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Effective symptom management is a critical component of cancer treatment. Computational tools that predict the course and severity of these symptoms have the potential to assist oncology clinicians to personalize the patient's treatment regimen more efficiently and provide more aggressive and timely interventions. Three common and inter-related symptoms in cancer patients are depression, anxiety, and sleep disturbance. In this paper, we elaborate on the efficiency of Support Vector Regression (SVR) and Non-linear Canonical Correlation Analysis by Neural Networks (n-CCA) to predict the severity of the aforementioned symptoms between two different time points during a cycle of chemotherapy (CTX). Our results demonstrate that these two methods produced equivalent results for all three symptoms. These types of predictive models can be used to identify high risk patients, educate patients about their symptom experience, and improve the timing of pre-emptive and personalized symptom management interventions.

Extracellular vesicles (EVs) released by virtually every cell of all organisms are involved in processes of intercellular communication through the delivery of their functional mRNAs, proteins and bioactive lipids. We previously demonstrated that mouse embryonic stem cell-released EVs (mESEVs) are able to transfer their content to different target retinal cells, inducing morphological and biochemical changes in them. The main objective of this paper is to characterize EVs derived from human embryonic stem cells (hESEVs) and investigate the effects that they have on cultured retinal glial, progenitor Müller cells, which are known to give rise to retinal neurons under specific conditions. This would allow us to establish if hESEVs have a pro-regenerative potential not yet described that could be used in the future for treatment of human retinal degenerative diseases. Initially, we showed that hESEVs are heterogeneous in size, contain mRNAs and proteins involved in the induction and maintenance of stem cell pluripotency and can be internalized by cultured Müller cells. After a single exposure to hESEVs these cells display changes in their gene expression profile, and with multiple exposures they de-differentiate and trans-differentiate into retinal neuronal precursors. hESEVs were then fractionated into microvesicles (MVs) and exosomes (EXOs), which were characterized by size, specific surface proteins and biochemical/molecular components. We demonstrate that despite the similar internalization of non-fractionated hESEVs, MVs and EXOs by Müller progenitor cells, in vitro, only the release of MVs' cargo into the cells' cytoplasm induces specific changes in their levels of pluripotency mRNAs and early retinal proteins. EXOs do not produce any detectable effect. Thus, we conclude that MVs and MVs-containing hESEVs are promising agents that possibly could promote the regeneration of diseased or damaged retinas in vivo through inducing glial Müller cells to become replacement neurons.

Viscoelasticity of soft tissue is often related to pathology, and therefore, has become an important diagnostic indicator in the clinical assessment of suspect tissue. Surgeons, particularly within head and neck subsites, typically use palpation techniques for intra-operative tumor detection. This detection method, however, is highly subjective and often fails to detect small or deep abnormalities. Vibroacoustography (VA) and similar methods have previously been used to distinguish tissue with high-contrast, but a firm understanding of the main contrast mechanism has yet to be verified. The contributions of tissue mechanical properties in VA images have been difficult to verify given the limited literature on viscoelastic properties of various normal and diseased tissue. This paper aims to investigate viscoelasticity theory and present a detailed description of viscoelastic experimental results obtained in tissue-mimicking phantoms (TMPs) and ex vivo tissues to verify the main contrast mechanism in VA and similar imaging modalities. A spherical-tip micro-indentation technique was employed with the Hertzian model to acquire absolute, quantitative, point measurements of the elastic modulus (E), long term shear modulus (η), and time constant (τ) in homogeneous TMPs and ex vivo tissue in rat liver and porcine liver and gallbladder. Viscoelastic differences observed between porcine liver and gallbladder tissue suggest that imaging modalities which utilize the mechanical properties of tissue as a primary contrast mechanism can potentially be used to quantitatively differentiate between proximate organs in a clinical setting. These results may facilitate more accurate tissue modeling and add information not currently available to the field of systems characterization and biomedical research.

Salmonid farming in Ireland is mostly organic, which implies limited disease treatment options. This highlights the importance of biosecurity for preventing the introduction and spread of infectious agents. Similarly, the effect of local network properties on infection spread processes has rarely been evaluated. In this paper, we characterized the biosecurity of salmonid farms in Ireland using a survey, and then developed a score for benchmarking the disease risk of salmonid farms. The usefulness and validity of this score, together with farm indegree (dichotomized as ≤ 1 or > 1), were assessed through generalized Poisson regression models, in which the modeled outcome was pathogen richness, defined here as the number of different diseases affecting a farm during a year. Seawater salmon (SW salmon) farms had the highest biosecurity scores with a median (interquartile range) of 82.3 (5.4), followed by freshwater salmon (FW salmon) with 75.2 (8.2), and freshwater trout (FW trout) farms with 74.8 (4.5). For FW salmon and trout farms, the top ranked model (in terms of leave-one-out information criteria, looic) was the null model (looic = 46.1). For SW salmon farms, the best ranking model was the full model with both predictors and their interaction (looic = 33.3). Farms with a higher biosecurity score were associated with lower pathogen richness, and farms with indegree > 1 (i.e. more than one fish supplier) were associated with increased pathogen richness. The effect of the interaction between these variables was also important, showing an antagonistic effect. This would indicate that biosecurity effectiveness is achieved through a broader perspective on the subject, which includes a minimization in the number of suppliers and hence in the possibilities for infection to enter a farm. The work presented here could be used to elaborate indicators of a farm's disease risk based on its biosecurity score and indegree, to inform risk-based disease surveillance and control strategies for private and public stakeholders.

ObjectiveThe overall aim of this paper is to examine effectiveness of an evidence-based intervention in community settings, and the factors associated with effectiveness. Limited research in the area of HIV prevention has focused on evaluating intervention program effectiveness in real-world settings.MethodsWe implemented an efficacious theory-based sexual risk reduction intervention for female sex workers (FSW) called Mujer Segura across 13 different clinics in 13 sites across Mexico. The overall design was a cluster randomized Type I design simultaneously testing intervention program effectiveness with an observational study of implementation factors. We aimed to examine the effectiveness of Mujer Segura at reducing HIV/STI incidence among FSW participants at each site, and to examine the client-, provider-, organization-, and structure-related factors associated with program effectiveness.ResultsWe found lower HIV/STI incidence density in the intervention relative to the control group in 5 sites we labeled as "program effective sites," but not in 8 sites we labeled as "program ineffective sites." Using generalized estimating equations controlling for site and computed mean difference effect sizes, we examined statistically and practically significant differences, respectively, between the two groups of sites along various client-, provider-, organization-, and structure-related characteristics. Results indicated that client-level HIV/AIDS related knowledge, and proficiency and engagement in the organizational social context were associated with program effectiveness.ConclusionsEnormous resources are required to systematically and adequately test the role of multilevel factors on program effectiveness. We successfully implemented Mujer Segura in 13 sites in Mexico. Results suggest that other measures may need to be included in future implementation studies than the ones included here. We were able to point to a few specific factors that should be targeted to increase effectiveness of similar evidence-based programs in low- and other middle-income countries like Mexico.Trial registrationClinicalTrials.gov NCT01465607.

Milk oligosaccharides (OS) are a key factor that influences the infant gut microbial composition, and their importance in promoting healthy infant development and disease prevention is becoming increasingly apparent. Investigating the structures, properties, and sources of these compounds requires a host of complementary analytical techniques. Relative compound quantification by mass spectral analysis of isobarically labeled samples is a relatively new technique that has been used mainly in the proteomics field. Glycomics applications have so far focused on analysis of protein-linked glycans, while analysis of free milk OS has previously been conducted only on analytical standards. In this paper, we extend the use of isobaric glycan tags to the analysis of bovine milk OS by presenting a method for separation of labeled OS on a porous graphitized carbon liquid chromatographic column with subsequent analysis by quadrupole time-of-flight tandem mass spectrometry. Abundances for 15 OS extracted from mature bovine milk were measured, with replicate injections providing coefficients of variation below 15% for most OS. Isobaric labeling improved ionization efficiency for low-abundance, high-molecular weight fucosylated OS, which are known to exist in bovine milk but have been only sporadically reported in the literature. We compared the abundances of four fucosylated OS in milk from Holstein and Jersey cattle and found that three of the compounds were more abundant in Jersey milk, which is in general agreement with a previous study. This novel method represents an advancement in our ability to characterize milk OS and provides the advantages associated with isobaric labeling, including reduced instrumental analysis time and increased analyte ionization efficiency. This improved ability to measure differences in bioactive OS abundances in large datasets will facilitate exploration of OS from all food sources for the purpose of developing health-guiding products for infants, immune-compromised elderly, and the population at large.

ObjectiveThe overall aim of this paper is to examine effectiveness of an evidence-based intervention in community settings, and the factors associated with effectiveness. Limited research in the area of HIV prevention has focused on evaluating intervention program effectiveness in real-world settings.MethodsWe implemented an efficacious theory-based sexual risk reduction intervention for female sex workers (FSW) called Mujer Segura across 13 different clinics in 13 sites across Mexico. The overall design was a cluster randomized Type I design simultaneously testing intervention program effectiveness with an observational study of implementation factors. We aimed to examine the effectiveness of Mujer Segura at reducing HIV/STI incidence among FSW participants at each site, and to examine the client-, provider-, organization-, and structure-related factors associated with program effectiveness.ResultsWe found lower HIV/STI incidence density in the intervention relative to the control group in 5 sites we labeled as "program effective sites," but not in 8 sites we labeled as "program ineffective sites." Using generalized estimating equations controlling for site and computed mean difference effect sizes, we examined statistically and practically significant differences, respectively, between the two groups of sites along various client-, provider-, organization-, and structure-related characteristics. Results indicated that client-level HIV/AIDS related knowledge, and proficiency and engagement in the organizational social context were associated with program effectiveness.ConclusionsEnormous resources are required to systematically and adequately test the role of multilevel factors on program effectiveness. We successfully implemented Mujer Segura in 13 sites in Mexico. Results suggest that other measures may need to be included in future implementation studies than the ones included here. We were able to point to a few specific factors that should be targeted to increase effectiveness of similar evidence-based programs in low- and other middle-income countries like Mexico.Trial registrationClinicalTrials.gov NCT01465607.

Adverse Childhood Experiences (ACEs) are associated with poor health outcomes, underlining the significance of early identification and intervention. Currently, there is no validated tool to screen for ACEs exposure in childhood. To fill this gap, we designed and implemented a pediatric ACEs questionnaire in an urban pediatric Primary Care Clinic. Questionnaire items were selected and modified based on literature review of existing childhood adversity tools. Children twelve years and under were screened via caregiver report, using the developed instrument. Cognitive interviews were conducted with caregivers, health providers, and clinic staff to assess item interpretation, clarity, and English/Spanish language equivalency. Using a rapid cycle assessment, information gained from the interviews were used to iteratively change the instrument. Additional questions assessed acceptability of screening within primary care and preferences around administration. Twenty-eight (28) caregivers were administered the questionnaire. Cognitive interviews conducted among caregivers and among 16 health providers and clinic staff resulted in the changes in wording and addition of examples in the items to increase face validity. In the final instrument, no new items were added; however, two items were merged and one item was split into three separate items. While there was a high level of acceptability of the overall questionnaire, some caregivers reported discomfort with the sexual abuse, separation from caregiver, and community violence items. Preference for methods of administration were split between tablet and paper formats. The final Pediatric ACE and other Determinants of Health Questionnaire is a 17-item instrument with high face validity and acceptability for use within primary care settings. Further evaluation on the reliability and construct validity of the instrument is being conducted prior to wide implementation in pediatric practice.

RNA SHAPE experiments have become important and successful sources of information for RNA structure prediction. In such experiments, chemical reagents are used to probe RNA backbone flexibility at the nucleotide level, which in turn provides information on base pairing and therefore secondary structure. Little is known, however, about the statistics of such SHAPE data. In this work, we explore different representations of noise in SHAPE data and propose a statistically sound framework for extracting reliable reactivity information from multiple SHAPE replicates. Our analyses of RNA SHAPE experiments underscore that a normal noise model is not adequate to represent their data. We propose instead a log-normal representation of noise and discuss its relevance. Under this assumption, we observe that processing simulated SHAPE data by directly averaging different replicates leads to bias. Such bias can be reduced by analyzing the data following a log transformation, either by log-averaging or Kalman filtering. Application of Kalman filtering has the additional advantage that a prior on the nucleotide reactivities can be introduced. We show that the performance of Kalman filtering is then directly dependent on the quality of that prior. We conclude the paper with guidelines on signal processing of RNA SHAPE data.

Effective symptom management is a critical component of cancer treatment. Computational tools that predict the course and severity of these symptoms have the potential to assist oncology clinicians to personalize the patient's treatment regimen more efficiently and provide more aggressive and timely interventions. Three common and inter-related symptoms in cancer patients are depression, anxiety, and sleep disturbance. In this paper, we elaborate on the efficiency of Support Vector Regression (SVR) and Non-linear Canonical Correlation Analysis by Neural Networks (n-CCA) to predict the severity of the aforementioned symptoms between two different time points during a cycle of chemotherapy (CTX). Our results demonstrate that these two methods produced equivalent results for all three symptoms. These types of predictive models can be used to identify high risk patients, educate patients about their symptom experience, and improve the timing of pre-emptive and personalized symptom management interventions.

Collaboration among scientists has a major influence on scientific progress. Such collaboration often results from scientific meetings, where scientists gather to present and discuss their research and to meet potential collaborators. However, most scientific meetings have inherent biases, such as the availability of research funding or the selection bias of professional societies that make it difficult to study the effect of the meeting per se on scientific productivity. To evaluate the effects of scientific meetings on collaboration and progress independent of these biases, we conducted a study of the annual symposia held by the International Milk Genomics Consortium (IMGC) over a 12-year period. In our study, we conducted permutation testing to analyze the effectiveness of the IMGC in facilitating collaboration and productivity in a community of milk scientists who were meeting attendees relative to non-attendees. Using the number of co-authorships on published papers as a measure of collaboration, our analysis revealed that scientists who attended the symposium were associated with more collaboration than were scientists who did not attend. Furthermore, we evaluated the scientific progress of consortium attendees by analyzing publication rate and article impact. We found that IMGC attendees, in addition to being more collaborative, were also more productive and influential than were non-attendees who published in the same field. The results of our study suggest that the annual symposium encouraged interactions among disparate scientists and increased research productivity, exemplifying the positive effect of scientific meetings on both collaboration and progress.

This paper presents the results of a consensus-driven process identifying 50 priority research questions for historical ecology obtained through crowdsourcing, literature reviews, and in-person workshopping. A deliberative approach was designed to maximize discussion and debate with defined outcomes. Two in-person workshops (in Sweden and Canada) over the course of two years and online discussions were peer facilitated to define specific key questions for historical ecology from anthropological and archaeological perspectives. The aim of this research is to showcase the variety of questions that reflect the broad scope for historical-ecological research trajectories across scientific disciplines. Historical ecology encompasses research concerned with decadal, centennial, and millennial human-environmental interactions, and the consequences that those relationships have in the formation of contemporary landscapes. Six interrelated themes arose from our consensus-building workshop model: (1) climate and environmental change and variability; (2) multi-scalar, multi-disciplinary; (3) biodiversity and community ecology; (4) resource and environmental management and governance; (5) methods and applications; and (6) communication and policy. The 50 questions represented by these themes highlight meaningful trends in historical ecology that distill the field down to three explicit findings. First, historical ecology is fundamentally an applied research program. Second, this program seeks to understand long-term human-environment interactions with a focus on avoiding, mitigating, and reversing adverse ecological effects. Third, historical ecology is part of convergent trends toward transdisciplinary research science, which erodes scientific boundaries between the cultural and natural.

The dynamic relationship between reefs and the people who utilize them at a subsistence level is poorly understood. This paper characterizes atoll-scale patterns in shallow coral reef habitat and fish community structure, and correlates these with environmental characteristics and anthropogenic factors, critical to conservation efforts for the reefs and the people who depend on them. Hierarchical clustering analyses by site for benthic composition and fish community resulted in the same 3 major clusters: cluster 1-oceanic (close proximity to deep water) and uninhabited (low human impact); cluster 2-oceanic and inhabited (high human impact); and cluster 3-lagoonal (facing the inside of the lagoon) and inhabited (highest human impact). Distance from village, reef exposure to deep water and human population size had the greatest effect in predicting the fish and benthic community structure. Our study demonstrates a strong association between benthic and fish community structure and human use across the Ulithi Atoll (Yap State, Federated States of Micronesia) and confirms a pattern observed by local people that an 'opportunistic' scleractinian coral (Montipora sp.) is associated with more highly impacted reefs. Our findings suggest that small human populations (subsistence fishing) can nevertheless have considerable ecological impacts on reefs due, in part, to changes in fishing practices rather than overfishing per se, as well as larger global trends. Findings from this work can assist in building local capacity to manage reef resources across an atoll-wide scale, and illustrates the importance of anthropogenic impact even in small communities.

Insertion sequence elements (IS elements) are proposed to play major roles in shaping the genetic and phenotypic landscapes of prokaryotic cells. Recent evidence has raised the possibility that environmental stress conditions increase IS hopping into new sites, and often such hopping has the phenotypic effect of relieving the stress. Although stress-induced targeted mutations have been reported for a number of E. coli genes, the glpFK (glycerol utilization) and the cryptic bglGFB (β-glucoside utilization) systems are among the best characterized where the effects of IS insertion-mediated gene activation are well-characterized at the molecular level. In the glpFK system, starvation of cells incapable of utilizing glycerol leads to an IS5 insertion event that activates the glpFK operon, and enables glycerol utilization. In the case of the cryptic bglGFB operon, insertion of IS5 (and other IS elements) into a specific region in the bglG upstream sequence has the effect of activating the operon in both growing cells, and in starving cells. However, a major unanswered question in the glpFK system, the bgl system, as well as other examples, has been why the insertion events are promoted at specific locations, and how the specific stress condition (glycerol starvation for example) can be mechanistically linked to enhanced insertion at a specific locus. In this paper, we show that a specific DNA structural feature (superhelical stress-induced duplex destabilization, SIDD) is associated with "stress-induced" IS5 insertion in the glpFK, bglGFB, flhDC, fucAO and nfsB systems. We propose a speculative mechanistic model that links specific environmental conditions to the unmasking of an insertional hotspot in the glpFK system. We demonstrate that experimentally altering the predicted stability of a SIDD element in the nfsB gene significantly impacts IS5 insertion at its hotspot.

Insertion sequence elements (IS elements) are proposed to play major roles in shaping the genetic and phenotypic landscapes of prokaryotic cells. Recent evidence has raised the possibility that environmental stress conditions increase IS hopping into new sites, and often such hopping has the phenotypic effect of relieving the stress. Although stress-induced targeted mutations have been reported for a number of E. coli genes, the glpFK (glycerol utilization) and the cryptic bglGFB (β-glucoside utilization) systems are among the best characterized where the effects of IS insertion-mediated gene activation are well-characterized at the molecular level. In the glpFK system, starvation of cells incapable of utilizing glycerol leads to an IS5 insertion event that activates the glpFK operon, and enables glycerol utilization. In the case of the cryptic bglGFB operon, insertion of IS5 (and other IS elements) into a specific region in the bglG upstream sequence has the effect of activating the operon in both growing cells, and in starving cells. However, a major unanswered question in the glpFK system, the bgl system, as well as other examples, has been why the insertion events are promoted at specific locations, and how the specific stress condition (glycerol starvation for example) can be mechanistically linked to enhanced insertion at a specific locus. In this paper, we show that a specific DNA structural feature (superhelical stress-induced duplex destabilization, SIDD) is associated with "stress-induced" IS5 insertion in the glpFK, bglGFB, flhDC, fucAO and nfsB systems. We propose a speculative mechanistic model that links specific environmental conditions to the unmasking of an insertional hotspot in the glpFK system. We demonstrate that experimentally altering the predicted stability of a SIDD element in the nfsB gene significantly impacts IS5 insertion at its hotspot.

Cofilin and other Actin-regulating proteins are essential in regulating the shape of dendritic spines, which are sites of neuronal communications in the brain, and their malfunctions are implicated in neurodegeneration related to aging. The analysis of cofilin motility in dendritic spines using fluorescence video-microscopy may allow for the discovery of its effects on synaptic functions. To date, the flow of cofilin has not been analyzed by automatic means. This paper presents Dendrite Protein Analysis (DendritePA), a novel automated pattern recognition software to analyze protein trafficking in neurons. Using spatiotemporal information present in multichannel fluorescence videos, the DendritePA generates a temporal maximum intensity projection that enhances the signal-to-noise ratio of important biological structures, segments and tracks dendritic spines, estimates the density of proteins in spines, and analyzes the flux of proteins through the dendrite/spine boundary. The motion of a dendritic spine is used to generate spine energy images, which are used to automatically classify the shape of common dendritic spines such as stubby, mushroom, or thin. By tracking dendritic spines over time and using their intensity profiles, the system can analyze the flux patterns of cofilin and other fluorescently stained proteins. The cofilin flux patterns are found to correlate with the dynamic changes in dendritic spine shapes. Our results also have shown that the activation of cofilin using genetic manipulations leads to immature spines while its inhibition results in an increase in mature spines.

Marine Protected Areas (MPA) are important management tools shown to protect marine organisms, restore biomass, and increase fisheries yields. While MPAs have been successful in meeting these goals for many relatively sedentary species, highly mobile organisms may get few benefits from this type of spatial protection due to their frequent movement outside the protected area. The use of a large MPA can compensate for extensive movement, but testing this empirically is challenging, as it requires both large areas and sufficient time series to draw conclusions. To overcome this limitation, MPA models have been used to identify designs and predict potential outcomes, but these simulations are highly sensitive to the assumptions describing the organism's movements. Due to recent improvements in computational simulations, it is now possible to include very complex movement assumptions in MPA models (e.g. Individual Based Model). These have renewed interest in MPA simulations, which implicitly assume that increasing the detail in fish movement overcomes the sensitivity to the movement assumptions. Nevertheless, a systematic comparison of the designs and outcomes obtained under different movement assumptions has not been done. In this paper, we use an individual based model, interconnected to population and fishing fleet models, to explore the value of increasing the detail of the movement assumptions using four scenarios of increasing behavioral complexity: a) random, diffusive movement, b) aggregations, c) aggregations that respond to environmental forcing (e.g. sea surface temperature), and d) aggregations that respond to environmental forcing and are transported by currents. We then compare these models to determine how the assumptions affect MPA design, and therefore the effective protection of the stocks. Our results show that the optimal MPA size to maximize fisheries benefits increases as movement complexity increases from ~10% for the diffusive assumption to ~30% when full environment forcing was used. We also found that in cases of limited understanding of the movement dynamics of a species, simplified assumptions can be used to provide a guide for the minimum MPA size needed to effectively protect the stock. However, using oversimplified assumptions can produce suboptimal designs and lead to a density underestimation of ca. 30%; therefore, the main value of detailed movement dynamics is to provide more reliable MPA design and predicted outcomes. Large MPAs can be effective in recovering overfished stocks, protect pelagic fish and provide significant increases in fisheries yields. Our models provide a means to empirically test this spatial management tool, which theoretical evidence consistently suggests as an effective alternative to managing highly mobile pelagic stocks.

United States-based biorepositories are on the cusp of substantial change in regulatory oversight at the same time that they are increasingly including samples and data from large populations, e.g. all patients in healthcare system. It is appropriate to engage stakeholders from these populations in new governance arrangements. We sought to describe community recommendations for biorepository governance and oversight using deliberative community engagement (DCE), a qualitative research method designed to elicit lay perspectives on complex technical issues. We asked for stakeholders to provide input on governance of large biorepositories at the University of California (UC), a public university. We defined state residents as stakeholders and recruited residents from two large metropolitan areas, Los Angeles (LA) and San Francisco (SF). In LA, we recruited English and Spanish speakers; in SF the DCE was conducted in English only. We recruited individuals who had completed the 2009 California Health Interview Survey and were willing to be re-contacted for future studies. Using stratified random sampling (by age, education, race/ethnicity), we contacted 162 potential deliberants of whom 53 agreed to participate and 51 completed the 4-day DCE in June (LA) and September-October (SF), 2013. Each DCE included discussion among deliberants facilitated by a trained staff and simultaneously-translated in LA. Deliberants also received a briefing book describing biorepository operations and regulation. During the final day of the DCE, deliberants voted on governance and oversight recommendations using an audience response system. This paper describes 23 recommendations (of 57 total) that address issues including: educating the public, sharing samples broadly, monitoring researcher behavior, using informative consent procedures, and involving community members in a transparent process of biobank governance. This project demonstrates the feasibility of obtaining meaningful input on biorepository governance from diverse lay stakeholders. Such input should be considered as research institutions respond to changes in biorepository regulation.

BackgroundVoluntary Medical Male Circumcision (VMMC) is an effective method for HIV prevention and the World Health Organization (WHO) has recommended its expansion in 14 African countries with a high prevalence of HIV and low prevalence of male circumcision. The WHO has recently pre-qualified the PrePex device, a non-surgical male circumcision device, which reduces procedure time, can increase acceptability of VMMC, and can expand the set of potential provider cadres. The PrePex device was introduced in Zimbabwe as a way to scale-up VMMC services in the country. With the rapid scale-up of the PrePex device, as well as other similar devices, a strong surveillance system to detect adverse events (AE) is needed to monitor the safety profile of these devices. We performed a systems-based evaluation of the PrePex device AE active surveillance system in Zimbabwe.MethodsThe evaluation was based on the Centers for Disease Control and Prevention's Updated Guidelines for Evaluating Public Health Surveillance Systems. We adapted these guidelines to fit our local context. The evaluation incorporated the review of the standard operating procedures and surveillance system documents. Additionally, structured, in-person interviews were performed with key stakeholders who were users of the surveillance system at various levels. These key stakeholders were from the Ministry of Health, implementing partners, and health facilities in Harare.ResultsClients were requested to return to the facility for follow-up on days 7, 14 and 49 after placement of the device. In the event of a severe AE, a standard report was generated by the health facility and relayed to the Ministry of Health Child and Care and donor agencies through predefined channels within 24 hours of diagnosis. Clinic staff reported difficulties with the amount of documentation required to follow up with clients and to report AEs. The surveillance system's acceptability among users interviewed was high, and users were motivated to identify all possible AEs related to this device. The surveillance system was purely paper-based and both duplicate and discrepant reporting forms between sites were identified.ConclusionThe PrePex AE active surveillance system was well accepted among participants in the health system. However, the amount of documentation which was required to follow-up with patients was a major barrier within the system, and might lead to decreased timeliness and quality of reporting. A passive surveillance system supported by electronic reporting would improve acceptance of the program.

This paper presents the results of a consensus-driven process identifying 50 priority research questions for historical ecology obtained through crowdsourcing, literature reviews, and in-person workshopping. A deliberative approach was designed to maximize discussion and debate with defined outcomes. Two in-person workshops (in Sweden and Canada) over the course of two years and online discussions were peer facilitated to define specific key questions for historical ecology from anthropological and archaeological perspectives. The aim of this research is to showcase the variety of questions that reflect the broad scope for historical-ecological research trajectories across scientific disciplines. Historical ecology encompasses research concerned with decadal, centennial, and millennial human-environmental interactions, and the consequences that those relationships have in the formation of contemporary landscapes. Six interrelated themes arose from our consensus-building workshop model: (1) climate and environmental change and variability; (2) multi-scalar, multi-disciplinary; (3) biodiversity and community ecology; (4) resource and environmental management and governance; (5) methods and applications; and (6) communication and policy. The 50 questions represented by these themes highlight meaningful trends in historical ecology that distill the field down to three explicit findings. First, historical ecology is fundamentally an applied research program. Second, this program seeks to understand long-term human-environment interactions with a focus on avoiding, mitigating, and reversing adverse ecological effects. Third, historical ecology is part of convergent trends toward transdisciplinary research science, which erodes scientific boundaries between the cultural and natural.

United States-based biorepositories are on the cusp of substantial change in regulatory oversight at the same time that they are increasingly including samples and data from large populations, e.g. all patients in healthcare system. It is appropriate to engage stakeholders from these populations in new governance arrangements. We sought to describe community recommendations for biorepository governance and oversight using deliberative community engagement (DCE), a qualitative research method designed to elicit lay perspectives on complex technical issues. We asked for stakeholders to provide input on governance of large biorepositories at the University of California (UC), a public university. We defined state residents as stakeholders and recruited residents from two large metropolitan areas, Los Angeles (LA) and San Francisco (SF). In LA, we recruited English and Spanish speakers; in SF the DCE was conducted in English only. We recruited individuals who had completed the 2009 California Health Interview Survey and were willing to be re-contacted for future studies. Using stratified random sampling (by age, education, race/ethnicity), we contacted 162 potential deliberants of whom 53 agreed to participate and 51 completed the 4-day DCE in June (LA) and September-October (SF), 2013. Each DCE included discussion among deliberants facilitated by a trained staff and simultaneously-translated in LA. Deliberants also received a briefing book describing biorepository operations and regulation. During the final day of the DCE, deliberants voted on governance and oversight recommendations using an audience response system. This paper describes 23 recommendations (of 57 total) that address issues including: educating the public, sharing samples broadly, monitoring researcher behavior, using informative consent procedures, and involving community members in a transparent process of biobank governance. This project demonstrates the feasibility of obtaining meaningful input on biorepository governance from diverse lay stakeholders. Such input should be considered as research institutions respond to changes in biorepository regulation.

Cofilin and other Actin-regulating proteins are essential in regulating the shape of dendritic spines, which are sites of neuronal communications in the brain, and their malfunctions are implicated in neurodegeneration related to aging. The analysis of cofilin motility in dendritic spines using fluorescence video-microscopy may allow for the discovery of its effects on synaptic functions. To date, the flow of cofilin has not been analyzed by automatic means. This paper presents Dendrite Protein Analysis (DendritePA), a novel automated pattern recognition software to analyze protein trafficking in neurons. Using spatiotemporal information present in multichannel fluorescence videos, the DendritePA generates a temporal maximum intensity projection that enhances the signal-to-noise ratio of important biological structures, segments and tracks dendritic spines, estimates the density of proteins in spines, and analyzes the flux of proteins through the dendrite/spine boundary. The motion of a dendritic spine is used to generate spine energy images, which are used to automatically classify the shape of common dendritic spines such as stubby, mushroom, or thin. By tracking dendritic spines over time and using their intensity profiles, the system can analyze the flux patterns of cofilin and other fluorescently stained proteins. The cofilin flux patterns are found to correlate with the dynamic changes in dendritic spine shapes. Our results also have shown that the activation of cofilin using genetic manipulations leads to immature spines while its inhibition results in an increase in mature spines.

The dynamic relationship between reefs and the people who utilize them at a subsistence level is poorly understood. This paper characterizes atoll-scale patterns in shallow coral reef habitat and fish community structure, and correlates these with environmental characteristics and anthropogenic factors, critical to conservation efforts for the reefs and the people who depend on them. Hierarchical clustering analyses by site for benthic composition and fish community resulted in the same 3 major clusters: cluster 1-oceanic (close proximity to deep water) and uninhabited (low human impact); cluster 2-oceanic and inhabited (high human impact); and cluster 3-lagoonal (facing the inside of the lagoon) and inhabited (highest human impact). Distance from village, reef exposure to deep water and human population size had the greatest effect in predicting the fish and benthic community structure. Our study demonstrates a strong association between benthic and fish community structure and human use across the Ulithi Atoll (Yap State, Federated States of Micronesia) and confirms a pattern observed by local people that an 'opportunistic' scleractinian coral (Montipora sp.) is associated with more highly impacted reefs. Our findings suggest that small human populations (subsistence fishing) can nevertheless have considerable ecological impacts on reefs due, in part, to changes in fishing practices rather than overfishing per se, as well as larger global trends. Findings from this work can assist in building local capacity to manage reef resources across an atoll-wide scale, and illustrates the importance of anthropogenic impact even in small communities.

BackgroundVoluntary Medical Male Circumcision (VMMC) is an effective method for HIV prevention and the World Health Organization (WHO) has recommended its expansion in 14 African countries with a high prevalence of HIV and low prevalence of male circumcision. The WHO has recently pre-qualified the PrePex device, a non-surgical male circumcision device, which reduces procedure time, can increase acceptability of VMMC, and can expand the set of potential provider cadres. The PrePex device was introduced in Zimbabwe as a way to scale-up VMMC services in the country. With the rapid scale-up of the PrePex device, as well as other similar devices, a strong surveillance system to detect adverse events (AE) is needed to monitor the safety profile of these devices. We performed a systems-based evaluation of the PrePex device AE active surveillance system in Zimbabwe.MethodsThe evaluation was based on the Centers for Disease Control and Prevention's Updated Guidelines for Evaluating Public Health Surveillance Systems. We adapted these guidelines to fit our local context. The evaluation incorporated the review of the standard operating procedures and surveillance system documents. Additionally, structured, in-person interviews were performed with key stakeholders who were users of the surveillance system at various levels. These key stakeholders were from the Ministry of Health, implementing partners, and health facilities in Harare.ResultsClients were requested to return to the facility for follow-up on days 7, 14 and 49 after placement of the device. In the event of a severe AE, a standard report was generated by the health facility and relayed to the Ministry of Health Child and Care and donor agencies through predefined channels within 24 hours of diagnosis. Clinic staff reported difficulties with the amount of documentation required to follow up with clients and to report AEs. The surveillance system's acceptability among users interviewed was high, and users were motivated to identify all possible AEs related to this device. The surveillance system was purely paper-based and both duplicate and discrepant reporting forms between sites were identified.ConclusionThe PrePex AE active surveillance system was well accepted among participants in the health system. However, the amount of documentation which was required to follow-up with patients was a major barrier within the system, and might lead to decreased timeliness and quality of reporting. A passive surveillance system supported by electronic reporting would improve acceptance of the program.

BackgroundAntiretroviral therapy has increased longevity for people living with HIV (PLWH). As a result, PLWH increasingly experience the common diseases of aging and the resources needed to manage these comorbidities are increasing. This paper characterizes the number and types of comorbidities diagnosed among PLWH covered by Medicare and examines how non-HIV comorbidities relate to outpatient, inpatient, and pharmaceutical expenditures.MethodsThe study examined Medicare expenditures for 9767 HIV-positive Californians enrolled in Medicare in 2010 (7208 persons dually covered by Medicare and Medicaid and 2559 with Medicare only). Costs included both out of pocket costs and those paid by Medicare and Medicaid. Comorbidities were determined by examining diagnosis codes.FindingsMedicare expenditures for Californians with HIV averaged $47,036 in 2010, with drugs accounting for about 2/3 of the total and outpatient costs 19% of the total. Inpatient costs accounted for 18% of the total. About 64% of the sample had at least one comorbidity in addition to HIV. Cross-validation showed that adding information on comorbidities to the quantile regression improved the accuracy of predicted individual expenditures. Non-HIV comorbidities relating to health habits-diabetes, hypertension, liver disease (hepatitis C), renal insufficiency-are common among PLWH. Cancer was relatively rare, but added significantly to cost. Comorbidities had little effect on pharmaceutical costs, which were dominated by the cost of antiretroviral therapy, but had a major effect on hospital admission.ConclusionsComorbidities are prevalent among PLWH and add substantially to treatment costs for PLWH. Many of these comorbidities relate to health habits that could be addressed with additional prevention in ambulatory care, thereby improving health outcomes and ultimately reducing costs.

Marine Protected Areas (MPA) are important management tools shown to protect marine organisms, restore biomass, and increase fisheries yields. While MPAs have been successful in meeting these goals for many relatively sedentary species, highly mobile organisms may get few benefits from this type of spatial protection due to their frequent movement outside the protected area. The use of a large MPA can compensate for extensive movement, but testing this empirically is challenging, as it requires both large areas and sufficient time series to draw conclusions. To overcome this limitation, MPA models have been used to identify designs and predict potential outcomes, but these simulations are highly sensitive to the assumptions describing the organism's movements. Due to recent improvements in computational simulations, it is now possible to include very complex movement assumptions in MPA models (e.g. Individual Based Model). These have renewed interest in MPA simulations, which implicitly assume that increasing the detail in fish movement overcomes the sensitivity to the movement assumptions. Nevertheless, a systematic comparison of the designs and outcomes obtained under different movement assumptions has not been done. In this paper, we use an individual based model, interconnected to population and fishing fleet models, to explore the value of increasing the detail of the movement assumptions using four scenarios of increasing behavioral complexity: a) random, diffusive movement, b) aggregations, c) aggregations that respond to environmental forcing (e.g. sea surface temperature), and d) aggregations that respond to environmental forcing and are transported by currents. We then compare these models to determine how the assumptions affect MPA design, and therefore the effective protection of the stocks. Our results show that the optimal MPA size to maximize fisheries benefits increases as movement complexity increases from ~10% for the diffusive assumption to ~30% when full environment forcing was used. We also found that in cases of limited understanding of the movement dynamics of a species, simplified assumptions can be used to provide a guide for the minimum MPA size needed to effectively protect the stock. However, using oversimplified assumptions can produce suboptimal designs and lead to a density underestimation of ca. 30%; therefore, the main value of detailed movement dynamics is to provide more reliable MPA design and predicted outcomes. Large MPAs can be effective in recovering overfished stocks, protect pelagic fish and provide significant increases in fisheries yields. Our models provide a means to empirically test this spatial management tool, which theoretical evidence consistently suggests as an effective alternative to managing highly mobile pelagic stocks.

BackgroundAntiretroviral therapy has increased longevity for people living with HIV (PLWH). As a result, PLWH increasingly experience the common diseases of aging and the resources needed to manage these comorbidities are increasing. This paper characterizes the number and types of comorbidities diagnosed among PLWH covered by Medicare and examines how non-HIV comorbidities relate to outpatient, inpatient, and pharmaceutical expenditures.MethodsThe study examined Medicare expenditures for 9767 HIV-positive Californians enrolled in Medicare in 2010 (7208 persons dually covered by Medicare and Medicaid and 2559 with Medicare only). Costs included both out of pocket costs and those paid by Medicare and Medicaid. Comorbidities were determined by examining diagnosis codes.FindingsMedicare expenditures for Californians with HIV averaged $47,036 in 2010, with drugs accounting for about 2/3 of the total and outpatient costs 19% of the total. Inpatient costs accounted for 18% of the total. About 64% of the sample had at least one comorbidity in addition to HIV. Cross-validation showed that adding information on comorbidities to the quantile regression improved the accuracy of predicted individual expenditures. Non-HIV comorbidities relating to health habits-diabetes, hypertension, liver disease (hepatitis C), renal insufficiency-are common among PLWH. Cancer was relatively rare, but added significantly to cost. Comorbidities had little effect on pharmaceutical costs, which were dominated by the cost of antiretroviral therapy, but had a major effect on hospital admission.ConclusionsComorbidities are prevalent among PLWH and add substantially to treatment costs for PLWH. Many of these comorbidities relate to health habits that could be addressed with additional prevention in ambulatory care, thereby improving health outcomes and ultimately reducing costs.

Conscientious objection to abortion, clinicians’ refusal to perform legal abortions because of their religious or moral beliefs, has been the subject of increasing debate among bioethicists, policymakers, and public health advocates in recent years. Conscientious objection policies are intended to balance reproductive rights and clinicians’ beliefs. However, in practice, clinician objection can act as a barrier to abortion access–impinging on reproductive rights, and increasing unsafe abortion and related morbidity and mortality. There is little information about conscientious objection from a medical or public health perspective. A quantitative instrument is needed to assess prevalence of conscientious objection and to provide insight on its practice. This paper describes the development of a survey instrument to measure conscientious objection to abortion provision.Methods: A literature review, and in-depth formative interviews with stakeholders in Colombia were used to develop a conceptual model of conscientious objection. This model led to the development of a survey, which was piloted, and then administered, in Ghana.Results: The model posits three domains of conscientious objection that form the basis for the survey instrument: 1) beliefs about abortion and conscientious objection; 2) actions related to conscientious objection and abortion; and 3) self-identification as a conscientious objector.Conclusions: The instrument is intended to be used to assess prevalence among clinicians trained to provide abortions, and to gain insight on how conscientious objection is practiced in a variety of settings. Its results can inform more effective and appropriate strategies to regulate conscientious objection.

Acetone-butanol-ethanol (ABE) fermentation by clostridia has shown promise for industrial-scale production of biobutanol. However, the continuous ABE fermentation suffers from low product yield, titer, and productivity. Systems analysis of the continuous ABE fermentation will offer insights into its metabolic pathway as well as into optimal fermentation design and operation. For the ABE fermentation in continuous Clostridium acetobutylicum culture, this paper presents a kinetic model that includes the effects of key metabolic intermediates and enzymes as well as culture pH, product inhibition, and glucose inhibition. The kinetic model is used for elucidating the behavior of the ABE fermentation under the conditions that are most relevant to continuous cultures. To this end, dynamic sensitivity analysis is performed to systematically investigate the effects of culture conditions, reaction kinetics, and enzymes on the dynamics of the ABE production pathway. The analysis provides guidance for future metabolic engineering and fermentation optimization studies.

The NIF Registry developed and maintained by the Neuroscience Information Framework is a cooperative project aimed at cataloging research resources, e.g., software tools, databases and tissue banks, funded largely by governments and available as tools to research scientists. Although originally conceived for neuroscience, the NIF Registry has over the years broadened in the scope to include research resources of general relevance to biomedical research. The current number of research resources listed by the Registry numbers over 13K. The broadening in scope to biomedical science led us to re-christen the NIF Registry platform as SciCrunch. The NIF/SciCrunch Registry has been cataloging the resource landscape since 2006; as such, it serves as a valuable dataset for tracking the breadth, fate and utilization of these resources. Our experience shows research resources like databases are dynamic objects, that can change location and scope over time. Although each record is entered manually and human-curated, the current size of the registry requires tools that can aid in curation efforts to keep content up to date, including when and where such resources are used. To address this challenge, we have developed an open source tool suite, collectively termed RDW: Resource Disambiguator for the (Web). RDW is designed to help in the upkeep and curation of the registry as well as in enhancing the content of the registry by automated extraction of resource candidates from the literature. The RDW toolkit includes a URL extractor from papers, resource candidate screen, resource URL change tracker, resource content change tracker. Curators access these tools via a web based user interface. Several strategies are used to optimize these tools, including supervised and unsupervised learning algorithms as well as statistical text analysis. The complete tool suite is used to enhance and maintain the resource registry as well as track the usage of individual resources through an innovative literature citation index honed for research resources. Here we present an overview of the Registry and show how the RDW tools are used in curation and usage tracking.

IntroductionFemale sex workers (FSWs) are the second most affected population by HIV in Iran. However, their HIV testing practices are poorly understood. The aim of this study was to investigate testing and its associated factors among HIV negative FSWs.Materials and methodsUsing facility based sampling, 1005 FSWs were recruited in 14 cities of Iran in 2010. Biological and survey data were collected through dried blood spot testing and standardized risk assessment questionnaire, respectively. In this paper, the prevalence of HIV testing and its correlates were explored among 714 HIV-negative FSWs using descriptive statistics and logistic regression models.ResultsOverall 65.4% had not tested in the past year. Only 27.5% had tested in the past year and received their results. FSWs who perceived themselves at risk of HIV (Adjusted Odds Ratio (AOR) = 8.35, 95% CI: 1.46, 47.6), had received free condom during past year (AOR = 3.90, 95% CI: 1.67, 9.14), started sex work at an older age (AOR18-24 = 2.83, 95% CI: 1.14, 7.0; AOR >24 = 2.76, 95% CI: 1.11, 6.84), and knew an HIV testing site (AOR = 5.67, 95% CI: 2.60, 12.4) had a significantly higher chance of having a recent HIV test result.ConclusionsLess than one third of FSWs in Iran knew their recent HIV status. Interventions to help FSWs evaluate their potential risk for HIV and integrate HIV testing services in condom distribution programs, could be viable strategies in increasing HIV testing uptake among FSWs. Health policy makers should also try to de-stigmatize HIV testing, identify the barriers to HIV testing, and make HIV testing sites more visible to FSWs.

BackgroundDengue virus (and Chikungunya and Zika viruses) is transmitted by Aedes aegypti and Aedes albopictus mosquitoes and causes considerable human morbidity and mortality. As there is currently no vaccine or chemoprophylaxis to protect people from dengue virus infection, vector control is the only viable option for disease prevention. The purpose of this paper is to illustrate the design and placement process for an attractive lethal ovitrap to reduce vector populations and to describe lessons learned in the development of the trap.MethodsThis study was conducted in 2010 in Iquitos, Peru and Lopburi Province, Thailand and used an iterative community-based participatory approach to adjust design specifications of the trap, based on community members' perceptions and feedback, entomological findings in the lab, and design and research team observations. Multiple focus group discussions (FGD) were held over a 6 month period, stratified by age, sex and motherhood status, to inform the design process. Trap testing transitioned from the lab to within households.ResultsThrough an iterative process of working with specifications from the research team, findings from the laboratory testing, and feedback from FGD, the design team narrowed trap design options from 22 to 6. Comments from the FGD centered on safety for children and pets interacting with traps, durability, maintenance issues, and aesthetics. Testing in the laboratory involved releasing groups of 50 gravid Ae. aegypti in walk-in rooms and assessing what percentage were caught in traps of different colors, with different trap cover sizes, and placed under lighter or darker locations. Two final trap models were mocked up and tested in homes for a week; one model was the top choice in both Iquitos and Lopburi.DiscussionThe community-based participatory process was essential for the development of novel traps that provided effective vector control, but also met the needs and concerns of community members.

This paper introduces a bibliometric, citation network-based method for assessing the social validation of novel research, and applies this method to the development of high-throughput toxicology research at the US Environmental Protection Agency. Social validation refers to the acceptance of novel research methods by a relevant scientific community; it is formally independent of the technical validation of methods, and is frequently studied in history, philosophy, and social studies of science using qualitative methods. The quantitative methods introduced here find that high-throughput toxicology methods are spread throughout a large and well-connected research community, which suggests high social validation. Further assessment of social validation involving mixed qualitative and quantitative methods are discussed in the conclusion.

There is great interest in the restoration and conservation of coastal habitats for protection from flooding and erosion. This is evidenced by the growing number of analyses and reviews of the effectiveness of habitats as natural defences and increasing funding world-wide for nature-based defences-i.e. restoration projects aimed at coastal protection; yet, there is no synthetic information on what kinds of projects are effective and cost effective for this purpose. This paper addresses two issues critical for designing restoration projects for coastal protection: (i) a synthesis of the costs and benefits of projects designed for coastal protection (nature-based defences) and (ii) analyses of the effectiveness of coastal habitats (natural defences) in reducing wave heights and the biophysical parameters that influence this effectiveness. We (i) analyse data from sixty-nine field measurements in coastal habitats globally and examine measures of effectiveness of mangroves, salt-marshes, coral reefs and seagrass/kelp beds for wave height reduction; (ii) synthesise the costs and coastal protection benefits of fifty-two nature-based defence projects and; (iii) estimate the benefits of each restoration project by combining information on restoration costs with data from nearby field measurements. The analyses of field measurements show that coastal habitats have significant potential for reducing wave heights that varies by habitat and site. In general, coral reefs and salt-marshes have the highest overall potential. Habitat effectiveness is influenced by: a) the ratios of wave height-to-water depth and habitat width-to-wavelength in coral reefs; and b) the ratio of vegetation height-to-water depth in salt-marshes. The comparison of costs of nature-based defence projects and engineering structures show that salt-marshes and mangroves can be two to five times cheaper than a submerged breakwater for wave heights up to half a metre and, within their limits, become more cost effective at greater depths. Nature-based defence projects also report benefits ranging from reductions in storm damage to reductions in coastal structure costs.

The tendency to mimic the behaviour of others is affected by a variety of social factors, and it has been argued that such "mirroring" is often unconsciously deployed as a means of increasing affiliation during interpersonal interactions. However, the relationship between automatic motor imitation and status/power is currently unclear. This paper reports five experiments that investigated whether social status (Experiments 1, 2, and 3) or power (Experiments 4 and 5) had a moderating effect on automatic imitation (AI) in finger-movement tasks, using a series of different manipulations. Experiments 1 and 2 manipulated the social status of the observed person using an associative learning task. Experiment 3 manipulated social status via perceived competence at a simple computer game. Experiment 4 manipulated participants' power (relative to the actors) in a card-choosing task. Finally, Experiment 5 primed participants using a writing task, to induce the sense of being powerful or powerless. No significant interactions were found between congruency and social status/power in any of the studies. Additionally, Bayesian hypothesis testing indicated that the null hypothesis should be favoured over the experimental hypothesis in all five studies. These findings are discussed in terms of their implications for AI tasks, social effects on mimicry, and the hypothesis of mimicry as a strategic mechanism to promote affiliation.

While climate scientists have developed high resolution data sets on the distribution of climate risks, we still lack comparable data on the local distribution of public climate change opinions. This paper provides the first effort to estimate local climate and energy opinion variability outside the United States. Using a multi-level regression and post-stratification (MRP) approach, we estimate opinion in federal electoral districts and provinces. We demonstrate that a majority of the Canadian public consistently believes that climate change is happening. Belief in climate change's causes varies geographically, with more people attributing it to human activity in urban as opposed to rural areas. Most prominently, we find majority support for carbon cap and trade policy in every province and district. By contrast, support for carbon taxation is more heterogeneous. Compared to the distribution of US climate opinions, Canadians believe climate change is happening at higher levels. This new opinion data set will support climate policy analysis and climate policy decision making at national, provincial and local levels.

Electrolysis, electrochemotherapy with reversible electroporation, nanosecond pulsed electric fields and irreversible electroporation are valuable non-thermal electricity based tissue ablation technologies. This paper reports results from the first large animal study of a new non-thermal tissue ablation technology that employs "Synergistic electrolysis and electroporation" (SEE). The goal of this pre-clinical study is to expand on earlier studies with small animals and use the pig liver to establish SEE treatment parameters of clinical utility. We examined two SEE methods. One of the methods employs multiple electrochemotherapy-type reversible electroporation magnitude pulses, designed in such a way that the charge delivered during the electroporation pulses generates the electrolytic products. The second SEE method combines the delivery of a small number of electrochemotherapy magnitude electroporation pulses with a low voltage electrolysis generating DC current in three different ways. We show that both methods can produce lesion with dimensions of clinical utility, without the need to inject drugs as in electrochemotherapy, faster than with conventional electrolysis and with lower electric fields than irreversible electroporation and nanosecond pulsed ablation.

Textural analysis might give new insights into the quantitative characterization of metabolically active tumors. More than thirty textural parameters have been investigated in former F18-FDG studies already. The purpose of the paper is to declare basic requirements as a selection strategy to identify the most appropriate heterogeneity parameters to measure textural features. Our predefined requirements were: a reliable heterogeneity parameter has to be volume independent, reproducible, and suitable for expressing quantitatively the degree of heterogeneity. Based on this criteria, we compared various suggested measures of homogeneity. A homogeneous cylindrical phantom was measured on three different PET/CT scanners using the commonly used protocol. In addition, a custom-made inhomogeneous tumor insert placed into the NEMA image quality phantom was imaged with a set of acquisition times and several different reconstruction protocols. PET data of 65 patients with proven lung lesions were retrospectively analyzed as well. Four heterogeneity parameters out of 27 were found as the most attractive ones to characterize the textural properties of metabolically active tumors in FDG PET images. These four parameters included Entropy, Contrast, Correlation, and Coefficient of Variation. These parameters were independent of delineated tumor volume (bigger than 25-30 ml), provided reproducible values (relative standard deviation< 10%), and showed high sensitivity to changes in heterogeneity. Phantom measurements are a viable way to test the reliability of heterogeneity parameters that would be of interest to nuclear imaging clinicians.

There is a foundational need for quality control tools in stem cell laboratories engaged in basic research, regenerative therapies, and toxicological studies. These tools require automated methods for evaluating cell processes and quality during in vitro passaging, expansion, maintenance, and differentiation. In this paper, an unbiased, automated high-content profiling toolkit, StemCellQC, is presented that non-invasively extracts information on cell quality and cellular processes from time-lapse phase-contrast videos. Twenty four (24) morphological and dynamic features were analyzed in healthy, unhealthy, and dying human embryonic stem cell (hESC) colonies to identify those features that were affected in each group. Multiple features differed in the healthy versus unhealthy/dying groups, and these features were linked to growth, motility, and death. Biomarkers were discovered that predicted cell processes before they were detectable by manual observation. StemCellQC distinguished healthy and unhealthy/dying hESC colonies with 96% accuracy by non-invasively measuring and tracking dynamic and morphological features over 48 hours. Changes in cellular processes can be monitored by StemCellQC and predictions can be made about the quality of pluripotent stem cell colonies. This toolkit reduced the time and resources required to track multiple pluripotent stem cell colonies and eliminated handling errors and false classifications due to human bias. StemCellQC provided both user-specified and classifier-determined analysis in cases where the affected features are not intuitive or anticipated. Video analysis algorithms allowed assessment of biological phenomena using automatic detection analysis, which can aid facilities where maintaining stem cell quality and/or monitoring changes in cellular processes are essential. In the future StemCellQC can be expanded to include other features, cell types, treatments, and differentiating cells.

This paper introduces a bibliometric, citation network-based method for assessing the social validation of novel research, and applies this method to the development of high-throughput toxicology research at the US Environmental Protection Agency. Social validation refers to the acceptance of novel research methods by a relevant scientific community; it is formally independent of the technical validation of methods, and is frequently studied in history, philosophy, and social studies of science using qualitative methods. The quantitative methods introduced here find that high-throughput toxicology methods are spread throughout a large and well-connected research community, which suggests high social validation. Further assessment of social validation involving mixed qualitative and quantitative methods are discussed in the conclusion.

Textural analysis might give new insights into the quantitative characterization of metabolically active tumors. More than thirty textural parameters have been investigated in former F18-FDG studies already. The purpose of the paper is to declare basic requirements as a selection strategy to identify the most appropriate heterogeneity parameters to measure textural features. Our predefined requirements were: a reliable heterogeneity parameter has to be volume independent, reproducible, and suitable for expressing quantitatively the degree of heterogeneity. Based on this criteria, we compared various suggested measures of homogeneity. A homogeneous cylindrical phantom was measured on three different PET/CT scanners using the commonly used protocol. In addition, a custom-made inhomogeneous tumor insert placed into the NEMA image quality phantom was imaged with a set of acquisition times and several different reconstruction protocols. PET data of 65 patients with proven lung lesions were retrospectively analyzed as well. Four heterogeneity parameters out of 27 were found as the most attractive ones to characterize the textural properties of metabolically active tumors in FDG PET images. These four parameters included Entropy, Contrast, Correlation, and Coefficient of Variation. These parameters were independent of delineated tumor volume (bigger than 25-30 ml), provided reproducible values (relative standard deviation< 10%), and showed high sensitivity to changes in heterogeneity. Phantom measurements are a viable way to test the reliability of heterogeneity parameters that would be of interest to nuclear imaging clinicians.

Single-molecule Förster Resonance Energy Transfer (smFRET) allows probing intermolecular interactions and conformational changes in biomacromolecules, and represents an invaluable tool for studying cellular processes at the molecular scale. smFRET experiments can detect the distance between two fluorescent labels (donor and acceptor) in the 3-10 nm range. In the commonly employed confocal geometry, molecules are free to diffuse in solution. When a molecule traverses the excitation volume, it emits a burst of photons, which can be detected by single-photon avalanche diode (SPAD) detectors. The intensities of donor and acceptor fluorescence can then be related to the distance between the two fluorophores. While recent years have seen a growing number of contributions proposing improvements or new techniques in smFRET data analysis, rarely have those publications been accompanied by software implementation. In particular, despite the widespread application of smFRET, no complete software package for smFRET burst analysis is freely available to date. In this paper, we introduce FRETBursts, an open source software for analysis of freely-diffusing smFRET data. FRETBursts allows executing all the fundamental steps of smFRET bursts analysis using state-of-the-art as well as novel techniques, while providing an open, robust and well-documented implementation. Therefore, FRETBursts represents an ideal platform for comparison and development of new methods in burst analysis. We employ modern software engineering principles in order to minimize bugs and facilitate long-term maintainability. Furthermore, we place a strong focus on reproducibility by relying on Jupyter notebooks for FRETBursts execution. Notebooks are executable documents capturing all the steps of the analysis (including data files, input parameters, and results) and can be easily shared to replicate complete smFRET analyzes. Notebooks allow beginners to execute complex workflows and advanced users to customize the analysis for their own needs. By bundling analysis description, code and results in a single document, FRETBursts allows to seamless share analysis workflows and results, encourages reproducibility and facilitates collaboration among researchers in the single-molecule community.

There is a foundational need for quality control tools in stem cell laboratories engaged in basic research, regenerative therapies, and toxicological studies. These tools require automated methods for evaluating cell processes and quality during in vitro passaging, expansion, maintenance, and differentiation. In this paper, an unbiased, automated high-content profiling toolkit, StemCellQC, is presented that non-invasively extracts information on cell quality and cellular processes from time-lapse phase-contrast videos. Twenty four (24) morphological and dynamic features were analyzed in healthy, unhealthy, and dying human embryonic stem cell (hESC) colonies to identify those features that were affected in each group. Multiple features differed in the healthy versus unhealthy/dying groups, and these features were linked to growth, motility, and death. Biomarkers were discovered that predicted cell processes before they were detectable by manual observation. StemCellQC distinguished healthy and unhealthy/dying hESC colonies with 96% accuracy by non-invasively measuring and tracking dynamic and morphological features over 48 hours. Changes in cellular processes can be monitored by StemCellQC and predictions can be made about the quality of pluripotent stem cell colonies. This toolkit reduced the time and resources required to track multiple pluripotent stem cell colonies and eliminated handling errors and false classifications due to human bias. StemCellQC provided both user-specified and classifier-determined analysis in cases where the affected features are not intuitive or anticipated. Video analysis algorithms allowed assessment of biological phenomena using automatic detection analysis, which can aid facilities where maintaining stem cell quality and/or monitoring changes in cellular processes are essential. In the future StemCellQC can be expanded to include other features, cell types, treatments, and differentiating cells.

The NIF Registry developed and maintained by the Neuroscience Information Framework is a cooperative project aimed at cataloging research resources, e.g., software tools, databases and tissue banks, funded largely by governments and available as tools to research scientists. Although originally conceived for neuroscience, the NIF Registry has over the years broadened in the scope to include research resources of general relevance to biomedical research. The current number of research resources listed by the Registry numbers over 13K. The broadening in scope to biomedical science led us to re-christen the NIF Registry platform as SciCrunch. The NIF/SciCrunch Registry has been cataloging the resource landscape since 2006; as such, it serves as a valuable dataset for tracking the breadth, fate and utilization of these resources. Our experience shows research resources like databases are dynamic objects, that can change location and scope over time. Although each record is entered manually and human-curated, the current size of the registry requires tools that can aid in curation efforts to keep content up to date, including when and where such resources are used. To address this challenge, we have developed an open source tool suite, collectively termed RDW: Resource Disambiguator for the (Web). RDW is designed to help in the upkeep and curation of the registry as well as in enhancing the content of the registry by automated extraction of resource candidates from the literature. The RDW toolkit includes a URL extractor from papers, resource candidate screen, resource URL change tracker, resource content change tracker. Curators access these tools via a web based user interface. Several strategies are used to optimize these tools, including supervised and unsupervised learning algorithms as well as statistical text analysis. The complete tool suite is used to enhance and maintain the resource registry as well as track the usage of individual resources through an innovative literature citation index honed for research resources. Here we present an overview of the Registry and show how the RDW tools are used in curation and usage tracking.

IntroductionForced migration is occurring at unprecedented levels. Forced migrants may be at risk for substance use for reasons including coping with traumatic experiences, co-morbid mental health disorders, acculturation challenges and social and economic inequality. This paper aimed to systematically review the literature examining substance use among forced migrants, and identify priority areas for intervention and future research.MethodsSeven medical, allied health and social science databases were searched from inception to September 2015 in accordance with PRISMA guidelines to identify original peer-reviewed articles describing any findings relating to alcohol and/or illicit drug use among refugees, internally displaced people (IDPs), asylum seekers, people displaced by disasters and deportees. A descriptive synthesis of evidence from quantitative studies was conducted, focusing primarily on studies which used validated measures of substance use. Synthesis of evidence from qualitative studies focused on identifying prominent themes relating to the contexts and consequences of substance use. Critical Appraisal Skills Programme (CASP) checklists were used to assess methodological quality of included studies.ResultsForty-four quantitative (82% cross-sectional), 16 qualitative and three mixed-methods studies were included. Ten studies were rated as high methodological quality (16%), 39 as moderate quality (62%) and 14 as low quality (22%). The majority of research was conducted among refugees, IDPs and asylum seekers (n = 55, 87%), predominantly in high-income settings. The highest-quality prevalence estimates of hazardous/harmful alcohol use ranged from 17%-36% in camp settings and 4%-7% in community settings. Few studies collected validated measures of illicit drug use. Seven studies compared substance use among forced migrants to other migrant or native-born samples. Among eight studies which conducted multivariable analysis, male sex, trauma exposure and symptoms of mental illness were commonly identified correlates of substance use.ConclusionOur understanding of substance use among forced migrants remains limited, particularly regarding persons displaced due to disasters, development and deportation. Despite a growing body of work among refugee-background populations, few studies include refugees in low and middle-income countries, where over 80% of the global refugee population resides. Findings suggest a need to integrate substance use prevention and treatment into services offered to forced migrants, particularly in camp settings. Efforts to develop and evaluate interventions to reduce substance use and related harms are needed.

There is great interest in the restoration and conservation of coastal habitats for protection from flooding and erosion. This is evidenced by the growing number of analyses and reviews of the effectiveness of habitats as natural defences and increasing funding world-wide for nature-based defences-i.e. restoration projects aimed at coastal protection; yet, there is no synthetic information on what kinds of projects are effective and cost effective for this purpose. This paper addresses two issues critical for designing restoration projects for coastal protection: (i) a synthesis of the costs and benefits of projects designed for coastal protection (nature-based defences) and (ii) analyses of the effectiveness of coastal habitats (natural defences) in reducing wave heights and the biophysical parameters that influence this effectiveness. We (i) analyse data from sixty-nine field measurements in coastal habitats globally and examine measures of effectiveness of mangroves, salt-marshes, coral reefs and seagrass/kelp beds for wave height reduction; (ii) synthesise the costs and coastal protection benefits of fifty-two nature-based defence projects and; (iii) estimate the benefits of each restoration project by combining information on restoration costs with data from nearby field measurements. The analyses of field measurements show that coastal habitats have significant potential for reducing wave heights that varies by habitat and site. In general, coral reefs and salt-marshes have the highest overall potential. Habitat effectiveness is influenced by: a) the ratios of wave height-to-water depth and habitat width-to-wavelength in coral reefs; and b) the ratio of vegetation height-to-water depth in salt-marshes. The comparison of costs of nature-based defence projects and engineering structures show that salt-marshes and mangroves can be two to five times cheaper than a submerged breakwater for wave heights up to half a metre and, within their limits, become more cost effective at greater depths. Nature-based defence projects also report benefits ranging from reductions in storm damage to reductions in coastal structure costs.

Resting-state functional brain imaging studies of network connectivity have long assumed that functional connections are stationary on the timescale of a typical scan. Interest in moving beyond this simplifying assumption has emerged only recently. The great hope is that training the right lens on time-varying properties of whole-brain network connectivity will shed additional light on previously concealed brain activation patterns characteristic of serious neurological or psychiatric disorders. We present evidence that multiple explicitly dynamical properties of time-varying whole-brain network connectivity are strongly associated with schizophrenia, a complex mental illness whose symptomatic presentation can vary enormously across subjects. As with so much brain-imaging research, a central challenge for dynamic network connectivity lies in determining transformations of the data that both reduce its dimensionality and expose features that are strongly predictive of important population characteristics. Our paper introduces an elegant, simple method of reducing and organizing data around which a large constellation of mutually informative and intuitive dynamical analyses can be performed. This framework combines a discrete multidimensional data-driven representation of connectivity space with four core dynamism measures computed from large-scale properties of each subject's trajectory, ie., properties not identifiable with any specific moment in time and therefore reasonable to employ in settings lacking inter-subject time-alignment, such as resting-state functional imaging studies. Our analysis exposes pronounced differences between schizophrenia patients (Nsz = 151) and healthy controls (Nhc = 163). Time-varying whole-brain network connectivity patterns are found to be markedly less dynamically active in schizophrenia patients, an effect that is even more pronounced in patients with high levels of hallucinatory behavior. To the best of our knowledge this is the first demonstration that high-level dynamic properties of whole-brain connectivity, generic enough to be commensurable under many decompositions of time-varying connectivity data, exhibit robust and systematic differences between schizophrenia patients and healthy controls.

Electrolysis, electrochemotherapy with reversible electroporation, nanosecond pulsed electric fields and irreversible electroporation are valuable non-thermal electricity based tissue ablation technologies. This paper reports results from the first large animal study of a new non-thermal tissue ablation technology that employs "Synergistic electrolysis and electroporation" (SEE). The goal of this pre-clinical study is to expand on earlier studies with small animals and use the pig liver to establish SEE treatment parameters of clinical utility. We examined two SEE methods. One of the methods employs multiple electrochemotherapy-type reversible electroporation magnitude pulses, designed in such a way that the charge delivered during the electroporation pulses generates the electrolytic products. The second SEE method combines the delivery of a small number of electrochemotherapy magnitude electroporation pulses with a low voltage electrolysis generating DC current in three different ways. We show that both methods can produce lesion with dimensions of clinical utility, without the need to inject drugs as in electrochemotherapy, faster than with conventional electrolysis and with lower electric fields than irreversible electroporation and nanosecond pulsed ablation.

The tendency to mimic the behaviour of others is affected by a variety of social factors, and it has been argued that such "mirroring" is often unconsciously deployed as a means of increasing affiliation during interpersonal interactions. However, the relationship between automatic motor imitation and status/power is currently unclear. This paper reports five experiments that investigated whether social status (Experiments 1, 2, and 3) or power (Experiments 4 and 5) had a moderating effect on automatic imitation (AI) in finger-movement tasks, using a series of different manipulations. Experiments 1 and 2 manipulated the social status of the observed person using an associative learning task. Experiment 3 manipulated social status via perceived competence at a simple computer game. Experiment 4 manipulated participants' power (relative to the actors) in a card-choosing task. Finally, Experiment 5 primed participants using a writing task, to induce the sense of being powerful or powerless. No significant interactions were found between congruency and social status/power in any of the studies. Additionally, Bayesian hypothesis testing indicated that the null hypothesis should be favoured over the experimental hypothesis in all five studies. These findings are discussed in terms of their implications for AI tasks, social effects on mimicry, and the hypothesis of mimicry as a strategic mechanism to promote affiliation.

IntroductionForced migration is occurring at unprecedented levels. Forced migrants may be at risk for substance use for reasons including coping with traumatic experiences, co-morbid mental health disorders, acculturation challenges and social and economic inequality. This paper aimed to systematically review the literature examining substance use among forced migrants, and identify priority areas for intervention and future research.MethodsSeven medical, allied health and social science databases were searched from inception to September 2015 in accordance with PRISMA guidelines to identify original peer-reviewed articles describing any findings relating to alcohol and/or illicit drug use among refugees, internally displaced people (IDPs), asylum seekers, people displaced by disasters and deportees. A descriptive synthesis of evidence from quantitative studies was conducted, focusing primarily on studies which used validated measures of substance use. Synthesis of evidence from qualitative studies focused on identifying prominent themes relating to the contexts and consequences of substance use. Critical Appraisal Skills Programme (CASP) checklists were used to assess methodological quality of included studies.ResultsForty-four quantitative (82% cross-sectional), 16 qualitative and three mixed-methods studies were included. Ten studies were rated as high methodological quality (16%), 39 as moderate quality (62%) and 14 as low quality (22%). The majority of research was conducted among refugees, IDPs and asylum seekers (n = 55, 87%), predominantly in high-income settings. The highest-quality prevalence estimates of hazardous/harmful alcohol use ranged from 17%-36% in camp settings and 4%-7% in community settings. Few studies collected validated measures of illicit drug use. Seven studies compared substance use among forced migrants to other migrant or native-born samples. Among eight studies which conducted multivariable analysis, male sex, trauma exposure and symptoms of mental illness were commonly identified correlates of substance use.ConclusionOur understanding of substance use among forced migrants remains limited, particularly regarding persons displaced due to disasters, development and deportation. Despite a growing body of work among refugee-background populations, few studies include refugees in low and middle-income countries, where over 80% of the global refugee population resides. Findings suggest a need to integrate substance use prevention and treatment into services offered to forced migrants, particularly in camp settings. Efforts to develop and evaluate interventions to reduce substance use and related harms are needed.