Accomplishments of this program have provided numerous dividends and might benefit areas outside infectious diseases. However, it took a 1992 Institute of Medicine report to emphasize the dynamic and modern factors that cause infectious diseases to emerge and re-emerge and to put to rest the idea of infectious diseases as a solved problem, a worry for earlier times (Haemophilus influenzae type b (Hib) and group B Streptococcus (GBS) infections, and meningococcal disease  formed an EIP Steering Group to provide guidance and strategy for EIP activities. By the time of the Steering Group meeting in November 1996, the group had adopted guiding principles and approved a framework for evaluating ideas for new projects, which has guided assessment of potential new areas of work and strategic directions .Responsibilities and authorities are distributed across the network’s membership. State public health agencies have legal authority for conducting surveillance; in this context, academic partners function as agents of the state health departments. CDC has responsibility for expending and managing federal funds invested in the EIP. Resources come from several funding streams, and each source requires accountability for ensuring that funds are spent well on appropriate activities. This distribution of responsibilities and authorities, coupled with the need for ensuring that the EIP can respond nimbly to emerging issues, has meant that governance works flexibly, not rigidly—through negotiations and consensus—for the network as a whole and also in each project area. If one considers the distribution of interests and authorities, this model has proven productive. In addition to internal governance, EIP work has benefited from external reviews that provided advice and guidance on strategic directions, and from representatives of professional organizations  serving on several EIP steering committees.EIP activities generally fall into the categories of surveillance, applied research, and enhanced and flexible public health practice. Active, population-based and laboratory-based surveillance, with collection of disease-causing isolates linked to epidemiologic information from case reports, forms the foundation of many EIP activities. This foundation accurately documents the burden of disease and key characteristics of disease-causing microbes and supports special applied research activities, such as evaluation of vaccine effectiveness and epidemiologic risk factor studies. On several occasions, the EIP has proved its flexibility and provided enhanced responses to precipitously emerging issues.With an established network of sites, governance, and a strategy in place, the main limbs, or programs, of the EIP grew in 4 broad thematic areas: invasive bacterial diseases; foodborne diseases; health care–associated infections; and influenza. Each program contains a portfolio of established and newer projects. Leveraging EIP resources flexibly as needed to provide fast public health responses to emerging outbreaks is a fifth limb of the EIP tree. Other branches fill out the tree.Streptococcus pneumoniae, groups A and B Streptococcus, H. influenzae, Neisseria meningitidis, and Bordetella pertussis  of the EIP determines the incidence and epidemiologic characteristics of invasive disease caused by bacterial pathogens, including Campylobacter, Cryptosporidium, Cyclospora, Listeria, and Salmonella spp.; Shiga toxin–producing Escherichia coli O157 and non-O157 E. coli; and Shigella, Vibrio, and Yersinia spp.) (The Foodborne Disease Active Surveillance Network (FoodNet), the principal foodborne disease component of the EIP, is a collaborative venture among the 10 EIP sites, the USDA and the FDA. This network monitors foodborne disease caused by bacterial and parasitic pathogens  investigates major and time-sensitive questions about emerging health care–associated infection (HAI) threats and antimicrobial drug resistance in the United States. The in-depth approach of the EIP to surveillance that monitors HAI diseases in health care institutions and the community and related research activities complements the broader approach used by the National Healthcare Safety Network  IMPACT projects  and concluded that the agent responsible for bovine spongiform encephalopathy might have spread to humans. The EIP then rapidly developed active CJD surveillance in 5 sites. This surveillance, coupled with other reviews of national CJD mortality rates, provided some assurance that the new variant CJD had not spread to the United States and helped substantiate effectiveness of death certificate reviews in identifying CJD deaths in the United States pdm09 virus. The EIP findings, that the excess risk was comparable with that associated with prior seasonal influenza vaccines and smaller than that observed in 1976, provided evidence for sustaining the vaccination campaign , 13-valent pneumococcal conjugate vaccine, and meningococcal conjugate A/C/Y/W-135 vaccines were supported by ABCs data, and the HPV IMPACT project provided outcome data that helped evaluate early effects of HPV vaccine implementation  infections, evaluated the relative effectiveness of initial screening vs. risk-based prevention strategies, provided assessments of prevention guidelines uptake and effect, and identified missed opportunities for additional prevention. A retrospective cohort study , Clostridium difficile, carbapenem-resistant Enterobacteriaceae, infections with Candida species, and patterns of antimicrobial drug use. The program documented a decrease in drug-resistant invasive pneumococcal isolates after widespread use of PCV7; emergence of resistant serotype 19A, which was not included in PCV7; and another decrease in drug-resistant pneumococcal disease after use of 13-valent pneumococcal conjugate vaccine, which included 19A . Clinical diagnoses are increasingly being made through culture-independent diagnostic test (CIDTs), particularly nucleic acid–based tests. Although CIDTs might represent advances in modern medical practice, they can also confound EIP surveillance. Culture-independent diagnostic tests vary in their performance characteristics, and also their market share across EIP sites, which can influence incidence measurements, potentially causing discontinuity of data or requiring modeling to estimate incidence in a way that has not been previously needed. Moreover, the EIP has relied on isolates for antimicrobial drug–susceptibility testing and molecular epidemiology, which cannot be conducted—or conducted in the same way—if there are no longer clinical isolates. EIP surveillance methods, analytic methods, and case definitions will need to adapt, as will laboratory methods applied for drug susceptibility and molecular typing in EIP projects.EIP active surveillance for bacterial diseases has depended on isolation of the disease-causing organism. Case finding started in clinical laboratories, and case definitions have included isolation of an organism as part of the case definition  initiative at CDC to explore and advance application of modern molecular technologies to the practice of public health. With its huge asset of collections of population-based and epidemiologically well-characterized strains, the EIP is well positioned to apply AMD methods, such as whole-genome sequencing and metagenomics. As the EIP applies these powerful new tools to characterize strains and understand pathogenesis, they will enhance the quality of the network’s science and contribute to the transformation of public health practice that the AMD initiative provides , which, when linked with other geospatial data, such as socioeconomic or climate or land use data, might help clarify underlying determinants of health and health disparities and the extent to which these pathways are similar across different diseases.Systematic review of paper medical records by EIP surveillance officers has been central in developing high-quality information for EIP surveillance and special studies. As electronic health records evolve, this historical approach is disappearing and new efforts by EIP staff are required to gain appropriate and ready access to electronic records and new skills are needed to use them effectively. However, the potential for more efficient, powerful, and innovative use of modern health information technology can outweigh the problems caused by the transition from paper to electronic health records. Instead of transcribing data from charts into EIP surveillance and study forms, well-structured outputs from electronic records can save substantial staff time and resources. Also, use of structured or even ad hoc queries could make EIP surveillance and research projects more flexible and powerful. For example, EIP HAI surveillance uses queries of laboratory-automated culture and susceptibility systems to identify patterns that fit the case definition of multidrug-resistant Health reform in the United States is affecting the way persons are obtaining health care and is also influencing the range of preventive services available, how they are delivered, and how they are funded. As the relationship between clinical care and public health evolves, there might be a role for the EIP in filling scientific gaps at the population level. The EIP could participate in assessment of the effect of health care reform on health department infectious disease control practice .The EIP model—close collaboration among state and federal public health agencies along with academic institutions and generation of reliable surveillance information coupled with special studies to address key policy and prevention issues that generally use a population-based approach—has provided numerous dividends for public health work in infectious diseases. The EIP tree is flourishing.Public health issues other than infectious diseases might also benefit from the EIP model. For example, opioid overdose in the United States, with its recent epidemic-like emergence, might be one such issue. During the coming year, the EIP will explore this idea through projects at 2 sites aimed at strengthening the scientific base for prevention of opioid overdose.,A central premise of the Institute of Medicine report on emerging infections was that the emergence and reemergence of infectious diseases are a consequence of dynamic processes and factors: societal events; health care; food production; human behavior; environmental changes; public health infrastructure; and microbial adaptation (


Micropterus spp.) in southern Africa. Additionally, catch data from standardized tournament events were used to assess the abundance and growth of non-native bass populations in southern Africa relative to their native distribution (southern and eastern United States). Differences in metrics of catch per unit effort (average number of fish retained per angler per day), daily bag weights (the average weight of fish retained per angler), and average fish weight were assessed using catch data from 14,890 angler days of tournament fishing . No significant differences were found between catch rates, average daily bag weight, or the average fish weight between countries, suggesting that bass populations in southern Africa reach comparable sizes and numbers relative to waters in their native distribution. Given the minimal cost associated with data collection (i.e. records are collected by tournament organizers), the standardized nature of the events, and consistent bias (i.e. selection for the biggest fish in a population), the use of angler catch data represents a novel approach to infer the status and distribution of invasive sport fish.Fishes are one of the most commonly introduced aquatic taxa worldwide, and invasive fish species pose threats to biodiversity and ecosystem function in recipient waters. Considerable research efforts have focused on predicting the invasibility of different fish taxa; however, accurate records detailing the establishment and spread of invasive fishes are lacking for large numbers of fish around the globe. In response to these data limitations, a low-cost method of cataloging and quantifying the temporal and spatial status of fish invasions was explored. Specifically, angler catch data derived from competitive bass angling tournaments was used to document the distribution of 66 non-native populations of black bass ( Lastly, many of the water bodies targeted by tournaments must be adequate in size to accommodate a moderate to large number of anglers. However, by incorporating data from local, regional, and national level events, data were drawn from events which spanned a range of sizes (both in water body size and number of angler participants). In spite of the above mentioned shortfalls, tournament angling data may serve to enhance our understanding of the distribution and population characteristics of invasive sport fishes worldwide.Despite the utility of tournament angling data in characterizing the status of invasive sport fish populations, several limitations associated with the data warrant discussion. First, angling tournaments are generally focused on water bodies with established populations, most of which are restricted to impoundments and not rivers. Interestingly, many of the tournaments held in the native US range were held on river systems 6 of 15), however events from southern Africa were almost entirely restricted to impoundments. That tournaments are focused on established populations and not those recently introduced implies tournament data is inappropriate to detect populations early in the invasion process  of 15, h. Second,The use of tournament data to assess invasion status represents a novel and cost effective method to document trends in fish populations in non-native waters relative to their home range. Given the global distribution of invasive black bass and widespread popularity of competitive angling, catch data derived from tournaments may serve as a valuable tool to update distribution records, assess invasions status, and track population trends through time. Generating real-time data from tournament catch data may aid in documenting illegal or unauthorized fish transfers, especially in areas where fisheries agency funds and personnel are limited. Future studies of invasion ecology should consider utilizing existing angler catch data for documenting the spatial and temporal trends in fish invasions.S1 TableMicropterus spp.) tournament angling events between 1999 and 2013 in southern Africa and their associated GPS coordinates. Population number refers to water bodies identified in A list of water bodies that hosted local club, regional, or national black bass ((DOCX)Click here for additional data file.


Rapid developments in technology have encouraged the use of mobile phones in smoking cessation, promoting healthy diet, nutrition, and physical activity, sun safety, and cancer screening. Although many apps relating to the prevention of cancer and other chronic diseases are available from major mobile phone platforms, relatively few have been tested in research studies to determine their efficacy.In this paper, we discuss issues related to the development and testing of new apps for preventing cancer through smoking cessation, sun safety, and other healthy behaviors, including key methodologic issues and outstanding challenges.An exploratory literature review was conducted using bibliographic searches in PubMed and CINAHL with relevant search terms  to identify papers published in English through October 2015.Only 4 randomized controlled trials of the use of mobile phone apps for smoking cessation and 2 trials of apps for sun safety were identified, indicating that it is premature to conduct a systematic search and meta-analysis of the published literature on this topic.Future studies should utilize randomized controlled trial research designs, larger sample sizes, and longer study periods to better establish the cancer prevention and control capabilities of mobile phone apps. In developing new and refined apps for cancer prevention and control, both health literacy and eHealth literacy should be taken into account. There is a need for culturally appropriate, tailored health messages to increase knowledge and awareness of health behaviors such as smoking cessation, cancer screening, and sun safety. Mobile phone apps are likely to be a useful and low-cost intervention for preventing cancer through behavioral changes. There has been increasing interest in the use of mobile phone apps to promote smoking cessation, healthy eating, physical activity, and other behaviors associated with reduced risk of cancer morbidity and mortality -6. MobilRapid technological advances have led to the emergence of smartphones that combine the voice and text messaging functions of mobile phones with powerful computing technologies that can support third-party apps, access to the Internet, and wireless connectivity with other devices . The booA mobile app is a computer program designed to run on smartphones or other mobile devices. All major smartphone platforms provide third-party developers with app programming interfaces that can be used to build special purpose apps referred to as native apps . SmartphA variety of apps relating to cancer prevention, smoking cessation, diet, nutrition, and weight control are available from major smartphone platforms such as iPhone, Android, Nokia, and BlackBerry. Common behavioral change techniques include providing feedback, goal-setting, self-monitoring, and planning social support and change . HoweverIn this viewpoint, we discuss issues related to the development and testing of new apps for preventing cancer through smoking cessation, healthy diet and nutrition, physical activity, weight management, cancer screening, and sun safety, including key methodologic issues and outstanding challenges related to methodology, design issues, and regulatory issues. In an exploratory literature review intended to inform our commentary, we review published studies on the acceptability and effectiveness of mobile phone apps designed to promote behaviors that reduce risk of cancer ,18.Of particular interest were randomized control trials of the effectiveness of mobile phone apps to promote healthy behaviors such as smoking cessation and sun safety. Although mobile health apps related to telemedicine, cancer diagnosis and treatment, and oncology clinical trials also hold promise for cancer prevention and control -21, the JMIR mHealth and uHealth and JMIR Cancer. In addition, we identified reports included in Cochrane reviews [We conducted bibliographic searches in PubMed and CINAHL with relevant search terms: (smartphones) and ((smoking cessation) or (cancer prevention) or (cancer screening) or (carcinogens)). Papers published in English through October 2015 were identified using relevant MeSH search terms and Boolean algebra commands. The searches were not limited to words appearing in the title of a paper. Studies that did not have a randomized controlled or pre-post test design were excluded along with those that focused on patients with cancer or other chronic diseases . Randomized controlled trials are the most rigorous study design and the standard for most of the cancer prevention and control interventions . Information obtained from bibliographic searches  was used to determine whether to retain each paper identified in this way. We also looked for relevant papers published in  reviews  and reviA total of 220 papers were identified in the bibliographic searches . By screP <.05).Buller et al  conducteBricker et al  conducteBaskerville et al  is conduOnly two trials of the use of mobile phone apps for promoting sun safety were identified ,26. Our n =94) or self-assessment tools (n =30). Few of the apps were evidence-based (14.2%) or involved medical professionals in their development (12.8%). Potential patient safety concerns were identified in 29 (15.7%) apps [Bender et al  examineded in 29 .7% apps elopment .8%. PoteThe number of randomized controlled trials of the efficacy of mobile phone apps in smoking cessation and sun safety is still modest ,26. DiffMobile apps, such as those used for cancer prevention and control, are developed using emulators in specialized development environments. The development of apps must take into account the wide variety of screen sizes, hardware specifications, and configurations of mobile devices, as well as the need to run on a battery. In order to have an understandable and user-friendly interface, mobile user interface design takes into account display screens and input. The interface of users with their device includes both hardware and software components. Constraints considered by mobile user interface design include the limited attention of users and the device’s screen size in relation to a user’s hand.Guidelines for developing mobile apps are available from academic and industry sources -29. To hOnce developed, prototype apps are subjected to heuristic evaluation and field-testing. Evidence-based heuristics have been developed for evaluating the demands that mobile apps make on users, in terms of health literacy and usability, that is, the extent to which the app is practical and convenient for users . The eva1. Immediately inform users of purpose and engage users (identify the purpose and audience on the home screen)2. Use complementary interaction methods  and outputs 3. Leverage interactivity 4. Provide accurate, colloquial, comprehensive, succinct content 5. Provide tailored, flexible, and layered content 6. Use visuals to complement text but avoid tables 7. Use simplistic consistent navigation 8. Use simplistic, consistent displays (avoid on screen complexity and the need for scrolling by limiting information on each page or screen).Simplicity and ease of use are often desirable. For example, if health apps require users to complete multiple steps in order to access information , the complex and repetitive process requires users to expend a great deal of their time and mental energy, which can negatively impact their willingness to use the app . It is hDepending on the app that is being evaluated, it may also be helpful to: (1) provide clear and comprehensive communication of risks ; (2) provide clear depiction of monitoring data ; and (3) allow users to adjust the display size using familiar input  . HeuristOne challenge for the development of mobile phone apps for cancer prevention is that people may be more likely to use an app for a regular behavior such as healthy eating, physical activity, or weight management than an app that focuses on behaviors such as cancer screening that are only required every 5-10 years or biannually. It may be helpful to address multiple cancer prevention behaviors  in the same app . A furthFor mobile apps to be useful for preventing and controlling cancer in diverse populations, they must be suitable for people with varying levels of health literacy, eHealth literacy, computer literacy, and scientific literacy. The Institute of Medicine defined health literacy as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions” . Health In contrast to the more general concept of health literacy, eHealth literacy is “the ability to seek, find, understand, and appraise health information from electronic sources and apply this knowledge gained to addressing or solving a health problem” . eHealthThe model of ehealth literacy proposed by Norman and Skinner, eHEALS, defines the concept using 6 sub-literacies . Eight statements are included  about an individual’s perception of their eHealth literacy measured on a 5-point Likert scale . The eHeLittle information is available about the general cognitive motivators that prompt people’s use of health apps . People In some countries, government agencies have begun to regulate or curate medical apps -56. TherAdditional cancer prevention and control research is needed to examine the efficacy of mobile phone apps . Future


Activins are members of the transforming growth factor β (TGFβ) family and serve as multifunctional regulatory proteins in many tissues and organs. In the brain, activin A, which is formed by two disulfide-linked βA subunits, is recognized as the predominant player in activin signaling. Over the last years, considerable progress has been made in elucidating novel and unexpected functions of activin in the normal and diseased brain and in deciphering the underlying molecular mechanisms. Initially identified as a neurotrophic and protective factor during development and in several forms of acute injury, the scope of effects of activin A in the adult central nervous system (CNS) has been considerably broadened by now. Here, we will highlight recent findings that bear significance for a better understanding of the pathogenesis of various neuropsychiatric diseases and might hold promise for novel therapeutic strategies. While the basal level of activin A in the adult brain is low, significant short-term up-regulation occurs in response to increased neuronal activity. In fact, brief exposure to an enriched environment (EE) is already sufficient to considerably strengthen activin signaling. Enhancement of this pathway tunes the performance of glutamatergic and GABAergic synapses in a fashion that impacts on cognitive functions and affective behavior, counteracts death-inducing signals through extrasynaptic NMDA receptors (NMDARs), and stimulates adult neurogenesis in the hippocampus. We will discuss how impaired activin signaling is involved in anxiety disorders, depression, drug dependence, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s, and how reinforcement of activin signaling might be exploited for therapeutic interventions. Inhba gene) and/or βB (encoded by the Inhbb gene) subunits. After proteolytic processing of their precursor proteins, activins are secreted as mature bioactive proteins. Activin A (βA/βA) is the most abundant and best characterized member of the activin family and plays the predominant role in activin signaling in the central nervous system (CNS). In the developing brain, activin A exerts distinct neurotrophic effects and is involved in proper cortical layering and corticostriatal wiring  family of growth and differentiation factors. They serve as multifunctional regulatory proteins in many tissues and organ systems, with particular emphasis on proliferation, differentiation, apoptosis, inflammation, immunoregulation and repair  activin enhances cognitive performance by augmenting synaptic plasticity of excitatory (glutamatergic) synapses; and that (ii) by tuning inhibitory (GABAergic) synapses, activin sets the level of anxiety-like behavior. These findings are testimony to the impact of activin on mental faculties as well as on affective behavior. Since the effects of activin on central synapses of the healthy adult brain and their behavioral consequences have been reviewed elsewhere  offer a plausible clue. Andreasson and Worley  were theA receptors (GABAARs), which is thought to exert anxiolytic effects  GABABR function is augmented in the transgenic mice, consistent with reports that positive GABABR modulators reduce anxiety-like behavior , has been associated with the clinical response to antidepressant drugs  neurogenic hypothesis of depression, which posits that adult-generated neurons of the DG are required for balanced mood and antidepressant efficacy . Compared to mice housed in standard cages, EE exposure produced a marked up-regulation of +-induced cell death in vitro (Krieglstein et al., synaptic NMDARs triggers synaptic plasticity and fosters genetic programs for stress resilience and survival. By contrast, activation of extrasynaptic NMDARs can incur lethal consequences for neurons, as it initiates pro-apoptotic pathways. Lau et al. (Bdnf transcription or administration of exogenous BDNF promotes activation of synaptic NMDARs, thereby inducing nuclear calcium signaling, which in turn activates transcription of Inhba. Secreted activin A then reduces potentially neurotoxic Ca2+ influx through extrasynaptic NMDARs, thereby counteracting pro-death pathways (Lau et al., In an excitotoxic rodent model of Huntington’s disease, intrastriatal administration of recombinant activin A for 1 week rescued striatal interneurons and projection neurons from death (Hughes et al., u et al.  have nowInhba as a BDNF-induced gene and the identification of the sequential and interdependent activation of BNDF and activin signaling as a health-promoting mechanism offer an intriguing new perspective on possibly shared functions of these two factors that might well go beyond their involvement in combating neuronal loss in neurodegenerative diseases. A quick review of the multiple roles of BDNF in the adult brain reveals a broad spectrum of effects that show a striking overlap with those of activin. Like activin, BDNF has been implicated in activity-dependent regulation of synaptic plasticity (Minichiello, The characterization of In contrast to BDNF, which has long since taken center stage as a master regulator of various neuronal properties and functions during development and in adulthood, the multiple roles of activin are only gradually being uncovered. It seems that, in many aspects, activin and BDNF are two players with very similar overall targets, which join forces in neuroprotection, synaptic plasticity and neuropsychiatric diseases. The commonalities and differences in the strategies these two factors pursue to achieve these goals and the extent to which the underlying mechanisms are complementary and interdependent should be exciting topics for future research.The manuscript was written by CA, with contributions of ASL and FZ. Schematic drawings were designed by ASL.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by deficits in episodic memory, working memory (WM), and executive function. Examples of executive dysfunction in AD include poor selective and divided attention, failed inhibition of interfering stimuli, and poor manipulation skills. Although episodic deficits during disease progression have been widely studied and are the benchmark of a probable AD diagnosis, more recent research has investigated WM and executive function decline during mild cognitive impairment (MCI), also referred to as the preclinical stage of AD. MCI is a critical period during which cognitive restructuring and neuroplasticity such as compensation still occur; therefore, cognitive therapies could have a beneficial effect on decreasing the likelihood of AD progression during MCI. Monitoring performance on working memory and executive function tasks to track cognitive function may signal progression from normal cognition to MCI to AD. The present review tracks WM decline through normal aging, MCI, and AD to highlight the behavioral and neurological differences that distinguish these three stages in an effort to guide future research on MCI diagnosis, cognitive therapy, and AD prevention. Alzheimer's disease (AD) is the sixth leading cause of death in the United States and the fifth leading cause of death in people over the age of 65, as determined by the Center for Disease Control . The risBetween 10 and 20 percent of adults above the age of 65 are diagnosed with MCI –5, and aBehavioral research indicates that MCI adults show cognitive deficits in WM, central executive function, and attentional resources compared to nonimpaired age-matched controls –15. Prec what differences exist between cognitively normal, MCI, and AD adults regarding neural activation and recruitment of WM resources? and (2) what can these differences tell us about an individual's likelihood of progressing to MCI or AD? Research suggests there is great potential for cognitive deficit reversal and strengthening of executive function at the MCI stage [These observations raise two unanswered questions: (1)CI stage . MCI aduCI stage , eating CI stage , reducinCI stage , and praCI stage . TherefoWM is a system that underpins cognitive activities ranging from attention allocation to specific stimuli  to complex decision-making . More spn-back task,” participants monitor a series of presented stimuli during encoding and are asked to recall whether a specific stimulus matches one presented n trial previously, typically 1, 2, or 3 [n-back task require divided attention and online monitoring, a process of updating the memory of presented stimuli which taxes the central executive's limited resources [WM capacity may be assessed using behavioral tasks that result in a quantitative measure of memory span. These tasks require participants to encode lists of stimuli , often involving either a selective attention task during encoding  or a divided attention task  to further tax WM capacity . As one  2, or 3 . The behesources .n-back task as one measure of WM, neuroimaging during the completion of that task reveals activation of the posterior parietal cortex, premotor cortex, rostral PFC, dorsolateral PFC, and ventrolateral PFC [Region-specific neural activation in response to a memory task is analyzed through neuroimaging techniques including functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). These neuroimaging methods depict recruitment of specific brain regions during a WM task, demonstrating that activation of the prefrontal cortex (PFC), parietal regions, cingulate gyrus, and hippocampus are associated with WM processing in nonimpaired young adults . To retueral PFC . These n compensatory view of bilateral activation where older adults compensate for age-related decline by recruiting additional neural networks to maintain performance on the task at lower levels of complexity. These tasks involve fewer stimuli for WM maintenance and do not require as many attentional resources as more complex task levels [One model addressing neural activation differences between nonimpaired older adults  and nonimpaired younger adults  during WM tasks is the Hemispheric Asymmetry Reduction in Older Age model, or HAROLD . Findingk levels . Furtherk levels . FrontalExpounding on the compensation view of the HAROLD model, the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH)  asserts n-back task). Young adults matched the probe image stimulus to target stimuli with greater accuracy than older adults, although there was no significant difference in response times between the two age groups. Interestingly, Payer et al.'s [The visual WM task involved encoding and identifying face and house stimuli that typically activate two regions of the VVC pathway: the fusiform face area and the parahippocampal place area, respectively. Twelve younger and 12 older adults were presented with three consecutive images of either faces or houses. Following image presentation, participants viewed a probe image and decided whether the image matched any one of the three preceding target images  than the control group, and there was no significant difference between the two MCI groups. For the divided attention task, the MCI lower-cognition group performed worse than both the MCI higher-cognition group and the nonimpaired control group, and there was no significant difference between the MCI higher-cognition group and the nonimpaired controls.The neuroimaging data showed that during the manipulation task MCI higher-cognition participants displayed significant overactivation in the left postcentral gyrus and the left middle and superior frontal gyri compared to the nonimpaired controls. The MCI lower-cognition group showed underactivation in the left inferior and middle frontal gyri and left occipitotemporal regions compared to the nonimpaired controls. As for the divided attention task, MCI higher-cognition participants demonstrated overactivation of the left inferior frontal gyrus, the left insula, the left caudate and putamen, the left thalamus, left cerebellum and midbrain, left fusiform gyrus, and the left and right anterior cingulate cortex. For the MCI higher-cognition group increased performance on the divided attention task was directly correlated with greater activation of the right putamen, the anterior cingulate cortex (responsible for WM), the left caudate, the left insula, and the left inferior frontal gyrus .Clément et al.  claim thIn order to examine when executive function and WM deficits appear, Belleville and colleagues  comparedOne year following the study, a subset of the MCI participants was assessed for progression to AD. Eight people were diagnosed with AD, leading authors to revisit the data to determine if there were factors that predicted their AD prognosis. Belleville et al.  reportedIn light of recent research suggesting the importance of deficits in attention, WM, and episodic memory in predicting the conversion of MCI to AD, Summers and Saunders  designedIn agreement with Summers and Saunders , KlekociThe present literature has not conclusively shown whether WM, specifically executive function, predicts the progression towards AD. For example, a fairly recent study by Peters et al.  examinedParticipants completed neuropsychological and brain imaging tests three times during a two-year period to determine which participants progressed to AD . At the Baudic et al.  examinedCastel and colleagues  examined underrecruitment theory [Researchers have learned much about WM decline in normal aging over the recent years. Reuter-Lorenz and Park  suggest t theory  suggestsLi et al.  conducteA theoretical rehabilitation model for MCI proposed by Huckans et al.  shows hoRecent research has illuminated compensatory mechanisms that occur in the brain as a result of aging. Older adults recruit bilateral regions of the PFC to complete WM tasks requiring executive control. Overactivation of bilateral PFC regions in older adults is an example of cognitive restructuring as individuals begin to experience difficulties with executive function tasks such as divided attention and inhibition of interfering stimuli. As a result older adults have a lower WM capacity than younger adults.Executive dysfunction becomes more pronounced during MCI, and an increasing number of studies have reported the existence of both cognitive and memory deficits in MCI. Brain imaging data also demonstrate that MCI individuals display underactivation compared to nonimpaired adults on WM tasks of increasing load. This evidence promotes the use of WM and executive function assessments to track behavioral and functional changes to distinguish between normal aging, MCI, and AD. One suggestion is to implement a robust set of neuropsychological tests into clinical practice which detect WM and executive functioning deficits over time. Follow-up on WM and executive function skills over time can pinpoint stages of cognitive decline and prompt for cognitive intervention during the preclinical stages of AD when interventions are likely to have the greatest effect on cognitive functioning.Importantly, very early stages of AD are marked by executive dysfunction and WM impairments in addition to episodic memory deficits. These cognitive deficits begin during MCI and appear to be a sign of progression to AD. Therefore, future studies are recommended to detect and monitor changes in WM, attention, and executive function in MCI and older nonimpaired individuals. The critical preclinical period also provides the opportunity for cognitive interventions to stop or slow the progression to AD. Such studies on therapeutic interventions should focus on tasks that emphasize executive function skills like selective or divided attention, inhibition, manipulation, and task switching. Incorporation of assessments and interventions that are targeted towards WM, attention, and executive function in research and clinical settings expands the tools available to monitor and treat patients at the early stage of disease and provide the benefit of being of low cost, noninvasive, and relatively easy to implement.


Rice is one of the main pillars of food security in India. Its improvement for higher yield in sustainable agriculture system is also vital to provide energy and nutritional needs of growing world population, expected to reach more than 9 billion by 2050. The high quality genome sequence of rice has provided a rich resource to mine information about diversity of genes and alleles which can contribute to improvement of useful agronomic traits. Defining the function of each gene and regulatory element of rice remains a challenge for the rice community in the coming years. Subsequent to participation in IRGSP, India has continued to contribute in the areas of diversity analysis, transcriptomics, functional genomics, marker development, QTL mapping and molecular breeding, through national and multi-national research programs. These efforts have helped generate resources for rice improvement, some of which have already been deployed to mitigate loss due to environmental stress and pathogens. With renewed efforts, Indian researchers are making new strides, along with the international scientific community, in both basic research and realization of its translational impact. Subsequently, the encoded proteins by such genes can be classified into families depending on the presence of a conserved domain or motif. Once the locus IDs of genes are delineated, gene organization and structure can be analyzed, to determine unique features of genes and their products. Similarly, evolutionary and phylogenetic analyses help classify the family members into distinct classes and define their origin. Hence, the availability of the annotated rice genome has paved the way for the identification of members of multifarious gene families, India being a major contributor to this analysis. Many of these have been linked with the Rice Genome Annotation Project (RGAP) and are available at the community annotation project, while others are yet to be added  by forward genetic approaches. Indian labs are making use of rich diversity of the rice genome for such purposes. The available genome/transcriptome sequences of diverse rice genotypes have been used to generate enormous resources in the form of genomic (genic) SSR (simple sequence repeat) and SNP (single nucleotide polymorphism) markers at a genome-wide scale especially in 2H2 zinc-finger family, encoded by 189 ZOS genes was found to have 97 new members, including 10 previously unnannotated members. Also, new types of zinc fingers were discovered, apart from the cannonical ones. These genes were found to differentially express during reproductive development and abiotic stresses  are integral components of any regulatory and/or metabolic pathway. Comprehensive genome wide analyses of their gene structure and expression have revealed interesting aspects about their regulation during development and stress and provided leads for their functional characterization. Amongst the first detailed analysis of large TF gene families, the COsAux/IAA genes were identified and most of them were found to be up-regulated upon auxin treatment, six of them at much higher levels  have also been characterized for clues to their structure-function relationships. Amongst hormone signaling pathways, 31 ARMADILLO genes, which have an ARM repeat  for unrestricted use  to accelerate genomics-assisted breeding for hybrid performance in rice  and 104,163 InDels for deciphering the genetic basis of complex glycemic index quantitative trait in rice  markers Essentially, the genomic and genic SSR and SNP markers developed especially by Indian initiatives are amenable to large-scale validation and high-throughput genotyping at the whole genome level. These informative markers are thus suitable for multi-dimensional genomics-assisted breeding applications.indica rice accessions . The phenotypic and molecular characterization of the huge Indian rice germplasm collections is, therefore, vital in order to use the natural allelic diversity information in genomics-assisted rice crop improvement program. Considering the economic importance of aromatic rice in Basmati trade and commerce, significant efforts have been made for varietal identification and understanding the genetic diversity and domestication patterns majorly among different traditional (landraces) and evolved (elite) long- and short-grained Basmati and between Basmati and non-Basmati indica (aus) rice accession, Nagina 22, has been induced with EMS (ethyl methane sulfonate) mutagen to generate and characterize 22,292 mutant lines through an Indian National initiative involving several research institutes  and NILs (near isogenic lines) in rice. One of the upland indica and aromatic rice based mapping population of rice  and PPR (pentatricopeptide repeat) genes regulating blast resistance and fertility restoration have been identified in rice  has been mapped on chromosome 4, and two genes encoding integral transmembrane protein DUF6 and cation chloride cotransporter co-localized in the significant QTL intervals on chromosomes 1, 8, and 12 for salt ion concentrations and two known genes, badh1 and badh2  at QTL interval governing aroma have been identified in rice , various quality component traits  and stress tolerance traits  have been identified and mapped on high-density SSR and SNP marker-based genetic linkage maps derived from diverse Pi54 and Pita regulating blast resistance, Xa21, Xa26 and xa5 for bacterial blight resistance, OsDREB1F for drought tolerance, GW2 for grain size/weight and nine candidate stress responsive genes governing abiotic and biotic stress tolerance traits in rice  and blast , brown plant hopper [Bph-3/17/18/20/21 and Bph18(t)], sheath blight (qSHB) and gall midge (Gm4 and Gm8) diseases has been performed by pyramiding the multiple genes/QTLs through marker-assisted back-crossing (MABC)/marker-assisted foreground and background selection , flood (sub-mergence) (Sub1) and salinity stress  tolerance  for their genetic enhancement. The genetic improvement of Basmati rice for yield, quality and resistance to bacterial leaf blight (The rice genome sequence has served as a catalyst to accelerate efforts on the functional analysis of genes/QTLs by reverse and forward genetics in India. This is coupled with use of genomics-assisted breeding of rice to improve traits such as yield, abiotic stress tolerance and biotic stress resistance. Diverse varieties of rice are grown in different regions of India and concerted efforts are required to introgress genes/QTLs for desirable traits into them. Some of these efforts have already led to release of improved varieties for submergence tolerance and biotic stress resistance. Indian rice researchers have highly benefited from new knowledge generated worldwide and from their own collaborative efforts in crop improvement programs. It is hoped that appropriate regulatory process will help move transgenic rice also to the field level evaluation and deregulation in due course. In the meantime, several projects related to molecular dissection of desirable agronomic traits of rice and introgression of appropriate genes/QTLs have been initiated. India is also poised to contribute to international projects in the area of functional genomics of rice and looks forward to launch of activities like riceENCODE. It is hoped that the outcome of rice genomics would go a long way to influence research in other related crops as well.


The Veterans Health Administration (VHA) has conducted a nation-wide implementation of three major initiatives for improving Veterans' access to specialty care in the past 2-3 years. The objective of this study was to identify the key factors affecting implementation success across these different initiatives.The Consolidated Framework for Implementation Research (CFIR) was used as the basis for defining potential factors affecting implementation success and guided data collection and analysis. For each of the initiatives, a sample of facilities was selected to maximize variability in implementation success, defined uniquely for each initiative. Semi-structured interviews were conducted with key stakeholders from each of the facilities. Interview responses were coded deductively based on the CFIR and were used to obtain an overall rating for each site, by construct. Site ratings were dichotomized and analyzed using crisp set Qualitative Comparative Analysis (cs-QCA).129 interview responses from 23 sites were coded and analyzed. CFIR constructs for which data were available consistently across all three initiatives included adaptability, compatibility, design quality and packaging, networks and communications, leadership engagement, available resources, and reflecting and evaluating. Across the three initiatives, the construct with the greatest necessity score was adaptability; 92% of sites with high implementation success rated positive for this construct. Compatibility also scored high (83%) on necessity. The constructs with the greatest sufficiency scores were leadership engagement as well as reflecting and evaluating; of all of those sites who had a positive rating for either of these constructs, two thirds achieved high implementation success. Findings varied by initiative; leadership engagement, as well as networks and communications, were more important for successful implementation of the most complex initiative  than for the other two initiatives. Certain combinations of constructs guaranteed high implementation success.


Global health innovators must navigate substantial complexities to successfully develop, implement and sustain global health innovations with impact through application of an Integrated Innovation™ approach. We sought to examine the nature of the literature and evidence around mentoring, training and support of global health innovators. We conducted a scoping review searching eight databases with terms capturing different kinds of innovation and support. Assessment of relevance and mapping was completed by two reviewers, with interpretation by the review team. Twenty-eight relevant papers provided perspectives on fostering global health innovators and innovation. Fifteen included empirical data on supports to global health innovators involving a wide range of innovators. Eight included documentation of outcomes but without designs to determine effectiveness. The diverse mentoring, training and support activities included: business incubators, support organizations and centres for entrepreneurship, technology transfer and intellectual property management, internship programs for business skill development, initiatives to bridge industry and researchers, and platforms for South-led innovation for global health. We propose the cultivation of a pipeline of global health innovators to increase the number of appropriate, sustainable innovations with impact in global health. Further empirical work on how to effectively support global health innovators is needed. Global public health is being impacted by ongoing innovation in a myriad of ways that may or may not promote health equity , dependiHowever, technological, business, and social sectors are highly influenced by the complexities of international relationships, national innovation systems, and the general national environment. Each can affect the discovery, development, effective implementation and equitable adoption of innovations which impact health . This ilIn the field of global health, young innovators are likely to face similar challenges, compounded by the complexities of innovation processes in different national innovation and public health systems. The Global Forum for Health Research aims to support strengthening of LMIC research and innovation systems for health, focusing on social, scientific/technological and business innovation research to impact on global health. The Canadian Coalition for Global Health Research (CCGHR), a network of global health researchers, organizations, and students, has expertise in mentorship, leadership and capacity development in global health research more generally. Grand Challenges Canada™ (GCC), funded by the government of Canada, is a non-profit organization that supports global health innovators in LMICs as well as Canada. However, we were unable to identify any sources that systematically examined requirements for and gaps in mentorship, training and support for global health innovators across the three Integrated Innovation™ sectors.Hence, we conducted this scoping review to systematically scan the evidence for mentorship, training and support of innovators who would take an Integrated Innovation™ to global health innovation. We used GCC's organizational process and innovation funding cycle for global health innovators as a case example to which we could apply our review findings.We chose a scoping review approach given our desire: (1) to map the extent, range and nature of research activity; (2) to help determine whether a full systematic review would be valuable and feasible; (3) to summarize and disseminate findings for an audience of innovators, mentors and funders; and (4) to identify research gaps in the current literature .Our review consisted of three phases between May and August 2012: (1) identifying the research questions, (2) selecting relevant literature and (3) charting, collating, summarizing and interpreting our findings .To improve our review's applicability to our case of interest, we briefly summarized information on GCC Stars in Global Health Round 1 and 2 grantees (n=34).http://www.grandchallenges.ca for further details).As shown in The review team included experience in commercialization of science-based health innovations in LMICs, strategy and operations analysis, and coordination of the Stars in Global Health program, all from GCC, along with global health research capacity development in LMICs. An MPH student specializing in health promotion and global health led discussions of the grantee context and GCC needs to formulate three questions for exploration in this scoping review:1)What is the nature of evidence around mentorship, training and support for innovators in global health?2)How is the Integrated Innovation™ approach in global health being reflected in the mentorship, training and support for innovators? And3)What type of initiatives in mentorship, training and support for innovators are applicable to the GCC Stars in Global Health program and implementable in its structure and context?Preliminary literature searches helped formulate a search strategy that encompassed the main concepts, appropriate terms and the most relevant databases.As seen in Retrieved English titles and abstracts were independently reviewed by one team member for initial relevance related to innovation, health, and mentorship/support/training. A five percent random sub-sample was reviewed by a second team member. Raw inter-rater agreement on relevance was 77%. Formal inclusion and exclusion criteria were devised at this stage, and these two researchers independently reviewed each title and abstract for relevance, with resolution of disagreements by consensus. Major reasons for exclusion were: (1) no focus on health; (2) no focus on innovation; (3) no mention of type, potential, or need for support/training/mentorship of innovators. Included papers that were accessible by University of Toronto libraries were reviewed in full. Reference lists from papers included for full review were searched, and relevant papers to the research questions were also retrieved. Mendeley software was used for data management.The following information was extracted from each paper: author(s), year, title, publication source, country, paper type, type of stakeholder(s), link to Integrated Innovation™ approach, and type of support/training/mentorship, either needs described or/and specific activities. The review leads held meetings to discuss extracted data and to synthesize our findings, following an inductive approach.The final search strategy generated 1535 titles and abstracts. Following initial title and abstract reviews and hand-searching of reference lists, 28 papers were judged relevant in this scoping review (full details in supplementary file).Most papers were published recently, with half (n=14) published in 2010. Eighteen (64%) were based in LMICs and the remainder in the USA and Canada (n=10). Most discussed all three of scientific/technology, business and, social innovation (n=23), with the rest (n=5) not including social innovation in a substantive manner. Four only discussed needs, ten focused on activities, half covered both. Nine provided perspectives , four described programs of different kinds and 15 (56%) took some kind of empiric approach.Eight of the latter papers included information on outcomes, including a promising framework for evaluation . Some reDrawing primarily on the empirical studies which included activities oriented by all three types of innovation (n=15) we found a wide variety of relevant activities, half with multiple stakeholders, reflecting innovation system perspectives.As outlined in Given the newness of the global health innovation field, our mapping found papers on perspectives, new programs, and a range of activities to support global health innovators but limited empirical work to inform training, mentoring and support practice. Literature on mentorship in global health clinical research  and acadPapers identified in this scoping review did indicate a number of mechanisms by which support, training and mentorship of global health innovators may be facilitated with the involvement of micro to macro level stakeholders. In LMICs, the identified mentorship, training, and support structures were highly focused on capacity building within the innovation system itself so that innovation might be better facilitated. A good example of a program  is the African Network for Drugs and Diagnostics . It enabResponding to Beyond the funding primarily for global health innovation activities , fundersThe approaches we uncovered in our review may apply at different stages of the innovation process, enabling discovery, development, implementation and sustainability of innovations for greater impact on global health, Mentoring, training and support could be conceptualized holistically from start to finish throughout the process of global health innovation. We applied approaches uncovered in our review to the phases of GCC's innovation cycle see  which buIn Phase I, GCC  could focus on partnerships and skill-building whereby grantees ground themselves in how their projects should be defined and conceptualized through an Integrated Innovation™ approach. Partnering to identify LMIC needs, context and partnerships and identifying other mentors who are not in the same field of expertise as the innovator, may fill gaps when undertaking proof of concept studies. Milestones in reporting for mentorship activities could be elicited. A repository of experts, particularly with business and social innovation acumen (as these areas of expertise seem to be lacking the most) and who have experience in global health contexts, could be built for grantees to contact if needed. Knowledge brokers could act as “middlemen” to guide and mentor grantees on bridging the challenges in taking an innovation to a specific commercial market, as well as to help with building core skills (e.g. writing a business plan). Innovations that merit Phase II funding could be showcased as part of an innovation marketplace for potential partners and investors, which would help grantees gain skills in presenting, making elevator pitches, networking, etc.In Phase II, supplementary sources addressing implementation science, translational science, product development partnerships  could beAs only papers written in English were included, other sources that may have been relevant may have been missed. In addition, due to financial resources and time, only papers that were available through the University of Toronto libraries were included. Nevertheless, the scoping review was sufficient to indicate the state of evidence available.Our scoping review has identified the nature of literature on global health innovators and their organizations, funders, and educators relevant to training, mentorship and support of innovation in global health. It applied our findings to one programme aiming for Integrated Innovation™ in GCC's Stars in Global Health. More rigorous research and evaluation is needed to determine better processes for programmes to train, mentor and support innovators in global health and their effectiveness in impacting on global health equity.


Over the last 10 yr, multiparametric magnetic resonance imaging (mp-MRI) has been suggested as a diagnostic test capable of detecting and ruling out clinically significant gland-confined prostate cancer before biopsy. The poor methodologic quality of many initial studies Although there has been significant improvement in the literature on mp-MRI, there remain limitations when evaluating clinical validity . For instance, many recent publications have limited sample sizes PROMIS PROMIS will provide level 1b evidence •Scanner set-up and qualification: PROMIS uses 1.5-T scanners, the most readily available in most centres. Each scanner had to be optimised in each centre in conjunction with the lead centre in an iterative manner over sometimes weeks and months. We noted significant differences between scanners from the same manufacturer, and even scanners of the same model. These differences required further changes to imaging parameters to remain compliant with international guidelines; one scanner by a certain manufacturer had to be excluded from the study as we were unable to obtain acceptable diffusion sequences after several iterations. These factors will allow us to assess how variations in scanner make, model, and condition may impact on subsequent diffusion and dissemination within the UK and beyond.•Lack of essential MRI and interventional ultrasound skills: To assure correct implementation of a standardised operating procedure in each trial intervention, the lead radiologist formally trained the participating radiologists and held several formal and informal meetings since trial inception to maintain quality control and address issues as they arose. Similarly, each site was required to observe the combined biopsy procedure at trained sites and subsequently required supervision of the conduct of the biopsies.•Running a surgical trial: As a surgical interventional study, issues with respect to resource use arose. First, the mp-MRI standardisation process revealed that some centres were not using gadolinium dynamic contrast enhancement, and the additional 15 min of scan time impacted on scanner capacity. Second, the combined biopsy procedure required between 60 and 90 min of operating theatre time. Third, with a growing body of literature pointing to the positive role of mp-MRI, there were an increasing number of physicians and patients lacking equipoise for the trial.This diagnostic trial set up in multiple centres proved to be a challenge, with many unforeseen obstacles.PROMIS recruitment is on track, with only a 6-mo extension to our original predicted end date. From 11 centres across the UK, 578 patients have been recruited and 98 have withdrawn up to April 2015. Recruitment is due to end in October/November 2015.PROMIS will provide an once-in-a-lifetime opportunity to evaluate the diagnostic accuracy of mp-MRI based on an adequately large sample size and a highly accurate reference test in comparison to standard TRUS biopsy. The biobank of tissue, imaging data, serum, and urine will offer a uniquely validated data set for further translational research.Conflicts of interest: Hashim Ahmed receives trial funding from SonoCare Medical, AngioDynamics, and Trod Medical, and a travel allowance from SonoCare Medical. Mark Emberton owns shares in Nuada Medical; is a consultant for Steba Biotech and GlaxoSmithKline; receives trial funding from GlaxoSmithKline, Steba Biotech, SonaCare Medical, AngioDynamics, and Trod Medical; and receives travel funding from Sanofi Aventis, Astellas, GlaxoSmithKline, and SonaCare Medical. Alex Kirkham and Alex Freeman own shares in Nuada Medical. The remaining authors have nothing to disclose.Acknowledgments: We acknowledge trial funding from the National Institute of Health Research – Health Technology Assessment (Project 09/22/67) and from Prostate Cancer UK for collection and processing blood and urine for the translational aspect of PROMIS (PROMIS-T). The project is also supported and partially funded by UCLH/UCL Biomedical Research Centre and The Royal Marsden and Institute for Cancer Research Biomedical Research Centre and is coordinated by the Medical Research Council Clinical Trials Unit (MRC CTU) at UCL. It is sponsored by University College London (UCL).Department of Health Disclaimer: The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Health Technology Assessment programme, the National Institute of Health Research, the National Health Service, or the Department of Health.


Cholera remains a significant threat to global public health with an estimated 100,000 deaths per year. Water, sanitation and hygiene (WASH) interventions are frequently employed to control outbreaks though evidence regarding their effectiveness is often missing. This paper presents a systematic literature review investigating the function, use and impact of WASH interventions implemented to control cholera.The review yielded eighteen studies and of the five studies reporting on health impact, four reported outcomes associated with water treatment at the point of use, and one with the provision of improved water and sanitation infrastructure. Furthermore, whilst the reporting of function and use of interventions has become more common in recent publications, the quality of studies remains low. The majority of papers (>60%) described water quality interventions, with those at the water source focussing on ineffective chlorination of wells, and the remaining being applied at the point of use. Interventions such as filtration, solar disinfection and distribution of chlorine products were implemented but their limitations regarding the need for adherence and correct use were not fully considered. Hand washing and hygiene interventions address several transmission routes but only 22% of the studies attempted to evaluate them and mainly focussed on improving knowledge and uptake of messages but not necessarily translating this into safer practices. The use and maintenance of safe water storage containers was only evaluated once, under-estimating the considerable potential for contamination between collection and use. This problem was confirmed in another study evaluating methods of container disinfection. One study investigated uptake of household disinfection kits which were accepted by the target population. A single study in an endemic setting compared a combination of interventions to improve water and sanitation infrastructure, and the resulting reductions in cholera incidence.This review highlights a focus on particular routes of transmission, and the limited number of interventions tested during outbreaks. There is a distinct gap in knowledge of which interventions are most appropriate for a given context and as such a clear need for more robust impact studies evaluating a wider array of WASH interventions, in order to ensure effective cholera control and the best use of limited resources. Vibrio cholera. It is a water- and foodborne disease with person-to-person transmission resulting from poor hygiene, limited access to sanitation, and inadequate water supply, which all contribute to the rapid progression of an outbreak.Cholera is a diarrhoeal disease caused by infection with the bacteria Cholera outbreaks can occur during emergencies, such as earthquakes and flood events, or in refugee settings when water supply, sanitation and hygiene (WASH) infrastructure is compromised. The World Health Organisation (WHO) estimates that there are between 3–5 million cholera cases and 100,000–120,000 deaths every year, of which only a fraction are officially reported [When an outbreak is detected the WHO recommends a response focussing on reducing mortality by ensuring prompt case management, and reducing morbidity by providing safe water, adequate sanitation and health promotion (for improved hygiene and safe food handling practices) for the affected community . ConsequDespite a wide body of evidence investigating the effectiveness of WASH interventions against endemic diarrhoeal disease, many studies are considered to be of poor quality and the relative impact of each separate WASH intervention remains a contentious issue –5. AssesA systematic review and meta-analysis evaluating the impact of WASH interventions on diarrhoeal disease concluded that each intervention type had a similar degree of effect and that water quality interventions were more effective than previously considered . This waThe discussion about the relative importance of each intervention seems trivial, as ideally for diseases like cholera, with multiple transmission routes, all interventions should be implemented simultaneously. However during outbreaks in resource-poor settings, choices need to be made as to which intervention should, and can be implemented in order to have the greatest impact. To inform further research, policy and practice, a systematic review was conducted on the current evidence for uptake, use and health impact of WASH interventions to control cholera.The guidelines for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were used to conduct a systematic search for original research of the impact of WASH interventions implemented to control cholera in a low, or middle income country . The keyFour main concepts; water supply, water quality, sanitation and hygiene, were searched in combination with cholera and associated synonyms of acute watery diarrhoea, and with low or middle income countries as defined by the World Bank. The search strategy is presented in Studies were initially categorised according to whether measurement of a statistical association between the intervention and a health outcome had been made (Category A), whether only a change in a health outcome was reported (Category B) or where this was not measured at all (Category C). A methodological quality assessment of the included studies was then conducted based on the STROBE and CONSORT standards  for obseA total of 5,519 citations were identified from Medline , Global Health  Embase  Web of Knowledge (374) and Africa Wide Information (785), and a further 21 from hand-searches and recommendations of articles submitted for publication. After removal of duplicates , screening of 3,010 titles and abstracts resulted in the exclusion of 2,947 papers. Content review of 63 full texts led to the exclusion of an additional 45 papers. The main reasons for exclusion were; no clearly defined WASH intervention (34), not related to cholera (9), or not peer-reviewed (2). Finally a total of 18 papers were included in the systematic review .Only 22% (4/18) of intervention studies conducted a test for statistical significance of any association between WASH interventions and a health outcome (Category A). One paper reported a change in health outcome without a statistical association (Category B). The remainder simply reported usage, or outputs of interventions (Category C). Using further quality assessment, no paper was deemed high quality, 44% were considered medium quality leaving the majority of low quality papers . The quaThe eighteen papers identified, presented research from Africa (48%), Latin America/Caribbean (26%) and Asia (26%), and included one paper presenting results from both Africa and Asia. Eleven studies (61%) investigated water quality interventions; those at source (17%) and those at point of use (44%). Four studies (22%) examined hygiene promotion, and three separate studies evaluated storage vessel disinfection, household disinfection and improvements to water and sanitation infrastructure .Three intervention trial studies in Africa conducted preliminary investigations into well chlorination –17; and The two remaining studies evaluated chlorinators; chlorine-containing devices that when suspended in well water gradually release chlorine leaving a continuous FRC , 17. BotEight studies presented a point of use water quality intervention; which included: filtration (2), solar disinfection (1) and chlorination products with, or without storage vessels (5).Two linked studies from Bangladesh evaluated, and followed-up an intervention using sari cloth to filter surface water , 19. A nA study conducted among the Maasai in Kenya evaluated the impact of solar disinfection (SODIS) using the number of self-reported cholera cases over a three month period following an outbreak . This stThe most published WASH intervention was chlorination of water stored in the household, investigated by five studies. The intervention consisted either of the distribution of chlorine products alone, or in combination with safe water storage vessels.Vibrio cholerae was confirmed in bacteriological tests in participants for up to 5 days after identification of the index case. Results of this testing showed that the incidence of cholera infection was reduced by 75% (p<0.001) and 58% (p<0.01) in the storage container and chlorination groups respectively when compared to the control group.A trial carried out in an endemic setting in India, randomised family contacts of 91 hospital admitted cholera patients to a study arm that received either: chlorine tablets (1.25mg/litre of water), a local narrow-necked storage container, or acted as a control arm . PresencThe Safe Water System developed by the US Centers for Disease Control and Prevention (CDC), comprises behaviour change techniques, alongside point of use treatment and safe storage of water. Two studies evaluated the safe water system. A programme in Antananarivo, Madagascar implemented in response to a major cholera outbreak, used community mobilisation and social marketing of a locally produced 0.5% solution of sodium hypochlorite (Sûr’Eau) and distributed product use information as well as a 20 litre jerry can . BaselinA trial in El Alto, Bolivia systematically selected 42 households of 55 community volunteers, who were then randomised to receive either; i) 0.5% calcium hypochlorite solution and a 20 litre narrow-mouthed jerry can with information on use, ii) a jerry can only or iii) nothing . During E. coli/100 ml). In Nepal, chlorine tablets (Aquatabs) and liquid chlorine  were continuously distributed to 1,565 homes in 2 sub-districts. Confirmed use was limited to 18.5% of households and effective use was not measured. In Kenya, chlorine tablets (Aquatabs) and flocculant/disinfectant (PuR) were distributed as part of kits to 5,592 homes in 4 communities. Confirmed use was 11.7% and effective use of Aquatabs and PuR was just 5.3% and 2.3% respectively.One study investigated distribution of chlorine products only. Results from cholera outbreaks in Kenya and Nepal were extracted from a four-country study . OutcomeThe most recent study evaluated the response to the Haiti cholera epidemic in 2010, where the government and other agencies implemented a free mass distribution of various chlorine products alongside hygiene promotion activities in a rural setting . The majFour cross-sectional studies, two in Africa and two in Latin America, were identified as evaluating community knowledge, and awareness of cholera prevention, and all reported a positive effect.E. coli, but 60% of stored water samples showed detectable FRC levels. The results of the survey suggest that the public health messages were effective, and promoted behaviour changes with regard to water treatment practice.One assessed the effectiveness of interventions implemented during the 2010 cholera outbreak in Haiti, which included mass media campaigns, community health worker activities, and distribution of water purification tablets, soap and oral rehydration solution . The preA study in rural Guinea Bissau during the 1994 cholera outbreak explored local views about cholera and the diffusion of health messages, and assessed whether the messages contributed to behaviour change . InterveMahadik reported that 99% of 442 respondents in 16 villages exposed to a cholera education programme in Zambia showed awareness of cholera compared to 92% of 131 respondents in two control villages in a different district, however no test of significance was reported . The papQuick et al. conducted a knowledge, attitudes and practice survey in urban and rural Amazon communities, to assess the impact of a nationwide prevention campaign, 6 months after the beginning of the Peruvian cholera epidemic in 1991 . The stuA study in a camp in Kitgum, Uganda (2007), assessed the effectiveness of jerry can cleaning using a strong disinfectant, and the recontamination potential after cleaning . Two difOne recent study measured the uptake of household disinfection kits as an additional prevention method in the Haiti cholera outbreak . DisinfeA study conducted in the Philippines attempted to evaluate the impact of improvements to WASH infrastructure on cholera incidence by comparing a control community with communities with: i) safe water supply, ii) shared toilet facilities, and iii) both water supply and shared toilet facilities . BacteriThe primary objective of this review was to identify and assess the evidence for the effectiveness of WASH interventions to control cholera, and provide recommendations to implementers during cholera outbreaks, while a secondary objective was to highlight the gaps in knowledge and identify areas for further research. This review presented findings from eighteen studies of which only five reported a health outcome. The studies were heterogeneous in their design, measurement of outcomes, contexts and interventions deeming a meta-analysis inappropriate. The review thus found a lack of good quality studies, while those studies that were included focussed predominantly on water quality interventions.The lack of good quality studies, with well defined health outcomes, and consequently a relaxing of exclusion criteria has left our search open to a number of potential biases and limitations which will have had an effect on the results reported. Whilst no time limit was set on the search, and hand searches were done of recent reviews for additional references a decision was made not to include unpublished literature. There is likely to be a wealth of useful information available in operational and evaluation reports by non-governmental organisations (NGOs) working in emergencies and cholera outbreaks, however it is unclear how much is available as not all is in the public domain, while some might contain sensitive information that NGOs are unwilling to share. The grey literature warrants a separate review, as it could provide valuable lessons learnt, not only regarding the approaches used, the types of intervention chosen and implemented, and their successes or failures, but could also provide valuable information regarding the setting in which the outbreaks occurred. Ideally a review should separate lessons learnt from natural disasters, and conflict responses, and distinguish between urban and rural settings, and of course between interventions implemented for those internally, or externally displaced, and those still living in their own housing. Currently the available literature does not allow for this distinction.This study found a clear lack of evidence to help guide implementers decide what approach and intervention to select during a cholera outbreak. This is, to a very large extent, a result of the difficulties associated with collecting epidemiological evidence and time constraints during epidemics, which often occur during, and following natural disasters or conflicts. The main desire of those involved in cholera control is to limit the speed of transmission and to reduce mortality, whilst establishing baselines, and research in general, is often seen as taking valuable time and resources away from life-saving activities. There is further a belief held by some involved in emergency response that only randomized controlled trials (RCT) can provide evidence, and therefore that any study looking to gather evidence is going to be prohibitively expensive, time consuming and will require a lot of man power. Although RCTs are unlikely to be feasible in emergency settings, and could raise serious ethical concerns, this does not mean that good evidence cannot be collected. Most of the studies presented in this survey failed to adhere to the minimum evaluation procedures  were the most reported interventions in this review with distribution of chlorination products the most popular. However, half of the six studies that distributed a water quality intervention and conducted a health education programme, reported inconsistency of product use throughout the year, with chlorination in particular seen as an emergency measure, and used sporadically depending on its affordability and accessibility. Furthermore, mass distributed chlorine products were poorly used even where prevention knowledge was high , 25, 26.With cholera largely perceived as a waterborne infection, other transmission routes like the consumption of contaminated food as a result of poor hand hygiene, and person-to-person transmission appear to be overlooked in the literature. However, outbreaks in which waterborne transmission has not been implicated are plentiful. An extensive review of epidemiological data of cholera outbreaks in India, Bangladesh and the Philippines in the 1980s, found that 35–80% of cholera infection in the contacts of index cases occurred after more than 2 days, thereby suggesting that these contacts were infected by person-to-person transmission within the family [A review of WASH interventions in 1991 concluded that those for sanitation and water supply for improved hygiene yielded greater reductions in diarrhoeal disease than those for water quality . This agIn light of the abundance of evidence supporting the promotion of hand washing to reduce diarrhoeal disease, and since the same WASH interventions apply to cholera it is surprising that so few studies specifically evaluate HWWS to prevent cholera. Only one study  presenteThe reductions that meta-analysis have shown can be achieved, speak in support of HWWS as a cholera prevention measure, but more research and evaluation are needed to confirm its effectiveness. Furthermore, epidemiological investigations have reported a protective effect of hand washing when food was associated in cholera outbreaks, as well as in outbreaks where the source remained unidentified –48. In aEvidence for diarrhoeal disease suggests that hygiene behaviour is sustained following implementation and is best delivered using small groups and frequent personal contact with a hygiene promoter . The stuThe study of disinfection of jerry cans  used forV. cholerae in stored water and food through contaminated fingers [In the past, it was a common practice in cholera outbreaks to spray the houses of cholera patients with disinfectant. This had the potential of causing damage to domestic property and stigmatising the patients and their families, putting in jeopardy the reporting and detection of cases and thus the whole outbreak control effort. Presently, household disinfection kits that normally include a bucket, bleach, soap, cloth and scrubbing brush, are increasingly being used as an alternative to household spraying. The distribution of kits places the responsibility with the family which reduces the stigma attached to the disease and may encourage sustained and improved hygiene at the household level . There i fingers . The pra fingers . The useSeveral recent reviews , 55, 56 S1 PRISMA Checklist(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


This meeting report presents the outcomes of a workshop held in Bangkok on December 1st 2014, where the following challenges were discussed: the threat of resistance to artemisinin and artemisinin-based combination therapy in the Greater Mekong Sub-region (GMS) and in Africa; access to treatment for most at risk and hard to reach population; insecticide resistance, residual and outdoors transmission. The role of operational research and the interactions between research institutions, National Malaria Control Programmes, Civil Society Organizations, and of financial and technical partners to address those challenges and to accelerate translation of research into policies and programmes were debated. The threat and the emergency of the artemisinin resistance spread and independent emergence in the GMS was intensely debated as it is now close to the border of India. The need for key messages, based on scientific evidence and information available and disseminated without delay, was highlighted as crucial for an effective and urgent response.The online version of this article (doi:10.1186/s12936-015-0802-4) contains supplementary material, which is available to authorized users. In over a decade, remarkable achievements in malaria control have been made. Malaria mortality rates have been reduced by 47% in all age groups worldwide, between 2000 and 2013, leading to an estimated 4.3 million malaria deaths averted during the same period. A total of 64 countries that had on-going malaria transmission in 2000 are actually meeting the millennium development goals (MDG) target of reversing the incidence of malaria, and 55 of these countries are on track to meet roll back malaria (RBM) and World Health Assembly targets of reducing malaria case incidence rates by 75% in 2015  occurred historically in western Cambodia, at the border with Thailand. The resistance then spread westward to reach India in the 1970s and East Africa in the 1980s to then extend to the whole African continent by 1992 , 4. A viNicholas White  reviewed the situation of anti-malarial drug resistance in South East Asia (SEA). The Tracking Resistance to Artemisinin Collaboration (TRAC) study conducted in South-East Asia and 3 countries in Africa, between May 2011 and April 2013, has documented slow parasite clearance time . The main objective is to see which tools can be standardized, the ultimate goal being to evaluate a given control method for less than 200.000US$ in 1 year.Operational research and new ways of evaluation are needed for MMP interventions, as routine health information systems have limitations and might not allow to capture the information needed, and existing type of surveys might not be sufficient for monitoring interventions for MMP. Examples of new approaches used for surveying the MMP recently are: respondent driven sampling, cross-border surveys, plantation surveys.Focusing on MMP is a priority given that they are at high risk of malaria and contributes to the spread of artemisinin resistance, however, more operational research (OR) is needed on documenting the malaria risk among different types of MMP, innovative tools and interventions as well as designing implementation in a way that can be evaluated, lessons learned and programmes adapted in an ongoing process.Addressing the issue of artemisinin resistance in the GMS requires a sense of urgency, a common spirit, good coordination, regionally adapted integrated strategies, impact evaluation and good surveillance, collaboration between public and private sector, targeting difficult to reach populations, targeting the asymptomatic reservoir, adequate funding, and persistence till the end goal is reached.Multi-disciplinary approaches should be further explored as the combination of methods used in synergy provides a better understanding of the determinants of effectiveness of malaria interventions than each of this method alone.The main recommendations from session 2 were:Residual and outdoor transmission, falling out of reach of effective and sustainable prevention measures, particularly for mobile people, constitute another emerging challenge for which new tools and strategies are urgently needed, both in Africa and in Asia , 35. ResAnopheles arabiensis, replacing progressively Anopheles gambiae [Anopheles farauti with outdoor and early biting behaviour has increased [Malaria vectors have heterogeneous behaviours (early biting or outdoor versus indoor biting) varying by species, but not only, as some species may have a different biting behaviour depending on the geographical location, all those variations illustrating behavioural plasticity , 37. Mos gambiae ; (2) a s gambiae ; (3) a sncreased .Anopheles dirus was suspected in Cambodia; resistance to pyrethroid of Anopheles minimus in Vietnam; or of Anopheles epiroticus in southern Vietnam [kdr mutations, that confer resistance to pyrethroids and DDT were also found, in different vectors, including Anopheles sinensis [Mosquito resistance to at least one insecticide has been identified in at least 64 malaria-endemic countries worldwide and it continues to rise in Africa, South East Asia and Latin America , 42. A G Vietnam . The kdrsinensis . Accordisinensis , howeverMarc Coosemans  reviewed the current status on residual transmission and the challenges it represents for malaria elimination. Whether the selection pressure on behavioural traits will lead to behavioural resistance and lead to a rebound of residual transmission remains a question. However, the emergence and the selection of heritably altered behaviour traits would be very complex to demonstrate. Regardless of whether this residual transmission is due to pre-existing behavioural resilience or behavioural resistance, new vector tools need to be developed to address the gap not covered by LLIN or IRS interventions [ventions , 35.Various vector control initiatives to address residual transmission are currently in place including: the Grand Challenges of the BMGF supporting “New approaches for addressing outdoor/residual malaria transmission”; the Innovative Vector Control Consortium (IVCC) call for “Responding to the challenge of outdoor transmission of malaria”; the WHO Vector Control Advisory Group (VCAG) evaluating new paradigms and tools; the RBM Vector Control working Group (VCWG) working on how to address outdoor/residual malaria transmission. A guidance note was recently issued by WHO-GMP on “Control of residual parasite transmission” .Some innovative tools to address residual transmission include: topical and spatial repellents, attractive baits and traps. Topical repellents are very effective against mosquito bites, and has been shown in Bolivia to offer personal protection against malaria . High coVincent Corbel  reviewed the current status of insecticide resistance (IR) globally and presented the MALVEC project currently implemented in the SEA region through the 5% Initiative. The growing threat of insecticide resistance for malaria control and elimination worldwide was emphasized. The MALVEC project was set up to evaluate IR levels, type and mechanisms in the Lao PDR and the Thai-Lao border through a collaboration between the Institut Pasteur in Lao PDR, the Center for Malarialogy, Parasitology and Entomology in Lao PDR, IRD and Kasetsart University in Thailand. The main objectives of the project are Research, Training and Expertise with four main components: (1) evaluation of anopheles bionomics and distribution and their role in malaria transmission; (2) evaluation of the level, type and mechanisms of resistance to public health pesticides; (3) evaluation of the impact of environmental determinants  on vector dynamics and resistance selection; (4) strengthening capacity of Lao partners in medical entomology. The project follows the recommendations of the GMAP which calls for member states to implement an active system of insecticide resistance monitoring in vectors in order to improve preventive strategies and the fight against malaria worldwide.Anopheles maculatus and An. minimus), respectively. WHO susceptibility tests showed that most of anopheles species were still susceptible to pyrethroids but some species  show incipient resistance to DDT, whereas An. vagus showed incipient resistance to pyrethroids. In Thailand, at the border with Lao PDR and Cambodia, among mosquitoes collected during the rainy season  and the dry season (378 anopheles), 1% (out of 13 species) and 27% (out of 11 species) were primary vectors, respectively WHO bioassays showed resistance in all sites in Anopheles peditaeniatus and resistance to permethrin was suspected in Anopheles barbirostris, a secondary malaria vector. Preliminary findings showed that IR was present in anopheles species among which secondary malaria vectors but not in primary vectors. To conclude, IR is present at low levels in the Lao PDR, but is likely to increase by migration from neighbouring countries where resistance has been detected [kdr mutations has spread to all Africa mainly by migration events [Preliminary surveys conducted in the Vientiane province, Lao PDR (using both human landing catch and cow bait collection) show that among mosquitoes collected during the rainy season  and the dry season  6% (out of 22 species) and 67% (out of 19 species) were primary vectors  is needed in order to set up clear priorities at country level.More involvement of heads of government is essential to engage in the multi-sectoral approach needed, including non-health ministries.India and Bangladesh should be invited to join the RAI oversight committee as observers, similar to China’s position at the moment. The need to find ways to include and engage African countries in this process was as well highlighted.Existing structures, like the RAI and RSC should be used and reinforced and the next East Asia summit of heads of states should be used to convey the emergency for deeper commitment and to propose a budgeted plan to address artemisinin resistance in the next few years, in the broader context of the 2030 target.Based on scientific evidence and information available, simple and clear key messages should be “packaged”, expressing a common position, a common voice, from the scientific community. It should address the problem, the needs, the priority actions, a budgeted plan and the risks of “doing something versus doing nothing”.Key messages should be disseminated to a broader, non-scientific audience, including grass root communities exposed to and affected by malaria, national malaria control programmes, donors and international institutions and importantly policy makers and governments.This meeting report present the outcomes of a 1-day workshop which convened a global community of over 80 researchers, representatives of NMCPs, of CSOs, and of financial and technical partners. More operational research and adapted evaluation methods are needed to better address challenges for malaria control and elimination and will require innovation. Those challenges include: ensuring adequate community participation for new strategies, i.e. MDA and preventions methods for residual and outdoors transmission; closing intelligence gaps regarding surveillance of drug and insecticide resistance, anti-malarial medicine quality; building capacity to better monitor insecticide resistance and mosquito behavioural changes linked to scale-up of vector control interventions.The threat and the emergency of the artemisinin resistance spread and independent emergence in the GMS was intensely debated as it is now close to the border of India. The need for key messages, based on scientific evidence and information available and disseminated without delay, was highlighted as crucial for an effective and urgent response. Those messages should be disseminated to broader, non-scientific audience, including grass root communities exposed to and affected by malaria, NMCPs, donors and international institutions and importantly policy makers and governments.