two major populations: ~65% random coil and ~24% polyproline type II helix (PPII helix). The PPII helix conformation in the glycine-rich region is proposed as a soluble prefibrillar region that subsequently undergoes intramolecular interactions. These findings unravel the mechanism underlying the initial step of β-sheet formation, which is an extremely rapid process during spider silk assembly. [ABSTRACT FROM AUTHOR]

We analyze the invisibility of fisheries and inadequacy of fishers’ participation in the process of hydropower development in the Amazon, focusing on gaps between legally mandated and actual outcomes. Using Ostrom’s institutional design principles for assessing common-pool resource management, we selected five case studies from Brazilian Amazonian watersheds to conduct an exploratory comparative case-study analysis. We identify similar problems across basins, including deficiencies in the dam licensing process; critical data gaps; inadequate stakeholder participation; violation of human rights; neglect of fishers’ knowledge; lack of organization and representation by fishers’ groups; and lack of governmental structure and capacity to manage dam construction activities or support fishers after dam construction. Fishers have generally been marginalized or excluded from decision-making regarding planning, construction, mitigation, compensation, and monitoring of the social-ecological impacts of hydroelectric dams. Addressing these deficiencies will require concerted investments and efforts by dam developers, government agencies and civil society, and the promotion of inter-sectorial dialogue and cross-scale participatory planning and decision-making that includes fishers and their associations. [ABSTRACT FROM AUTHOR]

Congenital heart defects can be caused by mutations in genes that guide cardiac lineage formation. Here, we show deletion of NKX2-5, a critical component of the cardiac gene regulatory network, in human embryonic stem cells (hESCs), results in impaired cardiomyogenesis, failure to activate VCAM1 and to downregulate the progenitor marker PDGFRα. Furthermore, NKX2-5 null cardiomyocytes have abnormal physiology, with asynchronous contractions and altered action potentials. Molecular profiling and genetic rescue experiments demonstrate that the bHLH protein HEY2 is a key mediator of NKX2-5 function during human cardiomyogenesis. These findings identify HEY2 as a novel component of the NKX2-5 cardiac transcriptional network, providing tangible evidence that hESC models can decipher the complex pathways that regulate early stage human heart development. These data provide a human context for the evaluation of pathogenic mutations in congenital heart disease. [ABSTRACT FROM AUTHOR]

When conducting robustness research where the focus of attention is on the impact of non-normality, the marginal skewness and kurtosis are often used to set the degree of non-normality. Monte Carlo methods are commonly applied to conduct this type of research by simulating data from distributions with skewness and kurtosis constrained to pre-specified values. Although several procedures have been proposed to simulate data from distributions with these constraints, no corresponding procedures have been applied for discrete distributions. In this paper, we present two procedures based on the principles of maximum entropy and minimum cross-entropy to estimate the multivariate observed ordinal distributions with constraints on skewness and kurtosis. For these procedures, the correlation matrix of the observed variables is not specified but depends on the relationships between the latent response variables. With the estimated distributions, researchers can study robustness not only focusing on the levels of non-normality but also on the variations in the distribution shapes. A simulation study demonstrates that these procedures yield excellent agreement between specified parameters and those of estimated distributions. A robustness study concerning the effect of distribution shape in the context of confirmatory factor analysis shows that shape can affect the robust χ2 and robust fit indices, especially when the sample size is small, the data are severely non-normal, and the fitted model is complex. [ABSTRACT FROM AUTHOR]

Brain metastases (BM) are the most common brain tumor in adults and are a leading cause of cancer mortality. Metastatic lesions contain subclones derived from their primary lesion, yet their functional characterization is limited by a paucity of preclinical models accurately recapitulating the metastatic cascade, emphasizing the need for a novel approach to BM and their treatment. We identified a unique subset of stem-like cells from primary human patient brain metastases, termed brain metastasis-initiating cells (BMICs). We now establish a BMIC patient-derived xenotransplantation (PDXT) model as an investigative tool to comprehensively interrogate human BM. Using both in vitro and in vivo RNA interference screens of these BMIC models, we identified SPOCK1 and TWIST2 as essential BMIC regulators. SPOCK1 in particular is a novel regulator of BMIC self-renewal, modulating tumor initiation and metastasis from the lung to the brain. A prospective cohort of primary lung cancer specimens showed that SPOCK1 was overexpressed only in patients who ultimately developed BM. Protein-protein interaction network mapping between SPOCK1 and TWIST2 identified novel pathway interactors with significant prognostic value in lung cancer patients. Of these genes, INHBA, a TGF-β ligand found mutated in lung adenocarcinoma, showed reduced expression in BMICs with knockdown of SPOCK1. In conclusion, we have developed a useful preclinical model of BM, which has served to identify novel putative BMIC regulators, presenting potential therapeutic targets that block the metastatic process, and transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one. [ABSTRACT FROM AUTHOR]

Climate change-driven range expansion of black mangroves ( Avicennia germinans) is predicted along the northern Gulf of Mexico, where sea level rise is also driving conversion of freshwater forest islands to salt marsh. While climate-driven A. germinans range expansion has garnered considerable scientific attention, the role of top-down controls on colonization is largely overlooked. We investigated the effects of abiotic (flooding frequency, soil depth, soil salinity) and biotic (predation, herbivory) controls on A. germinans establishment at its northern range limit along Florida's Gulf Coast by comparing fates of caged and non-caged propagules across four landscape positions (from creek edge to forest island interior) and at three sites along a tidal flooding frequency gradient. Within 12 days, grapsid crab, Sesarma reticulatum, consumed 99% of non-caged propagules. Among caged propagules, establishment increased with increasing flooding frequency; however, cages did not entirely prevent predation, which remained a primary cause of mortality, except in the rarely flooded island. Propagules that survived to seedlings experienced mild to fatal herbivory across landscape positions and sites. This study revealed that while relict forest islands and surrounding marshes can support A. germinans, predation and herbivory strongly suppress colonization, suggesting that mangrove expansion models should incorporate biotic controls. [ABSTRACT FROM AUTHOR]

A variety of artificial spinning methods have been applied to produce regenerated silk fibers; however, how to spin regenerated silk fibers that retain the advantages of natural silks in terms of structural hierarchy and mechanical properties remains challenging. Here, we show a bioinspired approach to spin regenerated silk fibers. First, we develop a nematic silk microfibril solution, highly viscous and stable, by partially dissolving silk fibers into microfibrils. This solution maintains the hierarchical structures in natural silks and serves as spinning dope. It is then spun into regenerated silk fibers by direct extrusion in the air, offering a useful route to generate polymorphic and hierarchical regenerated silk fibers with physical properties beyond natural fiber construction. The materials maintain the structural hierarchy and mechanical properties of natural silks, including a modulus of 11 ± 4 GPa, even higher than natural spider silk. It can further be functionalized with a conductive silk/carbon nanotube coating, responsive to changes in humidity and temperature. [ABSTRACT FROM AUTHOR]

How sleep influences brain plasticity is not known. In particular, why certain electroencephalographic (EEG) rhythms are linked to memory consolidation is poorly understood. Calcium activity in dendrites is known to be necessary for structural plasticity changes, but this has never been carefully examined during sleep. Here, we report that calcium activity in populations of neocortical dendrites is increased and synchronised during oscillations in the spindle range in naturally sleeping rodents. Remarkably, the same relationship is not found in cell bodies of the same neurons and throughout the cortical column. Spindles during sleep have been suggested to be important for brain development and plasticity. Our results provide evidence for a physiological link of spindles in the cortex specific to dendrites, the main site of synaptic plasticity. [ABSTRACT FROM AUTHOR]

Obesity is a rising issue especially in the United States that can lead to heart problems, type II diabetes, and respiratory problems. Since the 1970s, obesity rates in the United States have more than doubled in adults and children. Recent evidence suggests that exposure to certain chemicals, termed 'obesogens,' in utero may alter metabolic processes, predisposing individuals to weight gain. There is a need to develop a three-dimensional human tissue system that is able to model the effects of obesogens in vitro in order to better understand the impact of obesogens on early development. Human embryonic-derived stem cells in three-dimensional collagen embedded silk scaffolds were exposed to three different obesogens: Bisphenol A (BPA), Bisphenol S (BPS), and Tributyltin (TBT). The exposed tissues accumulated triglycerides and increased expression of adipogenic genes (Perilipin (PLIN1), peroxisome proliferator-activated receptor gamma (PPARy), fatty acid binding protein 4 (FABP4)) compared to equivalent control cultures with no obesogen exposure. These cultures were also compared to human adult stem cell cultures, which did not respond the same upon addition of obesogens. These results demonstrate the successful development of a representative tissue model of in utero obesogen exposures. This tissue system could be used to determine mechanisms of action of current obesogens and to screen other potential obesogens. [ABSTRACT FROM AUTHOR]

Policy makers from around the world are trying to emulate successful innovation systems in order to support economic growth. At the same time, innovation governance systems are being put in place to ensure a better integration of stakeholder views into the research and development process. In Europe, one of the most prominent and newly emerging governance frameworks is called Responsible Research and Innovation (RRI). This article aims to substantiate the following points: (1) The concept of RRI and the concept of justice can be used to derive similar ethical positions on the nano-divide. (2) Given the ambitious policy aims of RRI (e.g. economic competitiveness enhancer), the concept may be better suited to push for ethical outcomes on access to nanotechnology and its products rather than debates based on justice issues alone. It may thus serve as a mediator concept between those who push solely for competitiveness considerations and those who push solely for justice considerations in nano-technology debates. (3) The descriptive, non-normative Systems of Innovation approaches (see below) should be linked into RRI debates to provide more evidence on whether the approach advocated to achieve responsible and ethical governance of research and innovation (R&I) can indeed deliver on competitiveness (in nano-technology and other fields). [ABSTRACT FROM AUTHOR]

Enzyme catalysis in the synthesis of polyaniline is reviewed. Oxidoreductase enzymes and biomimetic catalysts have been used for the polymerization in aqueous, aqueous organic, and interfacial or templating environments to optimize polymer features. The results showed significant structural control in the presence of templates to produce water soluble and processable polymeric materials. Dip-pen nanolithography technology has also been used to process these materials into conducting nano-wires and thus provides new opportunities for the formation of electrical contacts among biological components for various applications such as synthetic biological interfaces. [ABSTRACT FROM AUTHOR]

This paper reviews recent research on causal inference with large-scale assessments in education from a Bayesian perspective. I begin by adopting the potential outcomes model of Rubin (J Educ Psychol 66:688-701, ) as a framework for causal inference that I argue is appropriate with large-scale educational assessments. I then discuss the elements of Bayesian inference arguing that methods and models of causal inference can benefit from the Bayesian approach to quantifying uncertainty. Next I outline one method of causal inference that I believe is fruitful for addressing causal questions with large-scale educational assessments within the potential outcomes framework-namely, propensity score analysis. I then discuss the quantification of uncertainty in propensity score analysis through a Bayesian approach. Next, I discuss a series of necessary conditions for addressing causal questions with large-scale educational assessments. The paper closes with a discussion of the implications for the design of large-scale educational assessments when the goal is in asking causal questions and warranting causal claims. [ABSTRACT FROM AUTHOR]

Mechanical reinforcement of silk membranes by embedding silk microfibers was studied. Silk microfibers of 10-600 μm long were prepared by hydrolyzing degummed silk fibers in alkali solution. The silk microfibers were mixed with silk fibroin solution (continuous phase) at various ratios to fabricate silk microfiber-reinforced composite scaffolds (SMCSs). The morphology, mechanical properties, structural characteristics, biodegradation, and cytotoxicity of the composites were investigated. Silk microfiber-reinforced membranes with 1 wt% of microfibers displayed the most homogeneous distribution of microfibers in the membrane matrix. The tensile strength and elongation at break were 10.5 ± 2.7 MPa and 56.7 ± 7.8 %, respectively, comparable to human meniscus tissue. The presence of silk microfibers did not significantly impact the secondary structure and crystallization of SMCSs. Proteolytic degradation in vitro using protease XIV showed that the 1 % silk microfiber-reinforced membranes lost 90 % weight after 5 days, a longer time frame than plain silk membrane controls. The viability of human fibroblasts (Hs 865.Sk) on the SMCSs demonstrated no cytotoxicity. SMCSs may be useful as biomaterial systems as tissue substitutes where mechanical strength is critical for functional performance. [ABSTRACT FROM AUTHOR]

Adipose tissue engineering is a diverse area of research where the developed tissues can be used to study normal adipose tissue functions, create disease models in vitro, and replace soft tissue defects in vivo. Increasing attention has been focused on the highly specialized metabolic pathways that regulate energy storage and release in adipose tissues which affect local and systemic outcomes. Non-invasive, dynamic measurement systems are useful to track these metabolic pathways in the same tissue model over time to evaluate long term cell growth, differentiation, and development within tissue engineering constructs. This approach reduces costs and time in comparison to more traditional destructive methods such as biochemical and immunochemistry assays and proteomics assessments. Towards this goal, this review will focus on important metabolic functions of adipose tissues and strategies to evaluate them with non-invasive in vitro methods. Current non-invasive methods, such as measuring key metabolic markers and endogenous contrast imaging will be explored. [ABSTRACT FROM AUTHOR]

Context: Strong reciprocal interactions exist between landscape patterns and ecological processes. In wetlands, hydrology is the dominant abiotic driver of ecological processes and both controls, and is controlled, by vegetation presence and patterning. We focus on binary patterning in the Everglades ridge-slough landscape, where longitudinally connected flow, principally in sloughs, is integral to landscape function. Patterning controls discharge competence in this low-gradient peatland, with important feedbacks on hydroperiod and thus peat accretion and patch transitions. Objectives: To quantitatively predict pattern effects on hydrologic connectivity and thus hydroperiod. Methods: We evaluated three pattern metrics that vary in their hydrologic specificity. (1) Landscape discharge competence considers elongation and patch-type density that capture geostatistical landscape features. (2) Directional connectivity index (DCI) extracts both flow path and direction based on graph theory. (3) Least flow cost (LFC) is based on a global spatial distance algorithm strongly analogous to landscape water routing, where ridges have higher flow cost than sloughs because of their elevation and vegetation structure. Metrics were evaluated in comparison to hydroperiod estimated using a numerically intensive hydrologic model for synthetic landscapes. Fitted relationships between metrics and hydroperiod for synthetic landscapes were extrapolated to contemporary and historical maps to explore hydroperiod trends in space and time. Results: Both LFC and DCI were excellent predictors of hydroperiod and useful for diagnosing how the modern landscape has reorganized in response to modified hydrology. Conclusions: Metric simplicity and performance indicates potential to provide hydrologically explicit, computationally simple, and spatially independent predictions of landscape hydrology, and thus effectively measure of restoration performance. [ABSTRACT FROM AUTHOR]

Silk materials with different nanostructures have been developed without the understanding of the inherent transformation mechanism. Here we attempt to reveal the conversion road of the various nanostructures and determine the critical regulating factors. The regulating conversion processes influenced by a hierarchical charge distribution were investigated, showing different transformations between molecules, nanoparticles and nanofibers. Various repulsion and compressive forces existed among silk fibroin molecules and aggregates due to the exterior and interior distribution of charge, which further controlled their aggregating and deaggregating behaviors and finally formed nanofibers with different sizes. Synergistic action derived from molecular mobility and concentrations could also tune the assembly process and final nanostructures. It is suggested that the complicated silk fibroin assembly processes comply a same rule based on charge distribution, offering a promising way to develop silk-based materials with designed nanostructures. [ABSTRACT FROM AUTHOR]

Recently, it has been provocatively claimed that dynamical modeling approaches signal the emergence of a new explanatory framework distinct from that of mechanistic explanation. This paper rejects this proposal and argues that dynamical explanations are fully compatible with, even naturally construed as, instances of mechanistic explanations. Specifically, it is argued that the mathematical framework of dynamics provides a powerful descriptive scheme for revealing temporal features of activities in mechanisms and plays an explanatory role to the extent it is deployed for this purpose. It is also suggested that more attention should be paid to the distinctive methodological contributions of the dynamical framework including its usefulness as a heuristic for mechanism discovery and hypothesis generation in contemporary neuroscience and biology. [ABSTRACT FROM AUTHOR]

Understanding the dynamics of marine populations is critical to managing marine systems effectively and requires information on patterns of population dispersal and connectivity that are still poorly known. We used transgenerational marking to study larval dispersal of the humbug damselfish, Dascyllus aruanus, in the patchy reef seascape of the southwest Lagoon of New Caledonia (SWL), southwest tropical pacific. The adult population of a patch reef located in the central part of the SWL was injected repeatedly with an enriched Ba solution to ensure mass production of marked larvae over two successive reproductive seasons. Multiple cohorts of newly settled larvae were sampled, and their otolith core was analyzed by laser ablation inductively coupled plasma mass spectrometry to assess the seasonal and interannual variability of self-recruitment at the central reef. Connectivity between this reef and ten neighboring reefs was also estimated. Analysis of >1200 settlers indicated that self-recruitment varied significantly between months (ranging from 0 to 68 %) and years (21 % in 2011 and 0 % in 2012). However, variable self-recruitment did not always correspond to variable numbers of self-recruits. Therefore, whereas self-recruitment is undoubtedly a good indication of the degree of population openness, it may not indicate local population persistence. Finally, being the first self-recruitment study to include such a large number of settlers, our study reveals that the threshold used to determine marked individuals significantly affects perceived self-recruitment and connectivity rates and, therefore, must be carefully chosen. [ABSTRACT FROM AUTHOR]

Various techniques have been employed to entrap fragrant oils within microcapsules or microparticles in the food, pharmaceutical, and chemical industries for improved stability and delivery. In the present work, we describe the use of silk protein microparticles for encapsulating fragrant oils using ambient processing conditions to form an all-natural biocompatible matrix. These microparticles are stabilized via physical crosslinking, requiring no chemical agents, and are prepared with aqueous and ambient processing conditions using polyvinyl alcohol-silk emulsions. The particles were loaded with fragrant oils via direct immersion of the silk particles within an oil bath. The oil-containing microparticles were coated using alternating silk and polyethylene oxide layers to control the release of the oil from the microspheres. Particle morphology and size, oil loading capacity, release rates as well as silk-oil interactions and coating treatments were characterized. Thermal analysis demonstrated that the silk coatings can be tuned to alter both retention and release profiles of the encapsulated fragrance. These oil-containing particles demonstrate the ability to adsorb and controllably release oils, suggesting a range of potential applications including cosmetic and fragrance utility. [ABSTRACT FROM AUTHOR]

Naturally derived polymeric biomaterials, such as collagens, silks, elastins, alginates, and fibrins are utilized in tissue engineering due to their biocompatibility, bioactivity, and tunable mechanical and degradation kinetics. The use of these natural biopolymers in biomedical applications is advantageous because they do not release cytotoxic degradation products, are often processed using environmentally-friendly aqueous-based methods, and their degradation rates within biological systems can be manipulated by modifying the starting formulation or processing conditions. For these reasons, many recent in vivo investigations and FDA-approval of new biomaterials for clinical use have utilized natural biopolymers as matrices for cell delivery and as scaffolds for cell-free support of native tissues. This review highlights biopolymer-based scaffolds used in clinical applications for the regeneration and repair of native tissues, with a focus on bone, skeletal muscle, peripheral nerve, cardiac muscle, and cornea substitutes. [ABSTRACT FROM AUTHOR]

The article focuses on an in vivo and in vitro study conducted to assess the biocompatibility of silk gel for cervical injection during pregnancy. It mentions injection of silk gel into cervix of rats pregnant with 13 days and the use of culture of human cervical fibroblasts on silk gel and tissue culture plastic to evaluate cell viability, proliferation, metabolic activity and gene expression, and the conclusion that silk gel can be used as an alternative to cervical cerclage.