Driven by rapid ongoing advances in humanoid robot, increasing attention has been shifted into the issue of emotion intelligence of AI robots to facilitate the communication between man-machines and human beings, especially for the vocal emotion in interactive system of future humanoid robots. This paper explored the brain mechanism of vocal emotion by studying previous researches and developed an experiment to observe the brain response by fMRI, to analyze vocal emotion of human beings. Findings in this paper provided a new approach to design and evaluate the vocal emotion of humanoid robots based on brain mechanism of human beings. People have long been dreaming of building brain-like intelligent machines. Ever since the first Artificial Intelligence conference taking place in 1956, AI development has been over half a century old. While the coming-ups of Kismet , 3 by MIWith the increasingly strict demands of robots, it is suggested that more attention should be shifted into the issue of vocal emotion design of AI robots to facilitate the communication between man-machines and human beings. To upgrade the voice design of robots, it is necessary to have a look at the mechanism for processing vocal emotions of human beings and the acoustic features of vocal stimuli. With this, it is expected that, apart from facial expression and recognition, future designs for interactive robots are not only emotionally rich in vocal expression but also able to perform vocal emotion recognition. Step 1: extraction of acoustic features of prosodic cues; Step 2: identification of vocally expressed emotion by means of multimodal integration; Step 3: explicit evaluation and cognitive elaboration of vocally expressed emotions.The mechanism of prosody comprehension is proposed to be mediated by a sequential multistep process unfolded from basics stages of acoustic voice analysis  and proceeding to higher-level stages of categorization and recognition . Following the processing of auditory information within the ear, brainstem, thalamus, and primary acoustic cortex (A1), three successive steps of prosody decoding can be identified:temporal voice areas in a variety of voice cognition skills  [Each of these steps, in turn, is differentially represented in the human brain: whereas the extraction of acoustic features has been linked to voice-sensitive structures of the middle part of superior temporal cortex (m-STC), more posterior aspects of the right STC have been recognized for their contribution to the identification and integration of emotional signals into a common percept . Beyond  voices) . ParticuThe ability to correctly interpret emotional signals from others is crucial for successful social interaction. A wealth of neuroimaging studies have indicated that voice sensitive auditory areas –8 activaT-values and MNI coordinates (in square brackets) of highest activated voxels within each region are presented: SMA, supplementary motor cortex; ACC, anterior cingulate cortex; DLFC, dorsolateral frontal cortex; OBFC, orbitobasal frontal cortex; IPL, inferior parietalis lobulus; STG, superior temporal gyrus; MTG, middle temporal gyrus. Respective Brodmann Areas (BA) are printed in brackets; by SPM99, random-effect analysis, n = 10, P b 0.05 corrected, T N 4.30, k N 38.In this table, According to the neuroanatomical model proposed by Ross , prosodiAmong previous research on vocal emotion, one has delineated the cerebral network engaged in the perception of emotional tone, with functional magnetic resonance imaging (fMRI) performed during recognition of prosodic expressions of five different basic emotions . As compared to baseline at rest, the results indicated widespread bilateral hemodynamic responses within frontal, temporal, and parietal areas, the thalamus, and the cerebellum. A comparison of the respective activation maps, however, revealed comprehension of affective prosody to be bound to a distinct right-hemisphere pattern of activation, encompassing posterior superior temporal sulcus (Brodmann Area (BA) 22), dorsolateral (BA 44/45), and orbitobasal (BA 47) frontal areas. These findings indicate that part of distinct cerebral networks subserve processing of intentional information during speech perception . Taken tFindings of research  suggesteIn recent years, there has been an explosion of research into the neural mechanism of human beings' emotions. The brain regions regarding to vocal emotions can be identified with the functional neuroimaging techniques such as fMRI  that measure hemodynamic changes. Previous fMRI studies relying on standard data analyses have indicated that the middle part of the superior temporal gyrus (STG) reacts more strongly to various vocal emotions –12 than According to the neuroanatomical model proposed by Ross , prosodir-test, the results indicated widespread bilateral hemodynamic responses within frontal, temporal, and parietal areas, the thalamus, and the cerebellum. A comparison of the respective activation maps, however, revealed comprehension of affective prosody to be bound to a distinct right-hemisphere pattern of activation, encompassing posterior superior temporal sulcus (Brodmann Area (BA) 22), dorsolateral (BA 44/45), and orbitobasal (BA 47) frontal areas. These findings indicate that part of distinct cerebral networks subserve processing of intentional information during speech perception [Among previous research on vocal emotion, one has delineated the cerebral network engaged in the perception of emotional tone, with fMRI performed during recognition of prosodic expressions of five different basic emotions . As compared to baseline at rception .Voice intensity corresponding to the perceived loudness of a given vocal signal.Tempo and pausing corresponding to the rate of vocalization .Fundamental frequency of vocal fold vibration (F0) defining the perceived pitch of a voice.Energy distribution in the frequency spectrum  .During speech production, information about a speaker's emotional state is predominantly conveyed by the modulation of intonation (affective prosody). At the perceptual level, emotional tone is characterized by variations of pitch, syllable durations, loudness, and voice quality across utterances  imposed upon segmental verbal information encoded in phonetic/phonological units –19. Amonanger generally has been described to be indexed by increasing voice pitch accompanied with increases in loudness; sadness, for instance, has been characterized to show decreases in voice pitch, speech rate, and loudness of a speakers voice. Fear, on the other hand, can be revealed by increases in voice pitch combined with increases in speech rate, while joy has been related to increases in voice pitch, loudness, and speech rate. Similar results have been obtained for various nonverbal vocalizations, which have been associated with distinct acoustic profiles which demonstrate the sophisticated interplay of acoustic properties related to voice quality, pitch, and intensity [Rigorous analysis of acoustic cues measured from samples of emotional speech helped to define distinctive acoustic profiles for a set of central emotions such as anger, joy, fear, or sadness. The corresponding findings are described in the literature as the following , 23, 24:ntensity , 26.In the design of vocal emotions of a humanoid robot, there are two problems involved: (1) the expression of speech emotion, this can be solved by choosing certain emotional words and adopting proper speech synthesis technology; there are a lot of research achievements in this field; (2) the recognition of human beings' emotions, this will help the humanoid robot to make appropriate reactions in interactive process; it needs to process the human beings' speech signals through emotional pattern recognition methods.For a humanoid robot, the acoustic features of received speech signals should be described by some extracted characteristic parameters. On this respect, Linear Prediction Cepstrum Coefficient (LPCC) and Mel Frequency Cepstrum Coefficient (MFCC) have been widely used as parametrically representing speech signal for speech recognition . LPCC coIn order to identify vocal emotions of human beings, it is necessary for us to adopt appropriate pattern recognition methods on the processing of speech signals. The state-of-the-art in pattern recognition techniques includes Dynamic Time Warping (DTW), Hidden Markov Modeling (HMM), and artificial neural networks (ANN). Dynamic Time Warping (DTW) is an early and classical algorithm which based on the thought of dynamic optimization and can resolve the matching problem of the difference of speech's length. In the isolated word speech recognition, the disadvantage of HMM and ANN is limitation of heavy computations and training templates that are required for higher accuracy, but the DTW algorithm training hardly needs the additional calculations. So DTW approach is usually used in the recognition of speech signals due to ease of implement and flexibility . In thisTo have a better look at mechanism for processing vocal emotions of human beings, we designed an experiment to demonstrate appropriate picture and text stimuli in use of f-MRI method. As seen from In order to generate appropriate verbal stimuli, 16 listening questions (2  runs) adopted from Part 1 of China Accreditation Test for Translators and Interpreters 2 (Catti 2) with emotionally neutral content were selected; all were news read by professional broadcasters. Materials were tested in a pilot study by 52 college students in Fudan University, China, to achieve appropriate level of difficulty. The subjects were required to pass a test split from the stimuli test, to confirm their ability to understand the question. Duration of each verbal recording ranged from 35 s to 40 s.Tape recordings of all 16 utterances were presented to 6 healthy subjects  without history of neurological or psychiatric diseases participated in the fMRI experiment and comparison of brain conditions were recorded as they process the stimuli.They lay supine in a 3-T whole body scanner (Siemens Vision), their eyes opened and their heads supported by a foam rubber within the head coil. Each session in the design included the part of rest for 30 seconds, the duration of each block lasted 120 s.Subjects were instructed to listen to the contents and to answer the following True/False questions. The results of the answering were not calculated for the reason that part of compulsory answering was suggested by previous research as a method to help subjects to focus while listening to the stimuli. They lay supine in a 3-T whole body scanner (Siemens Vision), their eyes closed and their heads supported by a foam rubber within the head coil, button placed under their index and middle fingers for them to choose the answers.Each session in the design included the part of rest for 24 seconds, stimuli for 35–40 seconds, blank for 2 seconds, question reading part for 10 seconds, and answering 2 seconds, two runs in total, lasting for 540 seconds, designed by E-prime2.0 as Z = 5.5).Findings of the present research was in line with the comparison revealed in previous research, indicating that the right auditory cortex is more sensitive to tonality, while the left auditory cortex has been shown to be more sensitive to minute sequential differences in sound, such as in speech. Comparing findings of the present study and those of , we can We notice that when some displeasure voice was heard, the task yielded specific activation within the brain Inferior Frontal Gyrus area , pitch, frequency spectrum, etc.), but also to their tendency toward tonality or speech. For example, home robots shall put more emphasis on their prosody decoding system, since the context fit the application tend to be soft and informal, while vocal system design for robots in public areas  shall be with emphasis on speech content rather than vocal emotion. The former tends to be more right-hemisphere oriented and the latter tends to be more left-hemisphere oriented. With this regard, the comparison between the findings of the present research and those of  may servWe have already applied these findings to the infants' speech recognition . InfantsWe selected 3 kinds of speech signals that reflect normal emotions and needs of infants such as happy, hungry, and sleepy which are very typical as well as easy for evaluation and acquisition in infants' daily life. The daily activity information of infants  and the environment information  were also recorded to assist the recognition; test results showed that the average recognition rate may be achieved more than 80%. This technology can be applied to the design of baby care humanoid robot with emotional intelligence.While contemporary technology of humanoid robot design have contributed greatly to the topic of emotion recognition as well as AI, only marginal attention has been paid to the vocal domain. Exploring the previous fMRI research on vocal emotion recognition has deepened our understanding about how the mechanism of vocal emotion processing works in the human brain, such as the contribution of right-sided temporal and frontal regions to the processing of emotional prosody independent of specific emotional categories. It will provide the inspiration to the design of humanoid robot with emotional intelligence, which has wide potential application such as emotion analysis in emergency events  and all


Cyclargus thomasi bethunebakeri), Key tree cactus (Pilosocereus robinii), Florida duskywing butterfly (Ephyriades brunnea floridensis), and Key deer (Odocoileus virginianus clavium). We also identify sources of uncertainty and the types of life history information consistently missing across taxonomic groups. This study characterizes the vulnerabilities to major threats of a broad swath of Florida’s biodiversity and provides a system for prioritizing conservation efforts that is quantitative, flexible, and free from hidden value judgments. Species face many threats, including accelerated climate change, sea level rise, and conversion and degradation of habitat from human land uses. Vulnerability assessments and prioritization protocols have been proposed to assess these threats, often in combination with information such as species rarity; ecological, evolutionary or economic value; and likelihood of success. Nevertheless, few vulnerability assessments or prioritization protocols simultaneously account for multiple threats or conservation values. We applied a novel vulnerability assessment tool, the Standardized Index of Vulnerability and Value, to assess the conservation priority of 300 species of plants and animals in Florida given projections of climate change, human land-use patterns, and sea level rise by the year 2100. We account for multiple sources of uncertainty and prioritize species under five different systems of value, ranging from a primary emphasis on vulnerability to threats to an emphasis on metrics of conservation value such as phylogenetic distinctiveness. Our results reveal remarkable consistency in the prioritization of species across different conservation value systems. Species of high priority include the Miami blue butterfly ( The combination of accelerated climate change, habitat loss and degradation, invasive species, overharvesting, sea level rise and other threats have dramatically increased extinction rates during recent centuries -3. Many Florida is a hotspot of endemism for plants ,28, vertIn this paper we describe a two-step method for prioritizing conservation efforts for species threatened by climate change, SLR, and land-use change projected by the year 2100. Our methods are complementary to existing prioritization schemes because we use most of the same criteria, but in addition we explicitly account for the effects of sea level rise in addition to factors traditionally considered in prioritization schemes. First, we compiled a list of 300 species identified by the Florida Natural Areas Inventory (FNAI) and the Florida Fish and Wildlife Conservation Commission as vulnerable to extinction in Florida or globally due to SLR and other threats. Second, we applied a novel vulnerability assessment, the Standardized Index of Vulnerability and Value (SIVVA) , which uThe Florida Natural Areas Inventory (FNAI) tracks approximately 1000 species of plants and animals of conservation concern in Florida. For each species FNAI keeps a spatially explicit database on distribution in the form of “element occurrences,” i.e., points or polygons representing observed species localities. Element occurrences correspond to discrete populations based on recorded or estimated dispersal and connectivity. Thus, species with state-wide distributions and high levels of connectivity may have a few large element occurrences throughout the state, while other species that are spottily distributed throughout the state and lacking connectivity may have several smaller and discrete element occurrences. Available funding and staff limited our ability to conduct vulnerability assessments for all 1000+ species. All species tracked by FNAI are vulnerable to extinction, but we wanted to identify those most at risk from SLR in addition to other threats. To do this, we used a 10 m digital elevation model (DEM) to create a “bathtub” projection showing 2 m of SLR. We limited our search to species for which some element occurrences overlapped with this SLR projection, assuming that this is a relatively liberal projection for the year 2100. Next, we identified species for which 50% of their element occurrences were each inundated by 50% or more according to our bathtub model. An additional 32 species of conservation concern were added to this list to conform to requirements of one of our funding agencies, which identified these species as of high conservation concern. http://noss.cos.ucf.edu/publications/sivva) and in To continue our species prioritization, we developed an expert opinion-based survey called the Standardized Index of Vulnerability and Value Assessment (SIVVA). Previously, we showed that existing vulnerability assessments and species prioritization protocols inconsistently estimated the vulnerability of species in Florida  and failFor each of the 300 species identified in www.climatewizard.org) and statistically downscaled global projections for a ‘medium’ (A1B) Emission Scenario (ES), and an Ensemble Average General Circulation Model (GCM) following the IPCC Fourth Assessment. We calculated the change in mean annual temperature in Florida from data modeled from 1900 to 2000 relative to temperature projections modeled from 2000 to 2100. We compared mean annual precipitation under the same GCM and ES above from modeled 1900-2000 and modeled 2000-2100 data. We calculated the difference between wet  and dry season  rainfall modeled over 1900 to 2000, and compared that to the difference between wet and dry season rainfall modeled over 2000 to 2100. This difference describes seasonal variability in rainfall, irrespective of total annual rainfall. We assessed land-use change using the projections provided in the Florida 2060 report [To project climate impacts, we used the Nature Conservancy Climate Wizard  for each of the four modules to determine if a significant portion of the variation in final scores was explained by variation among expert assessors. We reconciled two independent valuations of each species by first testing if the difference between the two assessors for the final score of each module was less than 95% of the distribution of pairwise differences among all other species. This approach is based on the expectation that variation among assessors is less than variation among species. We then reported the average score of the two valuations. For all remaining assessments, we used the evaluations of a single expert or a single group of experts and review by the first author to ensure compliance with SIVVA design and that adequate justification existed for their assessments of each criterion. The vast majority of assessments were completed in the presence of or over the phone with the authors of SIVVA.This assessment addressed three types of uncertainty: 1) expert uncertainty – when an expert believes that more than one value is equally likely to represent the true value for a criterion; 2) insufficient knowledge – when a small number of criteria are assessed due to limited knowledge about the species; 3) weighting uncertainty – when one or two criteria contribute disproportionately to the priority score for a species. Some VAs, such as the Climate Change Vulnerability Index (CCVI) ,24, accoUnless indicated otherwise, SIVVA results are reported based on scores averaged across all four SLR scenarios. Data are available on each of those SLR scenarios individually, but for simplicity we present here the averages across all scenarios. First, we identify those species for which extinction appears highly probable by 2100. Second, we report uncertainty measures and identify types of missing data by taxonomic group. Third, we report on the range of values suggested by experts across all modules to broadly characterize vulnerabilities, adaptive capacities, conservation values, and information availability. Fourth, we describe taxonomic patterns of vulnerability, and differences between listed and non-listed taxa at the State and Federal level, by comparing their SIVVA scores using t-tests assuming unequal variance. Fifth, we prioritize species based on SIVVA under five approaches that each emphasizes different types of information. Because all prioritization schemes contain bias, for example taxonomic or societal biases, we chose a variety of approaches, which is a strength of the SIVVA framework. We are unaware of similar flexibility in other existing assessments. The following are five prioritization schemes implemented within SIVVA to reflect differences in conservation priorities.1Stepwise Prioritization: We identified from our list of 300 species those that were above a threshold of Conservation Value by identifying natural breaks in the distribution of Conservation Value scores. We detected a natural break by ranking species from high to low by their Conservation Value scores, which resulted in a logistic curve. The mean and median values were identical, and were used as the cutoff. From these species we prioritized those with the highest scores for the combination of Vulnerability and Lack of Adaptive Capacity, where each module was weighted by the number of criteria (12 Vulnerability criteria versus 6 for Lack of Adaptive Capacity). We examined Information Availability scores to identify the types of data gaps critical to fill for the species at highest risk of extinction.2Equal Weighting: Each of the four SIVVA modules contributed equally to the final scores; criteria within each module were weighted as shown in Reece and Noss .3Emphasis on Vulnerability: The overall rank or score for each species is the weighted average of scores across all four modules, where Vulnerability (45%) and Lack of Adaptive Capacity (25%) together make up 70% of the final score, Conservation Value contributes an additional 20%, and Information Availability contributes the final 10%. 4Emphasis on Conservation Value: Conservation Value contributed 50% of the final score, with 20% from Vulnerability, 20% from Lack of Adaptive Capacity, and 10% from Information Availability.5Emphasis on Conservation Value and Information Availability: Vulnerability and Lack of Adaptive Capacity each contributes 15%, and Conservation Value and Information Availability each contribute 35% towards the final score. http://noss.cos.ucf.edu/publications/sivva.At the time of this study the FNAI tracking list consisted of 1049 species, of which 519 had distributions that overlapped our bathtub inundation model based on 2m of SLR. From this list, 268 species were projected to have 50% or more of their element occurrences inundated by at least 50% (by area). The additional 32 species of conservation concern resulted in a total of 300 species to be evaluated by SIVVA . The taxExpert assessments for the 40 species evaluated independently by multiple experts were remarkably similar, which largely reflects a carefully crafted assessment scale . None ofSeveral species merit special mention because of their exceedingly high extinction risk as identified by our expert panels. Because our list was biased initially towards those species exposed to SLR, most but not all of these species are primarily threatened by SLR. We list some examples of these species and the primary factors influencing their extinction risk in The SIVVA module scores vary from zero to one, where one is the maximum attributable priority. We considered species with a combined Vulnerability and Lack of Adaptive Capacity uncertainty that encompassed 1/3 of this scale to have too much uncertainty for prioritization. Surprisingly, only 15/300 species met this criterion. The mean level of uncertainty for each module in SIVVA was +/- 0.16 for Vulnerability, 0.19 for Lack of Adaptive Capacity, and 0.05 for Conservation Value. Experts displayed zero uncertainty regarding the published data available for these taxa. The greatest and most consistent uncertainties corresponded to the distributions of some rare coastal invertebrates, the responses of fishes to SLR, and reproductive rates of many invertebrate taxa. The criteria most commonly ranked as uncertain were the response of species to changes in overall and seasonal rainfall , response to projected changes in temperature (41%), the impacts of changes in biotic interactions (62%), and vulnerability to synergistic impacts of known threats (54%). Experts also consistently noted uncertainty in the adaptive capacity of species relative to phenotypic plasticity (44%) and the ability of species to recruit to novel habitats (61%). Expert uncertainty regarding the conservation value of species was greatest for the degree to which the species plays a keystone or foundation role in its environment (33%), and the probability of recovery success (58%).  On average, our experts scored 81% of the 12 Vulnerability criteria, 74% of the six Lack of Adaptive Capacity criteria, and 94% of the seven Conservation Value criteria; all Information Availability criteria were scored. The percentages of criteria answered by taxonomic groups are presented in The average SIVVA scores for each module, averaged across all four SLR scenarios, were 0.73 for Vulnerability, 0.67 for Lack of Adaptive Capacity, 0.42 for Conservation Value, and 0.32 for Information Availability. Given that a score of 0.5 corresponds to zero vulnerability , it is not surprising that our list of species  displayed relatively high levels of Vulnerability and low Adaptive Capacity . Contrastingly, Conservation Value and Information Availability scores varied from low value/information (score of zero) to high value/information (score of one). The relatively low conservation values of species on this list may result from the prevalence of plants  and invertebrates (22%) that are traditionally not considered to be of high economic, social, or conservation value relative to birds and mammals. We also considered species of greater conservation value when they are phylogenetically distinct, such as a monotypic genus; however, many of the near-coastal species tracked by FNAI are endemic subspecies restricted to barrier islands or the Florida Keys, and generally do not represent long, unique evolutionary histories. The scores follow a bell-curve distribution for Vulnerability, a dispersed or flat distribution for Lack of Adaptive Capacity, are clustered in the mid-range for Conservation Value, and steadily decrease in frequency from low to high scores for Information Availability . The distribution of Vulnerability, Lack of Adaptive Capacity, Conservation Value, and Information Availability also showed strong taxonomic biases . AmphibiSpecies that were federally or state listed as threatened or endangered did not show significantly different Vulnerability scores . The Lack of Adaptive Capacity scores of listed species was significantly higher . Listed species displayed greater Conservation Value , which is not surprising because listing status was a component of this SIVVA module. Lastly, the SIVVA metric for Information Availability was not significantly different for listed species versus non-listed species .  NatureServe Conservation Status Ranks  characteCyclargus thomasi bethunebakeri), Key tree cactus (Pilosocereus robinii), Florida duskywing (Ephyriades brunnea floridensis), Key deer (Odocoileus virginianus clavium), mangrove terrapin , Schaus swallowtail (Heraclides aristodemus ponceanus), Florida semaphore cactus , loggerhead turtle (Caretta caretta), truncate urocoptid (Cochlodinella poeyana), amethyst hairstreak (Chlorostrymon maesites), and narrowpod sensitive pea (Chamaecrsrista lineata keyensis). The forty species with the highest average scores across all prioritization approaches are given in We prioritized species for conservation efforts by calculating a summary SIVVA score across all four SLR scenarios, generally giving highest priority to those species with the greatest vulnerability to threats, the lowest adaptive capacity, the greatest conservation value, and the greatest information availability for making species-specific conservation decisions. Nevertheless, these factors may be weighted in many ways, so we calculated a SIVVA score under five weighting schemes. The relative rank of each species under each scheme, and the average rank across all schemes, can be viewed in We present the first statewide combined vulnerability assessment and conservation prioritization that includes multiple threats to species, including SLR, climate change, and land-use intensification, as well as other factors such as adaptive capacity; ecological, evolutionary, economic and social value; and the amount of life history, genetic, and population information available for crafting meaningful conservation plans or actions. We prioritize 300 species by these factors and provide rankings for each species under five different value schemes. Our prioritization system, the Standardized Index of Vulnerability and Value Assessment (SIVVA), also provides a mechanism for exploring the relative rank of each species across different value or weighting schemes, emphasizing for example, vulnerability over conservation value or vice versa. Several systems for assessing vulnerability and conservation priority currently exist, with the most commonly used including the US and state-level threatened and endangered species lists, NatureServe Conservation Status Assessments , and the International Union for the Conservation of Nature (IUCN) Red List. However, the same species often receive highly disparate ranks across these systems , and in  Our assessments depended on informed expert opinion. Although most assessments were completed by individuals or small groups of individuals working together, a subset of 40 species was evaluated by two independent groups, and we show that assessor bias was not a significant source of variation among scores. This consistency results from several efforts: 1) By providing experts with thorough guidance on our assessment, we avoided interpretation bias. 2) Clear explanation of scoring criteria for each question and generalized categories for scoring reduced ambiguity . For exa Multiple types of uncertainty exist in vulnerability assessments , includiConservation science is known to have a strong taxonomic bias towards mammals and birds and against plants, amphibians, and especially invertebrates and microbes -54. CompCycloptilum irregularis), the mangrove long-horned beetle (Heterachthes sablensis), and the Antillean spreadwing (Lestes spumarius). We do not advocate abandoning these and similar species. Nevertheless, conservation actions that target species or groups of species should, whenever possible, be based on knowledge of the life history and ecology of target species [ Several species, in particular invertebrates, were ranked as at high risk of extinction, but do not receive high priority for conservation due to a lack of basic life history information. Examples include the Keys scaly cricket , the weight or importance of each criterion in our assessment, and the criteria within each module. X's denote presence of the criteria in existing vulnerability assessments including the Climate Change Vulnerability Index (CCVI), International Union for the Conservation of Nature Red List (IUCN), NatureServe Conservation Status Assessment (CSA), and US Endangered Species Act (US ESA).(DOCX)Click here for additional data file.Table S2Latin names of species evaluated, organized by taxonomic group. Species names in bold comprise 32 species added to initial sea level rise analysis (see Methods).(XLSX)Click here for additional data file.Table S3List of taxonomic experts who participated in this study. In addition to those listed here, expert assessors included those listed by Dubois et al. (2011), and eight anonymous assessors.(DOCX)Click here for additional data file.


In the first article of a five-part series providing a global perspective on integrating mental health, Pamela Collins and colleagues set the scene for why mental health care should be combined with priority programs on maternal and child health, non-communicable diseases, and HIV, and how this might be done. Mental illnesses frequently co-occur with peripartum conditions, HIV-related disease, and non-communicable diseases. Care for mental disorders should be integrated into primary care and other global health priority programs.Integration of care for mental, neurological, and substance use (MNS) disorders should (1) occur through intersectoral collaboration and health system-wide approaches; (2) use evidence-based interventions; (3) be implemented with sensitivity to environmental influences; and (4) attend to prevention and treatment across the life course.Integration of care for MNS disorders with care for other conditions can occur through assimilation of activities, policies, or organizational structures at local, national, and global levels.Plans for health-related development targets post-2015 should consider the tremendous burden of disability associated with MNS disorders and co-morbid conditions.This paper is the first in a series of five articles providing a global perspective on integrating mental health.This is one article in a five-part series providing a global perspective on integrating mental health.More than a decade ago, the World Health Organization's (WHO) World Health Report 2001 called for the integration of mental health into primary care, acknowledging the burden of mental, neurological, and substance use (MNS) disorders globally; the lack of specialized health care providers to meet treatment needs—especially in low- and middle-income countries (LMICs); and the fact that many people seek care for MNS disorders in primary care The GBD Study 2010 brought welcome news of reductions in the DALYs for communicable, maternal, neonatal, and nutritional disorders since 1990. This progress is due, in part, to coordinated, global cooperation to meet the Millennium Development Goals (MDGs) and, specifically, to achieve targets set for child survival, maternal health, and combatting HIV/AIDS and malaria by 2015. Crucial for the global public health community, investments in achieving the health-related MDGs catalyzed the development, testing, and implementation of effective health interventions for priority conditions and stimulated the development of packages of care that bundle effective interventions—whether for reduction of maternal or child mortality or for HIV care and treatment. Stakeholders recognize that “synergies in the health system must be pursued” The need for integrated care that addresses emerging priority conditions, like non-communicable diseases (NCDs), including MNS disorders, is acknowledged less frequently in the global context At a minimum, packages of care for MNS disorders should be parceled with effective interventions in primary care or other priority health delivery platforms. In truth, adequate attention to the public's health requires that this integration also occur in sectors beyond health , through collaborative partnerships of government, non-governmental organizations (NGOs), and faith-based organizations, as well as in the implementation of global health and development policy.Despite the increasing burden of MNS disorders around the world and their frequent co-morbidities, affected individuals often lack access to mental health care in high-, middle-, and low-income countries PLOS Medicine, workshop participants focus on mental health care integration into maternal and child health programs In 2011, in an effort to stimulate solutions to these and other issues, researchers, clinicians, and advocates identified 25 Grand Challenges in Global Mental Health (GCGMH); i.e., “specific barriers that, if removed, would help to solve an important health problem. If successfully implemented, the intervention(s) … would have a high likelihood of feasibility for scaling up and impact” Four broad themes running across the Grand Challenges are consistent with arguments in favor of integration: use system-wide approaches, apply evidence-based interventions, understand environmental influences, and use a life course approach.Integration lies at the heart of system-wide approaches to care and aims to “create coherence and synergy between various parts of the health care enterprise in order to enhance system efficiency, quality of care, quality of life, and consumer satisfaction, especially for patients with complex and multiple problems” System-wide collaboration must go beyond the health sector. The well-being of the most vulnerable of health system users, whose symptoms due to mental or physical disorders lead to persistent impairments, may be a sensitive indicator of a society's need for integrated care BasicNeeds Mental Health and Development Program bridges sectors within and outside the health system in order to integrate health and social interventions for people with epilepsy and mental illnesses. The Nepal program, one of several international sites, operates through a local nongovernmental organization (NGO) with expertise in community-based rehabilitation and livelihoods support. In order to identify affected people, raise community awareness of mental illness, ensure access to treatment, and support employment, collaboration occurs among community members, district hospital staff, NGO staff, families, and affected individuals. In this setting, community-based workers facilitate access to mental health services, monitor treatment through home visits, and support livelihood activities The Services for People with Disabilities is a community mental health program in Abuja, Nigeria that provides services for people with psychosis and epilepsy. Established by CBM– an international nongovernmental organization that supports programs for people with disabilities in low-income countries–the Catholic Archdiocese of Abuja runs and partially funds the program. The program also delivers community-based rehabilitation services for people with physical disabilities; activities include interventions to support economic integration and social inclusion. Field workers visit local households to identify potential clients, consulting with village chiefs, parish priests, and other local informants. The program raises awareness of its services through public meetings and discussions with other NGOs and with government officials. A community psychiatric nurse delivers care in the home on a monthly basis Over the past decade, the potential for delivery of evidence-based packages of care for mental disorders has grown globally. Interventions that effectively treat mental disorders in high-income countries increasingly demonstrate efficacy in LMICs in varied settings with different kinds of health care providers The WHO Mental Health Gap Action Programme (mhGAP), through its mhGAP Intervention Guide, outlines interventions focused on depression, psychosis, bipolar disorder, epilepsy, developmental and behavioral disorders in children and adolescents, dementia, alcohol use disorders, drug use disorders, and self-harm/suicide Every attempt to integrate services or strengthen components of a health system occurs in a particular sociocultural, political, and health system environment with its unique configuration of risk factors across the population. Among these factors, epidemics, war, criminal violence, migration, discrimination, and poverty shape the health outcomes and life chances daily for billions worldwide. These conditions disrupt opportunities for maintenance of mental health and often increase risk for mental disorders, influencing the distribution of distress and illness in local settings In every setting, addressing mental health care needs requires consideration of how individuals understand their symptoms of mental illness or distress and, at the health system level, the ability to utilize available infrastructure and human resources. In low-income settings post-disaster, this may entail building on the resources of existing NGOs to mobilize mental health services in collaboration with local government Physical and social exposures at every stage of life influence risk for disease across the life cycle Symptoms for most mental disorders express themselves in adolescence. Preventive and early interventions that precede and continue into adolescence will have better reach through integrated services—particularly those occurring in schools and community settings outside of the health system. At older ages, the interaction of risks continues: accumulating co-morbid physical conditions increase risk for poor mental health as well as other NCDs domains of integration: what is being integrated ; level of integration, or where integration is occurring ; and degree of integration, or how integration is occurring . Grépin and Reich provide a useful framework for conceptualizing integration—i.e., what is integrated into what—that links these themes to actions The GCGMH also calls for parity “between mental and physical illness in investment into research, training, treatment and prevention”. A flexible, dynamic relationship between research and service delivery enables innovative “game changing” in global public health The European Union, the United States, China, Japan, and Russia account for 35% of the world's population, but 75% of its researchers Dissemination of study findings to decision makers, practitioners, managers, and advocates will be crucial to ensuring uptake of innovations. Research partnerships that include mental health service users, government officials, and knowledgeable stakeholders can facilitate dissemination to desired audiences. NIMH has required that investigators utilize these kinds of collaboration in its global mental health research funding announcements The existing evidence base, however, demonstrates that parity for MNS disorders in policy development is particularly relevant as plans for health-related development targets for the agenda after 2015 progress. As universal health coverage emerges as a feasible option, equitable coverage for MNS disorders must be clearly articulated so that targets and metrics take into account the significant disability associated with these conditions in every region of the world The fast approaching deadline for achieving the MDGs, the articulation of health-related targets for the post-2015 development agenda, the call for an AIDS-free generation, the imperative of equitable health care for all individuals (regardless of co-morbid conditions), and the requisite health systems strengthening activities that enable the meeting of these goals make this an ideal time to integrate mental health care services into priority global health programs. There are six other reasons.Global Burden of Mental Disorders and the Need for a Comprehensive, Coordinated Response from Health and Social Sectors at the Country Level, and the comprehensive 2013–2020 Global Mental Health Action Plan that has emerged, will encourage coordinated global expansion of mental health service delivery. The Plan is timely because the field is already prepared to move selected evidence-based interventions forward for scale-up.1. Just as progress toward the MDGs is in part attributable to shared global goals and vision, a clear agenda, and measurable targets 2. Donors are actively directing funding toward reducing morbidity and mortality associated with priority conditions identified by the MDGs 3. As those committed to improving health and development discuss promotion of universal health coverage as a potential development target post-2015, MNS disorders must be integrated equitably among the health conditions considered.4. The United States Agency for International Development (USAID) and like donors not only emphasize the importance of strengthening health systems, but also are exploring how to leverage the infrastructure gained through investments in HIV/AIDS, maternal and child health, family planning, and other key programs to achieve this goal 5. The effects of the global economic crisis underscore the need for greater efficiency in health programs while maintaining maximum effectiveness to ensure sustained productivity among populations—an aim of care integration.6. The evidence demonstrating that there truly is “no health without mental health” continues to grow, and the links between HIV and depression, cardiovascular disease and anxiety disorders, diabetes and depression—as well as other conditions—suggest that the best outcomes for these disorders require care that attends to all of them The sixth goal of the GCGMH is “to transform health system and policy responses to MNS disorders worldwide”. Despite our worldwide focus, the authors acknowledge their current affiliations with institutions in high-income countries and recognize the importance of perspectives from low-, middle-, and high-income countries. In the five-part series providing a global perspective on integrating mental health, we aim to help health care providers, donors, and decision makers understand the importance of including mental health care in global health programs, identify entry points for integration, select interventions to be introduced into existing health services, and take steps toward action.


NO/cGMP signaling is essential for normal brain function, including learning and memory, and mediation of long-term potentiation (LTP). NO/cGMP signaling is coupled to cholinergic, glutamatergic, and dopaminergic systems and plays key roles in motor function associated with Parkinson’s disease pathogenesis and L-DOPA therapy. In Alzheimer’s Disease (AD), early synaptic failure, has been linked to dysfunction of gene expression programs mediated via the transcription factor cAMP-response element binding protein (CREB), activation of which is tightly regulated by NO/cGMP. Since several neurodegenerative disorders continue to be dogmatically linked to the chemical toxicity of NO, activation of soluble guanylyl cyclase (sGC) represents a potential therapeutic approach in both AD and PD; whereas negative modulation of sGC may be of use in some stages of PD. Such small molecule sGC modulators (GCMs) can be assayed in cell cultures by measuring levels of phosphorylated CREB (pCREB). GCMs that allosterically potentiate NO activation of sGC have proven successful in clinical trials for peripheral indications, however, there are no reports directed at therapeutic activity in the CNS. The aim of this study is to develop GCMs for use in CNS disorders, including AD and PD. A library of GCMs was synthesized, including positive allosteric modulators (PAMs) and negative modulators, as assessed by increasing levels of pCREB in SH-SY5Y human neuroblastoma cell cultures. Molecules were designed by classical bioisosteric replacement, aiming for desirable physiochemical properties and chemical diversity. GCM PAMs were assayed for cGMP elevation and reversal of neurotoxicity induced by 6-hydroxydopamine in dopaminergic neuronal cells. One GCM PAM, active in cell culture, was further tested for the reversal of memory deficits in mice treated with scopolamine, and drug levels in brain and plasma measured. The ligand binding site for sGC stimulators and GCM PAMs on the sGC protein remains to be definitively defined. Photoaffinity probes were designed that retained the activity of the parent GCM PAM in cell cultures in order to elucidate the binding mode to sGC and to indicate other protein partners for such compounds.


Motivation: Data collection in spreadsheets is ubiquitous, but current solutions lack support for collaborative semantic annotation that would promote shared and interdisciplinary annotation practices, supporting geographically distributed players.Results: OntoMaton is an open source solution that brings ontology lookup and tagging capabilities into a cloud-based collaborative editing environment, harnessing Google Spreadsheets and the NCBO Web services. It is a general purpose, format-agnostic tool that may serve as a component of the ISA software suite. OntoMaton can also be used to assist the ontology development process.Availability: OntoMaton is freely available from Google widgets under the CPAL open source license; documentation and examples at: https://github.com/ISA-tools/OntoMaton.Contact:isatools@googlegroups.com Well-annotated and shared bioscience research data offer new discovery opportunities and drive science of the future. Several data management plans and sharing policies have emerged, along with a growing number of community-developed guidelines and ontologies to harmonize the reporting of experiments from different domains so that these can be comprehensible and in turn, reproducible and reusable. In many research projects however, the generation and collection of experimental data occur in a multicentric, distributed fashion; and a variety of data types are generated often in a single experiment. Use of spreadsheets and related editors, such as Microsoft Excel for collecting experimental description is widespread among researchers due to their flexibility, low learning curve and above all ubiquity of tooling. However, misalignment, conflicting versions, the heterogeneity of free text, and also silent and unwanted ‘auto-corrections’ are major shortcomings to be addressed (http://goo.gl/FjghA.Four main use cases drove the development of OntoMaton: (i) to allow collaborative, distributed and coordinated annotation while enabling configurations and restrictions to be defined; (ii) to reduce free text description in metadata tracking of experimental data; (iii) to assist design patterns-based ontology development by facilitating interaction with domain experts; and (iv) to ease mapping between models and semantic representations. Two use cases are discussed more specifically in the next sections: one insisting on the free form of the widget and its ability to integrate in any layout, agnostic of any framework; the other aligning with a standardization effort, the ISA syntax (http://goo.gl/JLG5d); Bioplatforms Australia (http://goo.gl/uXLve)—with a focus on soil metagenomics sample collection; and Metabolights  have been developed to support these activities. The developers of the Ontology of Biomedical Investigations (OBI)  to OWL representations through the intervention of knowledge engineers. Tools such as Populous (http://goo.gl/NV3lZ. Ongoing development of OntoMaton focuses on: (i) transformation of data into the Resource Description Framework and Linked Data; (ii) support for cell level, vocabulary drop-down list as soon as the Google API supports it; and (iii) further integration with the ISA software suite as requested by users.Developed by harnessing the Google Spreadsheet environment and the term lookup and annotation power of the NCBO Web services, OntoMaton is an effective tool assisting both collaborative semantic annotation of experiments and the ontology development process. Several annotation tools exist  tend to Funding: This work was supported by the Biotechnology and Biological Sciences Research Council  and the National Institutes of Health [grant U54 HG004028 supporting TW].Conflict of Interest: none declared.


Dear Sir:The article, “Compliance with Antimalaria Chemoprophylaxis in a Combat Zone,” confirmed the limited adherence to such preventive measures among military service members. The authors analyzed the reasons for noncompliance while presenting measures undertaken to address them. These measures include education and training, supply of medicines before departure, directly observed therapy, and an established discipline policy with consequences rarely applied but supported by the laws of the Uniform Code of Military Justice.1Given the importance of malaria chemoprophylaxis, solutions are needed urgently to address this critical weakness in malaria prevention and control systems, not just for troops but all other non-immune travelers and residents. Poor compliance affects the health of individuals improperly taking the medications. It has the potential to roll back the current gains in malaria control efforts in endemic countries by creating resistance and allowing the re-emergence of parasites in areas that have seen an impressive decline in parasitemia.For more than a decade, ExxonMobil has assigned thousands of non-immune workers in malaria-endemic countries. They face the same compliance challenges as the United States military service members and other long-term travelers1.A comprehensive awareness program that communicates and confirms the risk of malaria, the program requirements, and each individual's commitment to chemoprophylaxis with their willingness to be tested for compliance verification. Education begins before departure, with consistent reinforcement of key messages upon arrival, during site induction, and safety meetings. Training completion is verified before travel, at arrival in the country, and at specific check points such as company air transportation sites or camp offices. For company providers, malaria program requirements are specified in contractor agreements and subject to review at contractor mobilization.2.Provision of chemoprophylaxis medicines recommended by the World Health Organization (WHO)3.Monitoring chemoprophylaxis compliance through random testing of workers. The laboratory test method was developed with a United States-based company.4.A “show-me process” at arrival and departure from work sites. This process requires workers to verify that they are in possession of their malaria chemoprophylaxis and are practicing bite protection .5.Engagement of Senior Management for a malaria control program. Malaria cases, cases of non-detects for urine malaria drug tests, and periodic assessments of the malaria control program elements performed through Operations Integrity Management Systems are reported up line to senior company executives from affiliates. These reports are a part of the site performances in malaria locations. They are stewarded by a Corporate Malaria Steering Committee responsible for guidance and sponsor of program activities. Contractor companies are also assessed and notified of health expectations, including malaria program requirements through various mechanisms before, during, and after mobilization.The workplace malaria program measures are targeted at individual employees and contractors; they are also embedded into the verification and reporting systems of company operations. They include:Successful programs, including malaria chemoprophylaxis compliance, rely on clear expectations, personal and organizational engagement with effective verification of expectations, and application of corrective action when indicated. Like any behavior required from population groups , repeated training and awareness, individual and leadership commitment, verification of observance, and application of consequences for noncompliance are key enabling factors.


The clinical practice of recording skin conductance (SC) at acupuncture points (acupoints), as a diagnostic and/or therapeutic monitoring aid may have scientific merit. However, influences of age, gender and time of day on these recordings are unknown and it is unclear whether SC at acupoints differs from SC levels in general (as reported in psychophysiology research). This research will investigate these influences.This analysis summarizes SC data obtained with the AcuGraph 3 Digital Meridian Imaging System between June 2005 and March 31, 2010. An initial dataset of 117,725 SC examinations was scrubbed to include only the first SC examination on individual patients and exclude potentially faulty data. The final dataset consists of SC recordings at the 24 Source (Yuan) acupoints in 8637 patients, collected by 311 practitioners. Twelve left/right average conductance measures and an overall average of the 24 acupoints were assessed. Statistical analyses included two sample t tests, three way analyses of variance and linear regression.Results indicate that mean SC at acupoints, similar to SC in general, is higher in males, higher in afternoons and declines with age. Not previously reported, the rate of SC decline with age differs at different acupoints between males and females.These findings have substantial implications for acupuncture research and practice. Patterns derived from measures such as these should be investigated as potential early detectors of disease and predictors of treatment responsiveness.


Reported incidence of dengue has increased worldwide in recent decades, but little is known about its incidence in Africa. During 1960–2010, a total of 22 countries in Africa reported sporadic cases or outbreaks of dengue; 12 other countries in Africa reported dengue only in travelers. The presence of disease and high prevalence of antibody to dengue virus in limited serologic surveys suggest endemic dengue virus infection in all or many parts of Africa. Dengue is likely underrecognized and underreported in Africa because of low awareness by health care providers, other prevalent febrile illnesses, and lack of diagnostic testing and systematic surveillance. Other hypotheses to explain low reported numbers of cases include cross-protection from other endemic flavivirus infections, genetic host factors protecting against infection or disease, and low vector competence and transmission efficiency. Population-based studies of febrile illness are needed to determine the epidemiology and true incidence of dengue in Africa. When their distribution is combined with rapid population growth, unplanned urbanization, and increased international travel, extensive transmission of DENV is likely in Africa . OPublished, peer-reviewed literature, published and unpublished country reports, and the World Health Organization (WHO) library database, including Dengue Net, were reviewed for 1960–2010 for the key terms “dengue” and “Africa.” In addition, we examined peer-reviewed published literature and other sources to determine the extent of disease among travelers returning from Africa. We searched for publications in English by using MEDLINE and EMBASE electronic databases, Euro Surveillance, and ProMED-mail posts. A review for dengue reports in languages other than English did not find any reports that would change the conclusions of this article.Additionally, references in each paper identified during searches were checked. Those references not already identified by the search were reviewed. Abstracts presented at international forums were included if they contained epidemiologic, entomologic, or virologic data pertaining to dengue in Africa.,,–,Dengue was reported in Africa in the late 19th and early 20th centuries. Epidemics were reported in Zanzibar , Burkina Faso (1925), Egypt , South Africa (1926–1927), and Senegal (1927–1928) . Of these countries, 22 have reported local disease transmission, 20 have reported laboratory-confirmed cases, and 2 (Egypt and Zanzibar) have reported only clinical cases that were not laboratory confirmed. In the remaining 12 countries, dengue was diagnosed only for travelers returning to countries to which dengue was not endemic but never reported as occurring locally in these 12 countries (. Of thes––The European Network on Imported Infectious Disease Surveillance and other published data have reported 27 countries in Africa as locations where travelers/expatriates from regions to which dengue was not endemic acquired dengue  (11–15).Wilson et al. reported for the GeoSentinel Surveillance Network of the International Society of Travel Medicine and the Centers for Disease Control and Prevention that travelers reporting illness have disproportionately visited Africa  malaria is the most prominent endemic febrile illness in Africa and does not require complex clinical and laboratory diagnostic facilities; 2) a low awareness of dengue may contribute to health care workers not considering the disease; 3) dengue is not a reportable disease in most countries in Africa; 4) dengue surveillance and diagnostics are not widely and consistently available throughout Africa; and 5) funding for surveillance and other research activities pertaining to dengue in Africa are limited (Whether populations in Africa are susceptible to DENV infection and disease at rates comparable with those in populations in Asia or the Americas and the true incidence of dengue in these countries cannot be determined from data obtained from occasional reports of disease outbreaks. Given that safe and effective dengue vaccines should become available within the next decade (


AbstractThe 120 presently recognized genera and seven subgenera of the azooxanthellate Scleractinia are keyed using gross morphological characters of the corallum. All genera are illustrated with calicular and side views of coralla. All termes used in the key are defined in an illustrated glossary. A table of all species-level keys, both comprehensive and faunistic, is provided covering the last 40 years. PageBreakSince then the number of Recent azooxanthellate genera and species has almost doubled, and new observations on apozooxanthellate species (species that have facultative symbiosis with zooxanthellae) are also available. Furthermore, what keys exist to the species level of various taxa or geographic regions are scattered throughout the literature and of variable quality (PageBreakPageBreakThe ready identification of azooxanthellate Scleractinia (determined herein by depth of occurrence and previously published observations) to the genus and species levels has been hampered by a lack of a comprehensive key to the genera as well as a lack of species level keys. For instance, the last comprehensive set of keys to the genera was published by  quality . In this quality , the higSome genera are keyed two or even three times because of the variation within those genera regarding the characters used in the key. In theory, all variations of that genus will be correctly keyed. Although most couplets are dichotomous, some are polychotomous, such as the columella or colony shape, which allows the reader to clearly see the multiple states of a particular character.Although it would be desirable to follow the generic key with keys to all of the approximately 720 azooxanthellate species, it is a simple fact that not many species level keys have been published. Those that have been published in the last 35 years are listed in www.lophelia.org/online-appendices), which now includes junior synonyms and depth ranges of the species, and authors of the genera. A list of the 120 azooxanthellate genera, their authorship, and bathymetric ranges was also published in Other sources of useful taxonomic information include a list of all extant Recent scleractinian species as of 1999 , which aGeographic ranges within brackets in the key are not meant to be considered as distinguishing characters, but simply informational, which may nonetheless hint at an incorrect identification. Abbreviations: Ant. = Antarctic or Subantarctic, Atl. = Atlantic, IP = Indo Pacific, IWP = Indo-West Pacific, Pac. = Pacific, SubAnt = Subantarctic; Cosmopolitan implies occurrence in all three oceans as well as Subantarctic and/or Antarctic. Museums and Institutions acronyms: AM = Australian Museum (Sydney); AU = Auckland University Museum (Auckland); CSIRO = Commonwealth Scientific and Industrial Research Organisation (Hobart); JCU = James Cook University (Townsville); MNHN = Muséum national d’Histoire naturelle (Paris); SBMNH = Santa Barbara Natural History Museum (Santa Barbara); SIO = Scripps Institute of Oceanography (San Diego); NZOI = New Zealand Oceanographic Institution  (Wellington); USNM = United States National Museum  ; YPM = Yale Peabody Museum (New Heaven).Useful sources for more information about definitions of terms used in the glossary include: (An asterisk indicates genera that have azooxanthellate and zooxanthellate representatives)


To assess cerebral lesions and other medical as well as social characteristics as predictors of risk of mild and severe cognitive deficiencies in very preterm infants.As part of the EPIPAGE population-based prospective cohort study, perinatal data and cognitive outcome at 5 years of age were recorded for 1503 infants born before 33 weeks of gestation in nine regions of France in 1997. Mild cognitive deficiency was defined as a Mental Processing Composite score on the Kaufman Assessment Battery for Children test of between 70 and 84, and severe cognitive deficiency as a score of <70.After controlling for cerebral lesions and other medical as well as social factors, low parental socio-economic status and lack of breastfeeding were significant predictors of mild and severe cognitive deficiencies, whereas presence of cerebral lesions, being small for gestational age and having a large number of siblings were predictors of severe cognitive deficiency.Predictors of poor cognitive outcome in very preterm infants are low social status, lack of breastfeeding, presence of cerebral lesions on ultrasound scan, being born small for gestational age and having a high number of siblings. Social factors predicted both mild and severe cognitive deficiencies, whereas medical factors predicted mostly severe cognitive deficiencies. Very preterm infants (born before 33 weeks of gestation) are at high risk of cognitive deficiency , which iCognitive deficiency in very preterm infants is a complicated multifactorial issue. It depends on both biological and environmental events. Biological events can include the formation of brain abnormalities that represent a combination of destructive and developmental mechanisms influenced by antenatal and postnatal factors . EnvironStudies have identified several medical and social risk factors for cognitive deficiency. These factors include cerebral lesions, chronic lung disease, male sex and small head circumference, as well as ethnicity, parental occupation, maternal education and marital status –11. Yet,In this study, we assessed cerebral lesions on neonatal cranial ultrasound scan and other medical and social characteristics as predictors of mild and severe cognitive deficiencies in a large population-based cohort of very preterm infants.This study was approved by the French data protection agency .All infants born between 22 and 32 weeks of gestation in nine regions of France throughout 1997 (2901 live births) were included in the EPIPAGE study  Fig. 1)Fig. 1). At 5 years, children were invited for a check-up organized for the study in every region and were assessed by trained psychologists blinded to their perinatal data. The assessment used the Kaufman Assessment Battery for Children (K-ABC) test, which was validated in France in 1990–1991 . OverallCognitive deficiency was classified as mild when the MPC score was between 70 and 84, and as moderate to severe (later simply classified as severe) when the MPC score was below 70.The major characteristics recorded were cerebral lesions on neonatal cranial ultrasound scan, which is standard practice in very preterm infants. In France, usually one to three scans are performed during the first 2 weeks of life, then one every week for infants with lesions and one every 2 weeks for those without lesions . In totaOther recorded medical characteristics included information on pregnancy, infant characteristics and postnatal factors. Information on pregnancy included single or multiple pregnancy; antenatal corticosteroid administration; and complications of pregnancy, classified according to the following priority order of maternal hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg during pregnancy), then antepartum haemorrhage, and then preterm premature rupture of membranes at least 12 h before the beginning of labour or idiopathic preterm labour (spontaneous onset of labour before rupture of membranes). Infant characteristics were the following: gestational age, in completed weeks of amenorrhoea ; infantSocial characteristics considered were parental socio-economic status; defined as the highest occupational status between the mother and the father and classified into high , high intermediate , low intermediate (shop assistant or service worker) and low ; maternal educational level, classified into postsecondary education, high school level and less or no education; number of siblings in the family; and maternal age at birth. Information on parental socio-economic status and maternal educational level was obtained in the neonatal period or, when incomplete or unavailable, at the 5-year follow-up.We assessed medical and social characteristics in very preterm infants as potential predictors of cognitive deficiencies but did not aim to elucidate causal pathways or estimate causal effects. Specifically, two issues were considered, mild cognitive deficiency and severe cognitive deficiency, and predictors of each were studied in univariate then in multivariate modelling.First, univariate multinomial logistic regression was used to identify medical and social characteristics as risk factors separately for mild and severe cognitive deficiency. Second, a multivariate multinomial logistic regression model was used to assess independent predictors of mild versus severe cognitive deficiency among medical and social characteristics. Predictor variables that were studied in multivariable analyses were chosen based on previous studies –12 and tResults were expressed as crude and adjusted odds ratios and their 95% confidence interval (CI). Complementary analysis was conducted after excluding children with aid-free ambulatory cerebral palsy  to assess any change in predictors of cognitive outcome that may be influenced by mild motor deficiency.Statistical analyses were performed using STATA/SE, version 10, .We found that the prevalence of mild cognitive deficiency for children without moderate to severe neurosensorial disabilities was 21% (95% CI: 19–23%) and that of severe cognitive deficiency was 11% (95% CI: 10–13%). In this same population, mean MPC score was 94 (SD 19).In univariate analysis, characteristics significantly associated with mild cognitive deficiency were bronchopulmonary dysplasia at 36 weeks, no breastfeeding, low parental socio-economic status, low level of maternal education and large number of siblings . CharactIn multivariate analysis, parents’ socio-economic status was the main predictor of mild cognitive deficiency  . BronchoAfter exclusion of children with aid-free ambulatory cerebral palsy, the only notable change in the odds ratios was in the case of the association between severe cerebral lesions (cystic PVL or IPH) and severe cognitive deficiency for which the odds appeared to be lower , although still statistically significant.EPIPAGE is the largest population-based cohort assessing the outcome of very preterm children at 5 years of age in a contemporary obstetric and neonatal care context. It is also the first study to assess risk factors for mild and severe cognitive deficiency considering a large set of medical and social characteristics. We found that mild cognitive deficiency was mainly influenced by social status and breastfeeding, whereas severe cognitive deficiency was mainly influenced by cerebral lesions, in addition to social status, breastfeeding, having a high number of siblings and being small for gestational age. In particular, after controlling for medical and social factors, the odds of severe cognitive deficiency were increased sixfold in infants with cystic PVL or IPH and twofold in those born to parents of low socio-economic status.Cognitive ability in our study was assessed according to the MPC score, an IQ-equivalent measure that assesses overall cognitive ability of infants including sequential and simultaneous processing. MPC score is predictive of future learning difficulties and poor academic achievement ,3. ExcluIn our study, cerebral lesions were associated with severe, but not mild, cognitive deficiency. To our knowledge, EPIPAGE is the first study to consider risk factors of mild versus severe deficiency, relying on the hypothesis that risk factors may alter cognitive function to different extents. However, diagnosis of cerebral abnormalities by ultrasonography was not optimal for two important reasons. First, in our population-based study, we obtained information on cerebral lesions based on routine practice. Therefore, there was no unique standardized protocol for cranial scanning follow-up, and staff qualifications were heterogeneous. Although during the study period cranial ultrasound was generally performed with high-frequency 7.5 MHz transducers by qualified neonatalogists or radiologists who routinely performed ultrasonography, interobserver reliability in interpreting cranial ultrasound scan has been shown to be relatively poor for low grade IVHs resulting in some probable misclassifications . No cereSocial status is a major factor to be considered when assessing cognitive prognosis of very preterm infants. Three studies have used multivariate analysis to determine the associations between several social factors and the occurrence of cognitive deficiency, after controlling for medical factors –8. In thIn our large population-based study, cerebral lesions and being small for gestational age were significant predictors of mild and severe cognitive deficiencies after controlling for several other medical and social factors. This result is consistent with previous findings of an association between several medical factors and poor cognitive outcome at 5 years of age after adjustment for social characteristics . HoweverWe also explored breastfeeding, an infant factor that expresses both medical and social characteristics. A meta-analysis of 20 studies, published in 1999, concluded that breastfeeding has a beneficial effect on cognitive outcome . RecentlIn conclusion, our findings point to the importance of medical characteristics for predicting severe cognitive deficiency in very preterm infants. After taking into account several medical and social characteristics, the presence of cerebral lesions and being small for gestational age were significant predictors of severe cognitive deficiency. Our study also underscores the extent to which social characteristics influence cognitive ability in very preterm infants. In particular, after taking into account cerebral lesions and several other medical characteristics, infants born to parents with low socio-economic status still had more than a twofold increase in the odds of severe cognitive deficiency. Of interest, our study showed that breastfeeding, a generally understudied infant characteristic, is highly associated with lower odds of cognitive deficiencies. Finally, predictors of cognitive deficiencies certainly give a better idea of the prognosis of infants; however, prediction of cognitive outcome at the individual level is still difficult to achieve .


With the evolving evidence of the promise of botanicals/biologics for cancer chemoprevention and treatment, an Indo-U.S. collaborative Workshop focusing on “Accelerating Botanicals Agent Development Research for Cancer Chemoprevention and Treatment” was conducted at the Moffitt Cancer Center, 29–31 May 2012. Funded by the Indo-U.S. Science and Technology Forum, a joint initiative of Governments of India and the United States of America and the Moffitt Cancer Center, the overall goals of this workshop were to enhance the knowledge  of a multinational, multidisciplinary team of researcher's to systematically accelerate the design, to conduct a successful clinical trials to evaluate botanicals/biologics for cancer chemoprevention and treatment, and to achieve efficient translation of these discoveries into the standards for clinical practice that will ultimately impact cancer morbidity and mortality. Expert panelists were drawn from a diverse group of stakeholders, representing the leadership from the National Cancer Institute's Office of Cancer Complementary and Alternative Medicine (OCCAM), NCI Experimental Therapeutics (NExT), Food and Drug Administration, national scientific leadership from India, and a distinguished group of population, basic and clinical scientists from the two countries, including leaders in bioinformatics, social sciences, and biostatisticians. At the end of the workshop, we established four Indo-U.S. working research collaborative teams focused on identifying and prioritizing agents targeting four cancers that are of priority to both countries. Presented are some of the key proceedings and future goals discussed in the proceedings of this workshop. Cancer is a leading cause of death worldwide  with deaBotanicals/biologics have been shown to influence multiple biochemical and molecular cascades that inhibit mutagenesis, proliferation, induce apoptosis, and suppress the formation and growth of human cancers, thus modulating several hallmarks of carcinogenesis. These agents appear promising in their potential to make a dramatic impact in cancer prevention and treatment, with a significantly superior safety profile than most agents evaluated to date –12. HoweThe workshop opened with a keynote lecture focused on “Past Experiences and Lessons Learned from Definitive Chemoprevention Trials: What Went Wrong? Where Do We Go From Here? The identification of chemopreventive agents holds tremendous promise in reducing the burden of cancer. Past trials of preventive agents offer important lessons that can inform the design and conduct of future trials. Important lessons learned regarding agents come from ATBC  and CARE®; National Cancer Institute, National Institute of Health, Rockville, Bethesda, Maryland, USA), which has developed a grid-enabled web-based automated pipeline, as well as homology-based prediction of protein structures, with an emphasis on cancer-related proteins. Current drug design software also falls short of expectations even if the structures of drug targets are known [http://www.genome.gov), tertiary structure prediction of proteins (Bhageerath and Bhageerath-H), and protein/DNA-targeted lead molecule design (Sanjeevini) was discussed. These methods can be configured into an assembly line to deliver hit molecules from genomic information. The software and a host of other utilities are freely accessible to the global user community (http://www.scfbio-iitd.res.in) [This session was followed by the current approaches for screening agents for drug development. Adoption of computational methods to discover new drugs has recently experienced a true renaissance with several new and exciting techniques being developed and currently employed to design new drug candidates and to rapidly bring these agents to the clinic at relatively lower costs. Traditional approaches to drug discovery have involved target identification and validation and lead identification and optimization. However, in the past decade, several contemporary approaches and enabling technologies like High-Performance Computing, Grid Computing, and Cloud Computing have evolved. Virtual screening and molecular modeling for drug discovery including grid-based docking, quantum mechanics, molecular mechanics, molecular dynamics, normal-mode vibration, and mutational analysis were discussed. For complex diseases like cancer, traditional methods of targeting a single protein is found profoundly insufficient laying the foundation for polypharmacological and combinatorial analysis harnessing in silico techniques viz. Molecular Topology, Network Pharmacology, and Combinatorial Chemistry. A network perspective of complex cancers has direct implications in the drug discovery process as it changes the target entity from a single protein to entire molecular pathways and/or cellular networks. Examples of success included the work of the Bioinformatics Group at the Centre for Development of Advanced Computing (India) in collaboration with cancer Biomedical Informatics Grid  –18. It wAzadirachta indica) was reported with research demonstrating that both azadirachtin and nimbolide significantly suppressed the viability of HeLa cells in a dose-dependent manner by inducing cell cycle arrest at G0/G1 phase accompanied by p53-dependent p21 accumulation and downregulation of the cell cycle regulatory proteins cyclin B, cyclin D1, and PCNA [2, and nitric oxide and inhibition of NF-κB p65 activation. Decreased expression of S100A8/9 observed and inhibition of activation of STAT3 and AKT may in part be responsible for the observed results [This session was followed by presentations of a systematic approach using the traditional scientific paradigm to accelerate agent development using botanicals/biologics for cancer prevention and treatment in both countries. As cancers are caused by perturbations of multiple signaling pathways, the value of promiscuous targeting of botanicals/biologics was presented compared with mono-targeted “smart drugs,” using curcumin as an example of an agent that targets multiple signaling pathways –21. Addiand PCNA . Similarand PCNA . Quercetand PCNA ,26. Othe results .Presentations that followed focused on elucidating the molecular mechanism of action of several botanicals/biologics in preclinical studies and provided examples of subsequent clinical trial results on human breast, prostate, colon, and pancreatic cancer patients. The potential mechanisms of action of lycopene include its antioxidant and anti-inflammatory, antiproliferative effects as well as modulation of gene expression through epigenetic effects ,29. IsofDecursin, a novel coumarin compound, strongly inhibits growth and induces death in human prostate carcinoma DU145, PC-3, and LNCaP cells ,38. RepoAttempts to understand the cellular origin of cancer have advanced the theory of cancer stem cells (CSCs). These rare CSCs have indefinite proliferative potential and are believed to be responsible for tumor invasiveness and heterogeneity. Research approaches and rationale focused on identifying botanicals/biologics for prevention and therapy that target the stem cells were presented . The CSCCoptis sinensis, and two complex herbal formulations requiring investigator-initiated IND approvals from FDA were presented [Representatives from the regulatory bodies from India and United States discussed potential challenges and successes for international collaborative research. FDA, USA, published a draft Guidance for Industry-Botanical Drug Products (Guidance) in 2000 and finalized the Guidance in 2004, to illustrate the current thinking on the development of botanical drugs. The FDA Policy on the U.S. Clinical Trials for Botanical and Biologic Drugs and the Investigational New Drug Approval process was presented. Representatives from the Science and Technology Forum (India) described that the efforts are ongoing to uplift the infrastructure development and international harmonization of laboratories R&D through GLP, National Accreditation Board of Testing and Calibration of Laboratory, Metabolic Wards for GCP, Revision of Ethical Guidelines for Biomedical Research on Human and Animal research and Clinical Trial Registry (CTRI), and it is mandatory according to Drugs Controller General India that all the clinical trials undertaken in India need to be registered with CTRI. Examples of experience working with regulatory agencies and international pharmaceutical companies in early phase I–II clinical trials using agents' ranges from highly defined extract from Maitake mushroom, crude extract from a single herb resented ,48. BuilIt was reported that approximately $114 million of an NCI budget of $5 billion directly supports complementary and alternative medicine (CAM) research, including research of botanicals and botanical-related products. In fiscal year (FY) 2010, over 340 of grants funded by NCI supported CAM research, and about 15% of these supported botanical or botanical-related research . The OffOn the final day of the workshop, four collaborative working groups focused on initiating collaborative research projects using the traditional and novel funding mechanisms in both countries were established. We plan to establish a joint repository of botanicals/biologics ready for prioritization for preclinical and clinical trials, targeting major cancers in both countries. Guided by an independent advisory board of stakeholders from India and the United States, the group continues to communicate regularly with future meetings scheduled during national and international scientific conferences. It is clear that both countries have their strengths and resources, which when combined can actively facilitate the building of an interdisciplinary community harnessing system of Information and Communications Technology toward accelerating botanicals and biologic drug development on an international scale for cancer prevention and treatment. Of significant importance is also the impact this approach is likely to have on the economics of drug discovery. We predict that this collaborative effort can result in research breakthroughs, which will not only bring new hope but also create a new class of anticancer drugs that will help millions of cancer patients and those at high risk for this disease in both our countries and will benefit the world population at large.