Digital forms of direct-to-consumer pharmaceutical marketing (eDTCA) have globalized in an era of free and open information exchange. Yet, the unregulated expansion of eDTCA has resulted in unaddressed global public health threats. Specifically, illicit online pharmacies are engaged in the sale of purportedly safe, legitimate product that may in fact be counterfeit or substandard. These cybercriminal actors exploit available eDTCA mediums over the Internet to market their suspect products globally. Despite these risks, a detailed assessment of the public health, patient safety, and cybersecurity threats and governance mechanisms to address them has not been conducted.Illicit online pharmacies represent a significant global public health and patient safety risk. Existing governance mechanisms are insufficient and include lack of adequate adoption in national regulation, ineffective voluntary governance mechanisms, and uneven global law enforcement efforts that have allowed proliferation of these cybercriminals on the web. In order to effectively address this multistakeholder threat, inclusive global governance strategies that engage the information technology, law enforcement and public health sectors should be established.Effective global “eHealth Governance” focused on cybercrime is needed in order to effectively combat illicit online pharmacies. This includes building upon existing Internet governance structures and coordinating partnership between the UN Office of Drugs and Crime that leads the global fight against transnational organized crime and the Internet Governance Forum that is shaping the future of Internet governance. Through a UNODC-IGF governance mechanism, investigation, detection and coordination of activities against illicit online pharmacies and their misuse of eDTCA can commence. According to the International Telecommunications Union (“ITU”), an estimated 2.7 billion people (39% of the world’s population) are online in 2013 [This growth has led to the development of new concepts in health, including “e-Health”, i.e., a multidisciplinary “intersection of medical informatics, public health and business, referring to health services and information delivered or enhanced through the Internet and related technologies .” SimilaYet, e-Health advances also enable health-related digital marketing and promotion that can be of questionable quality, reliability, origin and authenticity -15. GenePerhaps most disturbing, vulnerabilities in the current global Internet governance and the pharmaceutical promotion regulatory regime provides fertile ground for promotion of dangerous medicines by illicit, or “rogue” online pharmacies ,20. Illist century [dual threat in that they present both challenges to global public health and risks to global cybersecurity that remain largely unaddressed by international stakeholders [Illicit cyberpharmacies that sell questionable medications without a prescription hence, represent a form of cybercrime that has been described as the preeminent global governance challenge of the 21 century . In facteholders ,20. Enabeholders ,17.Given these ongoing public safety concerns that intersect between the global health and information technology (“IT”) policy domains, it is essential to examine the mechanisms and infrastructures utilized by illicit online pharmacies to determine needed strategies in combating this unique form of transnational cybercrime. Consequently, we first describe the potential public health risks, patient safety dangers, and cyber security issues associated with illicit online pharmacies. On this basis, we also review key efforts by a variety of actors in the international community attempting to address this issue. Finally, we propose a novel global governance approach emphasizing public health priorities in current Internet governance activities as a foundation to combat illicit online pharmacies and their exploitation of unregulated eDTCA.Several studies have explored the public health implications of industry-based legally-allowable DTCA. Possible negative consequences include dissemination of misleading or unbalanced information about the risks and benefits of medications, overutilization of expensive prescription drugs, aggressive promotion of pharmaceuticals with questionable safety profiles often at early stages in their product life-cycle, and negative patient-physician interactions -29.Yet eDTCA use by illicit online pharmacies represents an even greater risk to patient safety and public health as this enterprise is largely populated by criminal actors, websites are unregulated and lack required licensure for operation, and eDTCA content often consists of misleading or fraudulent information directly targeted at the patient ,17. IndeHarm to prospective consumers sourcing medicines from illicit no prescription online pharmacies comes in two primary forms. First, consumers may engage in self-diagnosing and self-prescribing of their health conditions without partnership of a medical professional . This bewithout a prescription, which is a clear violation of laws and regulations of the vast majority of countries requiring controls for dispensing of regulated medical products. We focus on this predominant subset of online pharmacies as the quality and safety of medications sourced from “no prescription” websites largely cannot be determined, and even if there is the possibility of sourcing authentic medication, patients may nevertheless be exposed to safety risks as previously described. Specifically, the Internet poses unique challenges to counterfeit detection in that purchasing is difficult to trace, and testing products illegally sourced by individual online consumers is inherently difficult, intrusive and costly. Hence, false and misleading marketing utilized by no prescription online pharmacies can induce the unregulated and illegal sale of medications of unknown quality, with the consumer having no way of ensuring what they are sourcing is safe [In this discussion, we focus on the illegal online marketing and sale of any medication  is safe .These collective challenges have resulted in a general lack of data needed to identify the exact percentage of counterfeit medicines sold by illicit online pharmacies. However, documented patient injury and deaths in multiple countries directly associated with online medicines purchasing involving both substandard medications and authentic medicine taken incorrectly provides a clear indication of ongoing patient safety risks justifying regulation and enforcement ,22. FurtDespite lack of comprehensive data, organizations such as the USA National Association of Boards of Pharmacy (“NABP”) have attempted to analyze how widespread is the practice of illegal online marketing and operation of illicit online pharmacies. In March, 2013, NABP released its study of approximately 10,000 websites, reporting 97% of them did not meet adequate pharmacy laws and practice standards and 86% of these not requiring a valid prescription . This moIn addition, increasingly Medicine 2.0 or social media forms of eDTCA have been identified as a platform for the promotion of illicit online pharmacies ,17. ThisAlthough there is potential for harm from both legal industry-based and illicit online pharmacy eDTCA, illicit online marketing activity should be prioritized in global health and Internet governance efforts. There is, for the most part, no domestic means to ensure accountability for illegal and harmful actions by these criminal actors originating across geopolitical lines ,19. Pracsuccessful detection and prosecution in a digital environment where the majority of pharmaceutical crime often goes undetected. This continued expansion of pharmaceutical cybercrime is evident in the continued proliferation of illicit online pharmacies and their increasing use of various forms of eDTCA. eDTCA use includes spam and other solicitations that act as a vehicle for fraud, phishing scams, viruses, malware, and spyware, often targeted towards vulnerable consumer groups [rd of spam messages are health-related, generally eDTCA originating from suspect online pharmacies [The global vacuum of effective governance and regulatory approaches against illicit online pharmacies has predictably attracted large criminal networks looking to profit from this trade. Consequently, illicit online pharmacies threaten state sovereignty and global security due to their association with transnational organized crime syndicates, as well as cybercrime and cybersecurity threats . For exar groups ,19. Indearmacies .A wide array of public health and law enforcement stakeholders, including WHO, the UN Office of Drugs and Crime (“UNODC”), the International Criminal Police Organization (“Interpol”), the FDA, NAPB, the USA Federal Bureau of Investigation, the International Pharmaceutical Federation, the European Federation of Pharmaceutical Industries and Associations, the Pharmaceutical Research and Manufacturers of America, the Generic Pharmaceutical Association, the Pharmaceutical Security Institute and numerous other public and private sector groups have specifically recognized the global challenges posed by the Internet and illicit online pharmacies ,22,42-44Further, strategic approaches are complicated given the unclear applicability of domestic laws and general lack of enforcement in the Internet service sector. For example, although this criminal activity is perpetrated by a host of clearly criminal actors , others, including Internet Service Providers , enable illicit online pharmacy operations but often span multiple jurisdictions and legal regimes (including those that may be exempt from liability) -21,44  provides basic aspirational tenets . While trd) of countries have little to no regulatory oversight over pharmaceutical promotion [Despite their seeming uncontroversial, foundational nature, decades after introduction of the WHO Criteria, WHO surveys have found a large fraction  have also been tried as potential governance mechanisms beyond Interpol’s Operation Pangea. For example, the Alliance for Safe Online Pharmacies and Center for Safe Internet Pharmacies are attempting to coordinate efforts addressing marketing and sales by illicit online pharmacies in the USA ,56,57. IOur examination of governance efforts indicates that national government legislation, voluntary governance mechanisms, and global law enforcement efforts attempting to address the public health and cybersecurity risks of illicit online pharmacies have not been adequate, especially in the context of unregulated eDTCA. Illicit online pharmacy eDTCA use explicitly involves criminal actors that utilize false and misleading information meant to induce unjustified and unsafe use of medicines. These concerns clearly reside within the general principles of ethical standards enshrined in the WHO Criteria targeting industry-based promotion, yet which did not anticipate the development of illicit online pharmacies as a point of access and source of promotion. Further, even if the WHO Criteria had specifically addressed illegal online pharmacy promotion in its text, lack of adoption of its guidelines in national legislation would continue to limit effectiveness of its application. Improved global health and Internet governance is therefore urgently needed.Illicit global trafficking of medicines via the Internet directly impacts individual patients and population-based health outcomes. Yet infrastructures enabling this illicit e-commerce are primarily IT and private sector driven ,20. Cons“Internet governance” is a relatively new phenomena. Conceptually, it is defined as the establishment of shared principles, norms, rules, decisionmaking procedures and programs developed by governments, the private sector, and civil society on the use and evolution of the Internet . ReflectBeginning in 2005, the UN-initiated World Summit on the Information Society (“WSIS”) established the Internet Governance Forum (“IGF”) to engage, in an open and inclusive manner, multiple stakeholders in a policy dialogue regarding Internet governance . ImportaIGF has been successful in engaging a wide array of stakeholders, including national governments, the private sector, civil society, academia, and other technical communities . ImportaAs a UN Summit, WSIS is relatively flexible, allowing primary agenda setting by UN Member States, broad engagement with other UN agencies, while intergovernmental organizations, accredited civil society and private sector entities, and other associated entities can participate as observers . Howeverexpressly noting the need to take appropriate measures to combat illegal and harmful media content [Extant Internet governance approaches are very useful in addressing online health activities. WSIS and IGF’s structures and the WSIS plan of action have stated goals of building an “inclusive Information Society” promoting international and regional cooperation, incorporating public-private partnership (“PPP”) models into its action plans, promoting e-Health technologies and quality of online health information, and  content .Building upon emerging Internet governance, we believe an enhanced “e-Health Governance” model for cybercrime can be created, beginning a coordinated and focused effort to address illicit online pharmacies and their fraudulent and misleading use of eDTCA. Foundationally, this would entail promoting global health diplomacy efforts in all Internet governance activities, consistently prioritizing illicit online pharmacies as a preeminent cybersecurity and cybercrime issue, and building protections so that eDTCA is not false or misleading for consumers.Proposed e-Health Governance for cybercrime should be shaped like the more inclusive IGF infrastructure and include its broad membership. This is both most acceptable and apt, as IGF stakeholders have already begun discussions regarding eDTCA regulation, counterfeit medicines in developing countries, pharmaceutical authentication technologies, and fraudulent commercial practices of illicit online pharmacies in the context of subjects regarding international trade, privacy and security, digital access, and improving Internet governance -68. IGF However, beyond IGF infrastructure and membership, crucial to the success of e-Health cybercrime governance is partnership with organizations that currently focus on illicit online pharmacy networks, transnational crime, and cybersecurity. Here, the UNODC is well situated to coordinate IGF partner efforts. First, UNODC is the lead UN agency combatting global organized criminal networks, including trade in counterfeit medicines. Importantly, it has widespread political support and existing partnerships with organizations such as Interpol, the World Customs Organization and civil society that are already active in the fight against counterfeit medicines .Second, UNODC is empowered by the UN Convention against Transnational Organized Crime (“UNTOC”) ,69,70. Uth Session of UN Commission on Crime Prevention and Criminal Justice (“CCPCJ”), three resolutions were adopted that clearly have reinforced global empowerment of UNODC to fight illicit online pharmacy activities: Resolution 20/4, “Promoting further cooperation in countering transnational organized crime,” Resolution 20/6, “Countering fraudulent medicines, in particular their trafficking”  and Resolution 20/7, “Promotion of activities relating to combating cybercrime, including technical assistance and capacity-building [UNODC and application to UNTOC have recently converged regarding illicit online pharmacy and fraudulent eDTCA cybercrime–focused issues. At the 2011 20building .” Each cLeveraging its support and empowerment, UNODC can engage IGF and WSIS stakeholders to promote e-Health Governance investigation, detection, and coordination activities against illicit online pharmacies and their misleading eDTCA. Further, a UNODC-IGF partnership infrastructure can spearhead additional legal and enforcement capacity by creating model national legislation to address criminal oversight of online pharmacies, particularly given the current absence of regulatory development in the vast majority of countries worldwide .Once established, several matters could be on its early agenda. We believe five fundamental matters should be addressed as permanent agenda items in UNODC-led e-Health Governance efforts focusing on illicit online pharmacy related cybercrime. They focus upon security, diplomacy, partnerships, credentialing, and criminal surveillance strategies ; CCPCJ: The Commission on crime prevention and criminal justice; DTCA: Direct-to-consumer adverstising; DCWG: Dynamic coalition working group; eDTCA: Electronic or digital forms of direct-to-consumer advertising; FDA: United State of American food and drug administration; GOe: World Health Organization global observatory for e-health; ICANN: The internet corporation for assigned names and numbers; IGF: Internet governance forum; Interpol: International criminal police organization; IT: Information technology; ITU: International telecommunications Union; LMICs: Low-and-middle income countries; MAG: Multistakeholder advisory group; NABP: National association of boards of pharmacy; PPP: Public-private partnership; UNODC: United nations office of frugs and crime; WHO: World Health Organization; WHO Criteria: World Health Organization ethical criteria for medicinal drug promotion; WSIS: World summit on the information society.TKM (TKM) and BAL (BAL) received no extramural support from any organization for the submitted work that has an interest in the subject or that would present a conflict of interest. TKM is the 2011-2013 CLA Fellow of the Partnership for Safe Medicines (PSM), which supports his general research activities. BAL is a voluntary board member and Vice President of PSM, and receives no compensation for any PSM activities. PSM is not connected with the submitted work. BAL also serves as a member of the US Agency for Healthcare Research and Quality, Healthcare Safety and Quality Research Study Section, and the National Patient Safety Foundation Research Program Committee, both of which consider grant proposals addressing medication safety. TKM and BAL report no other relationships or activities that could appear to have influenced the submitted work.We note that with respect to author contributions, TKM and BAL jointly conceived the study, TKM and BAL jointly wrote the manuscript, TKM, and BAL jointly edited the manuscript, and BAL supervised its legal and policy analysis. Both authors read and approved the final manuscript.


Polypharmacy and inappropriate medication use among older adults contribute to adverse drug reactions, falls, cognitive impairment, noncompliance, hospitalization and mortality. While deprescribing - tapering, reducing or stopping a medication - is feasible and relatively safe, clinicians find it difficult to carry out. Deprescribing guidelines would facilitate this process. The aim of this paper is to identify and prioritize medication classes where evidence-based deprescribing guidelines would be of benefit to clinicians. A modified Delphi approach included a literature review to identify potentially inappropriate medications for the elderly, an expert panel to develop survey content and three survey rounds to seek consensus on priorities. Panel participants included three pharmacists, two family physicians and one social scientist. Sixty-five Canadian geriatrics experts  participated in the survey. Twenty-nine drugs/drug classes were included in the first survey with 14 reaching the required (≥ 70%) level of consensus, and 2 new drug classes added from qualitative comments. Fifty-three participants completed round two, and 47 participants completed round three. The final five priorities were benzodiazepines, atypical antipsychotics, statins, tricyclic antidepressants, and proton pump inhibitors; nine other drug classes were also identified as being in need of evidence-based deprescribing guidelines. The Delphi consensus process identified five priority drug classes for which expert clinicians felt guidance is needed for deprescribing. The classes of drugs that emerged strongly from the rankings dealt with mental health, cardiovascular, gastroenterological, and neurological conditions. The results suggest that deprescribing and overtreatment occurs through the full spectrum of primary care, and that evidence-based deprescribing guidelines are a priority in the care of the elderly. Overdiagnosis and overtreatment are potentially harmful and expensive –3. In 20Polypharmacy and inappropriate medication use among older adults are known to contribute to adverse drug reactions, falls, cognitive impairment, noncompliance, hospitalization and mortality –11. WhilInnovative approaches are needed to address these barriers in order to limit the negative impact of polypharmacy on our older population. Such approaches should facilitate decision-making about stopping a medication and provide clear recommendations for tapering and monitoring impact to ensure safety and effectiveness of the process. To achieve this, the Ontario (Canada) Ministry of Health and Long-Term Care has supported the systematic development and testing of a series of evidence-based guidelines for deprescribing.Given the large number of drug classes felt to be potentially inappropriate or risky in the elderly ,20, deteA modified Delphi approach , beginniEthics approval was obtained from the following Research Ethics Boards: Bruyère Continuing Care and Ottawa Health Science Network , Concordia University , University of Toronto  and University of Waterloo . All participants provided informed consent with each survey iteration.Six members of the research team, which included two family physicians and three pharmacists, all with expertise in geriatrics, and a social scientist with expertise in evaluating change, met in person in July 2013. The group reviewed literature and reports outlining the prevalence and impact of polypharmacy and potentially inappropriate medication use  ,24–33, aCanadian clinical experts from medicine, pharmacy and nursing were purposely identified using the following inclusion criteria: a) geriatrics expertise and/or b) academic appointment in teaching and/or c) research in the area of geriatric pharmacotherapy. Research team members considered those who had a background and experience with polypharmacy management and deprescribing in the elderly, ensuring that participants were highly trained and knowledgeable about the target subject . We usedhttp://fluidsurveys.com/) from November 2013 to February 2014. Each survey was live for two weeks; two reminders were sent. The definition of consensus was determined before the analysis of each round, by the investigator team, and in consultation with a statistician. Investigators were blinded to the results during analysis. Specific definitions of consensus are explained in each round described below.Three rounds of surveys were administered via Fluid Surveys  uncertainty of benefit in the elderly; 2) high risk of harms in the elderly; 3) availability of suitable alternatives; 4) potentially high impact of a deprescribing guideline for the elderly; and 5) feasibility for guideline development (i.e. an adequate amount of literature to create an evidence-based guideline). Using these criteria, they were asked to identify only the top five drug classes that they felt had an urgent and clear need for a deprescribing guideline. Similar to round two, mean rank with standard deviation was calculated. In addition, the number of respondents who chose each drug class as one of their top five choices was calculated . InvestiThe expert panel identified 29 drug/drug classes for inclusion in the first survey. Sixty-five experts agreed to participate in the Delphi process, including 8 geriatricians, 11 family physicians, 36 pharmacists and 10 nurse practitioners representing eight of the 10 Canadian provinces.  round one participants (including the respondent who incorrectly completed round 1 but completed rounds 2 and 3 correctly) completed round two. Twelve participants did not complete the round two ranking within the two week allotted timeframe; of these, we received 2 automatic replies indicating the recipient was away on vacation . The 16 drugs/drug classes are shown in order of their mean rank in Content analysis of qualitative comments suggested that respondents used five main criteria in making their selections for determining guideline priorities: a) risk of continuing the drug; 2) questions about ongoing indication or benefit of the drug; 3) prevalence of overuse of the drug; 4) challenge in stopping the drug; and 5) the availability of other treatment options. See In round two, benzodiazepines remained the top priority and atypical antipsychotics remained the second-highest priority for most participants, followed by tricyclic antidepressants, typical antipsychotics and statins. The qualitative comments suggest that those who ranked benzodiazepines highly did so because it is included in Beers Criteria , a conseNo participant rated bisphosphonates, zopiclone or trazodone as the highest priority (i.e. a score of one). Zopiclone and trazodone were the two drugs that were excluded at the end of round two.Of the round three surveys sent to the 53 round two responders, 47 were completed. Therefore, 47 of the 65 (72%) round one participants (including the respondent who incorrectly completed round 1 but completed rounds 2 and 3 correctly) completed the survey in round three. We received one automatic reply indicating the recipient was away during the timeframe allotted to complete the round three survey. Adults, especially elderly adults, often live with chronic diseases that are managed with multiple medications . Health A central goal of our guideline development project is to develop strategic evidence-based deprescribing guidelines to improve patient outcomes . The drurd and based on respondent comments, this may be related to concerns about benefit given the lack of elderly patients in trials, lack of clarity around ongoing indication and when they can be stopped, as well as an emerging recognition of side effects and overtreatment of low risk patients [th and based on respondent comments, this may be related to both challenges in stopping them, for example, managing family physician reluctance to alter sleep or mood stability while trying to limit risk, for example, known side effects such as confusion and falls [th, were seen by respondents as being overused and relatively easy to stop despite concerns over symptom recurrence [In our final wave, statins ranked 3patients ,58. Tricnd falls . Finallycurrence –62.In addition to the top five drug classes outlined above, the Delphi process identified nine other drug classes in need of evidence-based guidelines see . These iWe note that all participants from our Delphi process were Canadian clinicians, and that the resulting priorities reflect the conditions, drug benefit plans, experiences and judgments of prescribers operating within the multi-jurisdictional Canadian health system. Canada has a single payer universal access health system but it does not have a universal drug coverage plan. It is likely that deprescribing priorities are influenced by prescribing patterns, health conditions, and health system pressures that arise within specific contexts in different geographies and countries.This Delphi consensus process helped to identify and prioritize the five medication classes that clinicians believed would most benefit from deprescribing guidelines. The classes of drugs that emerged strongly from the rankings dealt with mental health, cardiovascular, gastroenterological, and neurological conditions. The process also identified nine other drug classes in need of evidence-based guidelines, including treatments for a range of chronic disease conditions. The results suggest that deprescribing and overtreatment occur through the full spectrum of primary care, and that the development of evidence-based deprescribing guidelines, and the inclusion of deprescribing components in all chronic disease guidelines, are a priority in the care of the elderly.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(DOCX)Click here for additional data file.


Biodiversity loss may alter ecosystem processes, such as herbivory, a key driver of ecological functions in species-rich (sub)tropical forests. However, the mechanisms underlying such biodiversity effects remain poorly explored, as mostly effects of species richness – a very basic biodiversity measure – have been studied. Here, we analyze to what extent the functional and phylogenetic diversity of woody plant communities affect herbivory along a diversity gradient in a subtropical forest.We assessed the relative effects of morphological and chemical leaf traits and of plant phylogenetic diversity on individual-level variation in herbivory of dominant woody plant species across 27 forest stands in south-east China.Individual-level variation in herbivory was best explained by multivariate, community-level diversity of leaf chemical traits, in combination with community-weighted means of single traits and species-specific phylodiversity measures. These findings deviate from those based solely on trait variation within individual species.Our results indicate a strong impact of generalist herbivores and highlight the need to assess food-web specialization to determine the direction of biodiversity effects. With increasing plant species loss, but particularly with the concomitant loss of functional and phylogenetic diversity in these forests, the impact of herbivores will probably decrease – with consequences for the herbivore-mediated regulation of ecosystem functions. The reserve covers Hu & Yu, . Within Ardisia crenata Sims, Camellia fraterna Hance, Castanopsis eyrei (Champ. ex Benth.) Tutch., Cyclobalanopsis glauca (Thunb.) Oerst., Eurya muricata Dunn, Lithocarpus glaber (Thunb.) Nakai, Loropetalum chinense (R. Br.) Oliv., Machilus thunbergii Sieb. et Zucc., Neolitsea aurata (Hayata) Koidz. and Schima superba Gardn. et Champ. These 10 evergreen species accounted for c. 50% of the total biomass of the tree and shrub layers in the study plots  of 10 dominant tree and shrub species: et al., et al., c. 80% of the 147 woody plant species recorded on the 27 study plots, and these species represented 95% of the total number of tree and shrub individuals at the study sites. As we used abundance-weighted indices to quantify functional community composition and diversity, these data should not be affected by the 5% of woody plant individuals for which trait values were missing. Data on leaf toughness, which has been shown in previous studies to potentially affect herbivory , which represented stand age and age-dependent aspects of stand structure and biomass, was related to herbivore damage , as well as two multivariate versions of Rao’s Q that assessed the overall diversity of morphological (Qmorph) and chemical (Qchem) leaf traits. We also tested for the effects of an overall Rao’s Q measure that integrates both the leaf morphological and chemical traits, but, as this measure was less strongly related to herbivory than was Qchem, we kept the distinction between morphological and chemical leaf trait diversity to allow for a better mechanistic interpretation of potential effects  and a Euclidean species distance matrix. For the multivariate measures of Rao’s Q based on the three morphological and four chemical traits, we used all axes of a PCA  on the standardized traits for the distance matrix to avoid collinearity effects . All measures of functional and phylogenetic diversity were weighted by plot-level abundance data to account for the relative impact of dominant vs rare species on community-level metrics.Rao’s Qspecphylo), based on the mean phylogenetic distance between an individual of a given focal species and all other woody plant individuals in a given study plot  used in other studies  and chemical (Qspecchem) leaf traits and measures for each individual trait  in our analysis. Species-specific indices were calculated from the same distance matrices as used for the calculation of plot-level Rao’s Q, but by contrasting individuals of the respective focal species to all other individuals in each of the communities. Again, all measures were weighted by plot-level abundance data.In each plot, and for each of the 10 focal species, we further calculated a species-specific phylogenetic distance measure  PC1abio and woody plant species richness; and (5) only PC1abio. PC1abio was included in all model sets to account for potentially confounding plot characteristics. Species identity, with individuals nested within species, and plot identity were considered as crossed random effects. The use of species identity as a random factor accounts for all interspecific differences in the levels of herbivory, leaving individual-level differences as the only source of variation. We also included a random factor with the total number of observations as factor levels to account for potential overdispersion in the data . The final set of predictors included the general plot characteristics PC1abio, woody plant species richness, the phylogenetic diversity measure Qphylo, the multivariate chemical trait diversity Qchem, the single-trait dispersion variables QLDMC, QC, QC : N, QPhenol, the CWM values CWMLA, CWMLDMC, CWMC, CWMPhenol, and the species-specific measures Qspecphylo, QspecLA, QspecLDMC, QspecC, QspecC : N, QspecC : P and QspecPhenol. We also included the interaction between woody plant species richness and overall phylogenetic diversity Qphylo, as this has been shown recently to influence species richness effects in grasslands  and the package lme4  and 17% . Species-specific damage levels varied by 15% (± 9.5% SD), on average, among the individual study plots. Species richness, functional characteristics and phylogenetic diversity of the plant communities all added essential explanatory value to the individual-level herbivory data. The minimal models based on abiotic characteristics and only phylogenetic or functional plant characteristics had a higher explanatory power than the models including only species richness and abiotic characteristics, or abiotic characteristics alone  and the CWM leaf C content of the plant communities (CWMC) contributed most to the overall best model, followed by weaker effects of woody plant species richness, the dispersion of leaf C content (QC), the species-specific mean phylogenetic distance (Qspecphylo), the species-specific mean distance in LA (QspecLA) and CWMLDMC within the plant communities. It should be noted that the effects of most predictors were highly significant, and so potential issues of testing on the boundary of parameter space do not affect our results  are well reflected in most of the individual species  which are considered to be of particular importance for the palatability of plants and their defense against herbivores . The study species belonged to the tree and shrub species with a relatively high leaf C content . Herbivore damage on these species might decline if increasing CWMC decreases the probability of herbivores being able to use alternative host plants with lower leaf C content (which are more abundant in low CWMC communities) to compensate for low nutrient quality in their preferred hosts ). We might also potentially have expected an effect of the species-specific QspecC in this case. However, the fact that this variable did not provide additional explanation could be because nutrient quality effects are largely captured by the more integrative Qchem, with additional variation already largely explained by the effects of CWMC and QC.Effects of dietary mixing could also underlie the negative relationship between herbivory and the CWM levels of leaf C content (CWMQC) on herbivory might be explained by interrelations with CWMC , such that low community-level variability in leaf C content could indicate better nutrient conditions. However, such a relationship would only be moderate in our case, as adding an interaction term for QC and CWMC did not improve the model fit .Effects of the variability in leaf C content , herbivory was positively related to the species-specific measure Qspecphylo. As also indicated by the results for CWMC, this makes it clear that the position of a focal species within trait space (in the case of Qspecphylo approximated by a phylogenetic measure) can provide information that is not captured by, and not necessarily dependent on, overall community diversity (Butterfield & Suding, Qspecphylo is contrary to the effects reported for similar measures from other species-rich forests, where phylogenetic diversity and relatedness have been observed to decrease species-specific levels of herbivory via mechanisms of negative density dependence (Webb et al., et al., et al., et al., et al., et al., In contrast with leaf chemical traits, phylogenetic diversity measures were of less importance in explaining variation in herbivory across the 27 study plots (and, for our system, we were unable to detect an interaction between phylogenetic diversity and plant species richness, as recently reported by Dinnage  for graset al., et al., et al., Although functional trait and phylogenetic information outperformed pure woody plant species richness in explaining the variability in herbivore levels across the 27 study plots, species richness was nevertheless retained as a predictor in the best minimal model (for a detailed discussion of the relationship between species richness and herbivory in our study system, see Schuldt et al., Qchem and Qphylo could potentially promote clustering over time in the phylogenetic composition and the trait space occupied by the woody plant communities (see also Cavender-Bares et al., et al., et al., et al., et al., et al., The patterns we observed are likely to result in negative effects on the growth of our study species, as even low levels of persistent herbivore damage can strongly decrease plant fitness (Zvereva Our study shows how a combined approach that incorporates different facets of functional and phylogenetic community composition and diversity can help in informing our mechanistic understanding of how biodiversity affects ecosystem functions along natural environmental gradients. It emphasizes the impact of community-level functional properties on a set of focal species, which deviates from previously reported effects of species-specific trait variation within and among these species. Considering that individual species usually form part of larger communities (see also Karban,


The Centers for Disease Control and Prevention’s National Center for Injury Prevention and Control (CDC) envisions a society where older adults (persons 65 and older) can live long, safe, and healthy lives. Falls are a threat to older adults’ health and can significantly limit their ability to live independently. One in three older adults falls each year, resulting in over $30 billion in direct medical costs .For more than 20 years, CDC has been conducting research to help prevent falls and resulting injuries among older adults. Research has identified important and modifiable risk factors. These include muscle weakness, gait and balance problems, psychoactive medication use, poor vision, and environmental hazards  identifiMedical providers can play an important role by identifying older adults who are likely to fall and providing clinical preventive services to help reduce fall risks. To aid medical providers, the American and British Geriatrics Societies (AGS/BGS) developed a clinical practice guideline that (1) encourages providers to conduct fall risk assessments to identify patients who are at risk of falling and (2) describes evidence-based interventions that can be incorporated into a patient’s plan of care . RecommeWithin the community, CDC-funded grantees – the Oregon Health Authority, New York State Department of Health, and Colorado Health Department of Public Health and Environment – are implementing evidence-based programs that reduce older adult falls. Supported programs include Tai Chi: Moving for Better Balance , SteppinThese state grantees are also leveraging additional resources from the Area Agencies on Aging (AAA), senior services network, the YMCA, and other community programs developed for seniors.Within the clinical setting, the CDC grantees and their partners are helping healthcare providers implement the AGS/BGS clinical practice guideline by providing the STEADI  tool kit . Based oBased on this information, CDC developed a fall prevention approach that integrates clinical practice and evidence-based community fall prevention programs. The approach expands current health care practice by supporting providers in making fall prevention a routine part of clinical care and encouraging providers to link clinical practice with community-based fall prevention programs. To this end, CDC’s Injury Center provides targeted technical and programmatic assistance to several state health departments and medical providers to help them implement fall prevention programs and measure impact.Scaling up and sustaining this approach is challenging and requires bringing health care and public health together. Indeed, healthcare management organizations, health care plans, health care providers, state health departments, and community organizations all have a role in this integrated approach to fall prevention. The combined contribution of all these sectors helps expand reach, reduce barriers to implementing clinical and community approaches, and maximize public health impact.To help make older adult fall prevention a routine part of clinical care, CDC is supporting efforts to increase market penetration of the STEADI tool kit and to scale up its use by health care providers. For example, to accomplish this, CDC’s Injury Center is creating electronic clinical decision support modules that can be adopted by most electronic health record (EHR) systems. The goal is to integrate fall prevention activities into EHR systems so that users can efficiently manage patient workflow, care, referrals, and billing.The STEADI EHR modules will incorporate the Centers for Medicare and Medicaid Services (CMS) incentive programs, which reward providers and health care organizations for screening patients for fall risk and implementing fall prevention strategies for their high-risk patients. For providers dedicated to promoting the health and well-being of their older patients, this offers an opportunity to receive incentive payments for their efforts to deliver evidence-based health care. Additionally, EHR modules will incorporate the reimbursable ICD-10 diagnostic codes that clinicians will be able to use when addressing fall risk with their patients.A STEADI online training course will soon be available that will teach clinicians  to conduct fall risk assessments and recommend appropriate interventions using materials from the STEADI tool kit. The online training will also provide information on the EHR modules and information on how medical staff can operationalize the EHR modules in their practice.As the U.S. population ages, fall injuries will increase . The effThe findings and conclusions in this commentary are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.This paper is included in the Research Topic, “Evidence-Based Programming for Older Adults.” This Research Topic received partial funding from multiple government and private organizations/agencies; however, the views, findings, and conclusions in these articles are those of the authors and do not necessarily represent the official position of these organizations/agencies. All papers published in the Research Topic received peer review from members of the Frontiers in Public Health  panel of Review Editors. Because this Research Topic represents work closely associated with a nationwide evidence-based movement in the US, many of the authors and/or Review Editors may have worked together previously in some fashion. Review Editors were purposively selected based on their expertise with evaluation and/or evidence-based programming for older adults. Review Editors were independent of named authors on any given article published in this volume.


This paper reviews Italian Development Assistance for Health and overall contribution to Global Health from 2001 to 2012. It analyses strategies and roles of central and decentralized authorities as well as those of private non-profit and corporate actors. The research illustrates a very low and unstable official contribution that lags far behind internationally agreed upon objectives, a highly fragmented institutional scenario, and controversial political choices favouring “vertical” global initiatives undermining national health systems, and in contrast with Italian deep-rooted principles, traditional approaches and official guidelines.Italy’s contribution to global health goes beyond official development aid, however. The raising movement toward Universal Health Coverage may offer an extraordinary opportunity for a leading role to a country whose National Health System is founded on the principles of universal and equitable access to care. At the same time, the distinctive experience of Italian decentralized cooperation, with the involvement of a multiplicity actors in a coordinated effort for cooperation in health with homologous partners in developing countries, may offer – if adequately harnessed - new opportunities for an Italian “system” of development cooperation. Nevertheless, the indispensable prerequisite of a substantial increase in public funding is challenged by the current economic crisis and domestic political situation. For a renewed Italian role in development and global health, a paradigm shift is needed, requiring both conceptual revision and deep institutional and managerial reforms to ensure an appropriate strategic direction and an efficient and effective use of resources. Its ODA/GNI  ratio has been constantly less than 0.20% since 2000, which is substantially below the average of the Organisation for Economic Cooperation and Development (OECD) countries, members of the Development Assistance Committee (DAC). Peer reviews from the OECD have been critical regarding the management of Italian aid and the capacity of the public administration to overcome structural deficiencies ,2. The dThe overall weakness of the Italian Development Cooperation has inevitably affected the role the country could have played in fostering global health. In addition, Italy’s vision of international health cooperation suffered from other specific limiting factors.Servizio Sanitario Nazionale - SSN), founded in 1978, is financed by general taxation and, despite a certain degree of variability in the quality of its services across Italian regions, provides universal coverage and ensures a free choice of providers to patients through a pluralistic delivery structure (public and private), at relatively low cost [Firstly, the decision to uncritically redirect Official Development Assistance in Health (DAH) to follow the push of more influential donors toward narrowly targeted, i.e. “vertical”, global initiatives, potentially undermining the effective delivery of integrated health care and the overall effectiveness of health systems , is incolow cost ,5.Secondly, Italy has not adequately leveraged the various energies of its country system  ,2 alreadApart from institutional documents  and some domestic reviews -10, inteThis article attempts to fill this gap. It first reviews principles and practice of the Italian approach to global health (and DAH). It then analyses relevant financial flows and trends, identifying main public and private actors involved in DAH, and exploring their contribution. We argue that there is a qualitative role for Italy to be plaid in the global health agenda, but economic and organizational challenges must be faced.We conclude highlighting the need for a paradigm shift both in the overall Italian ODA governance, strategic direction and management, and in the way development cooperation is conceived.The analysis is based on quantitative and qualitative information available on Italy’s engagement in global health. The overall observation period was limited to 2001–2012 since the beginning of the decade coincides with the “rapid-growth” period of DAH , as wellWe started by conducting a literature review through both Medline/Pubmed and Google Scholar without limiting the time period and variously combining the key word ‘Italy’ with ‘global health’, ‘international health,’ ‘Development Aid’, ‘Development Cooperation’ and ‘Development assistance’, and extending the search to studies written in both English and Italian.Istituto Superiore di Sanità, ISS, the National Council for Economy and Labour, - Consiglio Nazionale dell’Economia e del Lavoro, CNEL, the National Institute for Statistics, ISTAT, the Federations of Italian Development NGOs, and the Association of Banking Foundations (ACCRI). The search yielded official documents  and pertinent quantitative data.Due to very limited findings of some relevance, we then extensively explored the websites and databases of relevant Italian Institutions and non governmental organizations including: the Ministry of Foreign Affairs (MFA), the Parliament, Regions, Interregional and Municipal Institutions, the Ministry of Health (MoH) and the National Health Institute – We then searched the websites of relevant International Institutions including the World Health Organization (WHO), the World Bank and the OECD, as well as global initiatives such as the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria (GFATM) and the GAVI Alliance. From these sites we also retrieved quantitative data concerning the Italian participation in WHO programs and global initiatives. Quantitative data related to ODA of the OECD-CRS (Creditor Reporting System) database were analysed to compare Italy’s commitments and their trends with those of other countries belonging to the G7 group and of the total DAC . To this end we aggregated the two DAH related categories: Health (OECD-DAC code 120) and Populations Policies/Reproductive Health (OECD-DAC code130).Osservatorio Italiano sulla Salute Globale - OISG), the Italian Medical Students Secretariat, Segretariato Italiano Studenti in Medicina – SISM, the Italian Society of Migrations Medicine  and the Italian Network for Global Health Education .Information regarding global health advocacy and education was obtained through websites of leading civil society associations and networks such as the Italian Global Health Watch  peer reviews , several parliamentary attempts at reform have failed ,2. ItalyAziende Sanitarie Locali, ASL), are allowed allocating a limited portion of their annual budget to international cooperation initiatives [In addition to central authorities, Italian regions and autonomous provinces, have adopted laws to regulate decentralised international cooperation activities. Five regions  have also introduced specific regulations for their health development aid and established dedicated offices within their Regional Health Departments . Accorditiatives . Since ttiatives ,7.In addition, Italy’s National Civil Protection department also participates in international relief operations, humanitarian aid, and “post-emergency” reconstruction projects  at the sites of natural disasters.However, the lack of any mechanism to ensure policies are coherent with development objectives, make institutional co-ordination and monitoring difficult. In an attempt to respond to the challenge, in 2010, the MFA and the MEF jointly established an Inter-institutional Development Cooperation Board, open to representatives of central, regional and local public administrations, the corporate sector, academia, and NGOs. The vision is one of a “whole country approach” to development cooperation intended to reduce fragmentation and to build synergies among all the public and private stakeholders of the “System Italy” . In pracRegarding development cooperation in health, the twenty year-old DAH guiding principles  were revIn 2012, Italy’s net ODA amounted to 0.13% of its Gross National Income (GNI), far below the UN and EU’s targets of 0.7% for EU15 member states by 2015 .Based on OECD’s CRS  Italy coThe same data series show that over the period 2001–2011 Italy’s ODAH lags far behind that of its fellow G7 countries in absolute terms  Figure . HoweverFor years, Italy’s bilateral ODAH initiatives followed two main strategic lines: support to national and local health systems . Local oBesides supporting specific WHO-led initiatives through extra-budgetary contributions, Italy did not enter into global public-private partnerships until the GFATM’s launch at the Genoa G8 summit in 2001, which was itself the result of an “Tormented run-up” whereby economic actors heavily influenced the original agenda proposed by the Italian chaired G8 summit, which only a few months earlier was making explicit reference to the unaccomplished targets of Alma-Ata and recalled the ineffectiveness of selective approached to disease control . Indeed,Since its establishment in 2002, the GFATM became the most important beneficiary of Italian ODAH. With a total contribution of US$ 1008.3 million (2001–2009) Italy became GFATM’s eighth largest donor with a seat in GFATM’s board. However, Italy’s contribution has been unstable. For instance, in 2006 and in 2009, no contributions were made to the GFATM; Italy made up for this by honouring the pledges for 2008 in advance to regain credibility , althougOther global health initiatives received Italian support, including: the Global Polio Eradication Initiative  ; Roll BaNotwithstanding the concerns about supply-driven funding and earmarking of resources channelled through innovative financing mechanisms  and the The MoH and the ISS also undertake DAH interventions and have set up specialised offices for these activities.The MoH is involved in many twinning projects with new EU-member countries, non-EU Mediterranean countries, and countries that were part of the former Soviet Union. These projects often involve the ISS, regional governments, research institutions, offices of the SSN, and healthcare providers . AdditioISS is involved in DAH through the development of networks for promoting evidence-based medicine, health information systems, and training. Partner countries include China, South Africa, the Central Asian Republics, and multiple countries in Latin America, the Balkans, and the Middle East. ISS also provides humanitarian and technical assistance in collaboration with other international agencies .In the past the SSN and its principles represented a model for some low- and middle-income countries pursuing a universalistic approach. This was the case of the Brazilian Unified Health System  to whose development the Italian Development Cooperation contributed in the 1980’s .Since the late 1990s, Italian regional governments have increasingly undertaken development cooperation activities, primarily in the health sector, which accounts for a large part of their budgets . The regThe total financial contribution of the regional and municipal governments to overall Italian DAH is difficult to estimate . InformaOther Italian actors play an increasingly relevant role in global health. According to the most recent data, there are 221,412 non-profit organizations in Italy, including 4,720 foundations. 1,433 of them are involved in international cooperation and solidarity activities, including health . Non-proItaly is also home to many faith-based organizations that provide health services in low-income countries. Despite being independent and having international constituencies, they often rely on Italian personnel and refer to the Italian government and embassies for institutional support.Large Italian corporate foundations and banking foundations have also displayed an increasing interest in being involved in global health issues. Banking foundations represent 88 non-profit entities that were constituted with the assets of saving banks dissolved in the 1990’s in accordance with specific legislation . These fThe Italian corporate sector has also been showing an increasing interest in global health issues. For instance, the Italian Oil Company ENI and Giorgio Armani are among the few corporations that have contributed directly to the GFATM. In the countries where it has extraction activities , ENI has been funding several health system development projects, as well as activities of international organizations such as UNICEF and WHO, through its corporate foundation .ad hoc Coordinating body of academic institutions, the Coordinamento Universitario per la Cooperazione allo Sviluppo (CUCS) [Centro di Salute Internazionale) at the Public Health Institute at Bologna University (Bologna) [Finally, since 2002, the Italian Global Health Watch (OISG) has been raising public awareness about global health. With OISG’s support, the Italian academic community introduced global health courses in medical schools , business schools, and faculties of social sciences, economics and management . The Medo (CUCS)  Italian Bologna) , and theBologna) . DespiteItaly’s ODA financial performance has been poor for many years and the recent economic crisis is contributing to this downward trend with substantial cuts in traditional sources of Italian ODA. Waiting for a long overdue Reform, structural weakness of its governance and management structure further affects Italian ODA, which remains marked by fragmentation among various governmental bodies, lacking a clear political direction . These wTo be relevant, Italy, which pledged to be among the major players in supporting the GFATM and a number of new financing mechanisms, should instead push for the harmonization of global initiatives and their alignment with beneficiaries’ management systems, in line with international recommendations for DAH effectiveness . HarmoniLinee guida e indirizzi di programmazione) of the DGCS which focus on the repeatedly announced “whole country approach” [Indeed, this would be in line with DAC recommendations  and conspproach” ,18. To tSimilarly the peculiarity of the Italian approach to decentralized cooperation should be fully harnessed, as well as its contribution to the overall debate on the essence of human development as a social process primarily aiming at satisfying population needs, and the conditions for its sustainability. Nevertheless, the potential of such an approach, rests in wide spaces of dialogue and interaction, and cannot be harnessed without a substantial increase in public funding and a structural reform of Italian ODA. Combining responsibility for all aid in a single Government department rather that having it split among various government departments; high level representation (at Cabinet level) with strong leadership skills and political profiles; wide consultation with outside experts; focus on long-term strategies centred primarily on improved life conditions in low-income countries and resistance to short-term pressures, including the promotion of national commercial interests, have been indicated as a combination of factors for excellence of a development agency, based on the experience of the British Department for International Development (DFID) . WithoutThe potentials and energies that the Italian society can offer to the global health community are important and are currently undermined by country’s institutional and political weaknesses. The raise of Universal Health Coverage (UHC) on the global health agenda, despite ambiguities in the definition and little consensus in the concept , represeaIn 2012, reached a historic minimum of 0.13% of the GNI. The lowest among OECD-DAC countries.ACCRI: Association of Italian banking foundations; AMC: Advanced market commitments; ASL: Aziende Sanitarie Locali ; CNEL: Consiglio Nazionale dell’Economia e del Lavoro ; CRS: Creditor reporting system; CUCS: Coordinamento Universitario per la Cooperazione allo Sviluppo (Coordination of universities for development cooperation); DAC: Development assistance committee; DAH: Development assistance in health; DFID: Department for international development; DGCS: Direzione Generale per la Cooperazione allo Sviluppo ; EU: European union; GFATM: Global fund to fight HIV/AIDS, tuberculosis and malaria; GNI: Gross national income; IFFIm: International finance facility for immunisations; IFI: International financial institutions; ISS: Istituto Superiore di Sanità ; ISTAT: National institute fro statistics; MEF: Minister of economy and finance; MFA: Ministry of foreign affairs; MoH: Ministry of health; NGOs: Non governmental organizations; ODA: Official development assistance; ODAH: Official development assistance in health; OECD: Organisation for economic cooperation and development; OISG: Osservatorio Italiano sulla Salute Globale ; RIISG: Rete Italiana per l’Insegnamento della Salute Globale ; SIMM: Società Italiana di Medicina delle Migrazioni ; SISM: Segretariato Italiano Studenti in Medicina ; SSN: Servizio Sanitario Nazionale ; SUS: Sistema Unico de Saude ; SWAp: Sector wide approach; UHC: Universal health coverage; WHO: World health organization.The authors declare that they have no competing interests.EM, FT and GP conceived the original idea for the paper, designed the conceptual framework and equally contributed to the literature review and analysis of the results. LG contributed to the literature review and data collection, and provided comments and edits on various drafts. EM and FT wrote the manuscript. All authors have read and approved the final manuscript.


European Journal of Psychotraumatology on intimate partner violence and mental health. The European Journal of Psychotraumatology has been growing, continuously contributing to the body of knowledge pertaining to mental health and psychology. We are honored to present this special issue of the European Journal of Psychotraumatology. The combination of intimate partner violence and psychological trauma is a very common occurrence and to target one of these problems implies managing both . This review looks at the outcomes of intimate partner violence on mental health and found that the most significant outcomes were depression, post-traumatic stress disorder, and anxiety. These authors also report that the severity of the outcome is dependent on the severity of the abuse.Intimate partner violence and mental health outcomes are not secluded to a single jurisdiction and women's experiences around the globe share similarity. “Predictors of change in mental health and distress among women attending a women's shelter,” based in Canada, focused on the mental health predictors of women who attended the shelter system more than once (Hoyeck, Madden, Freeman, Scott, & Bhandari, Providing possible solutions always provokes thought and further ideas about how we can help to alleviate these detrimental outcomes. “Effects of an intervention program for female victims of intimate partner violence on psychological symptoms and perceived social support” evaluates a three-phase intervention program for female victims with the purpose of increasing perceived social support (Hansen, Eriksen, & Elklit, Finally, “‘It will always continue unless we can change something’: Consequences of intimate partner violence for indigenous women, children, and families” has a special focus on violence against indigenous women and girls (Burnette & Cannon, Sheila SpragueDivision of Orthopaedic SurgeryDepartment of SurgeryMcMaster UniversityHamilton, OntarioCanadaMiranda OlffDepartment of Psychiatry, Academic Medical CentreUniversity of Amsterdam &Arq Psychotrauma Expert GroupDiemen, the Netherlands


Cognitive impairment is known to occur in bipolar disorder (BD), even in euthymic patients, with largest effect sizes often seen in Verbal Learning and Memory Tasks (VLT). However, comparisons between BD Type-I and Type-II have produced inconsistent results partly due to low sample sizes.This study compared the performance of 183 BDI with 96 BDII out-patients on an adapted version of the Rey Verbal Learning Task. Gender, age, years of education, mood scores and age at onset were all used as covariates. Current medication and a variety of illness variables were also investigated for potential effects on VLT performance.BDI patients were significantly impaired relative to BDII patients on all five VLT outcome measures after controlling for the other variables [Effect Sizes=.13–.17]. The impairments seem to be unrelated to drug treatment and largely unrelated to illness variables, although age of onset affected performance on three outcome measures and number of episodes of mood elevation affected performance on one.This study used historical healthy controls. Analysis of potential drug effects was limited by insufficient participants not being drug free. Cross-sectional nature of the study limited the analysis of the potential effect of illness variables.This study replicates earlier findings of increased verbal learning impairment in BDI patients relative to BDII in a substantially larger sample. Such performance cannot be wholly explained by medication effects or illness variables. Thus, the cognitive impairment is likely to reflect a phenotypic difference between bipolar sub-types. •Largest sample to directly compare cognition in Bipolar I and II subtypes.•BDI patients impaired relative to BDII on all five verbal memory measures.•Results remain after adjusting for age, gender, education, mood, and onset age.•Deficits appear to be unrelated to medication and illness effects.•Cognitive impairment differences a potential phenotype of bipolar subtypes. Meta-anFor example, A systematic review of primary studies of cognition in BDII  reflecteFinally, All of the studies and reviews that have considered cognitive impairment in BDII patients have been interested in describing a cognitive endophenotype for each subtype that could be the result of underlying neurobiological differences in the subtypes. However, the studies have also noted the potential confounding effects of variables related to illness presentation  and treatment (greater use of antipsychotics in BDI patients).N=279) in an attempt to clarify the existing literature.The current study investigated cognitive performance of BDI and BDII patients on a verbal learning and memory task in a relatively large patient sample  age; (ii) years of education; (iii) current mood; (iv) age at onset; (v) number of prior episodes of mood elevation (i.e. manic or hypomanic); (vi) number of prior depressed episodes; (vii) number of prior manic hospitalisations; (viii) number of prior depressed hospitalisations; and (ix) drug treatment history. Participants undertook a very brief battery consisting of four neuropsychological tests, although data presented here are only from an adapted form of the Rey Verbal Learning Task  as this The study received ethical approval from a local National Research Ethics Service committee  of the UK National Health Service. Each participant was required to provide written confirmation of their consent to participate.2.2post-hoc analysis was undertaken that used healthy controls taken from two previously published cohorts ; score on Short Delay (ShortDelay); score on Long Delay (LongDelay); score on Recognition (Recognition); score for Recognition minus score for False Positives (Recog-FP). Three other cognitive tasks were also used although the data from these other tasks are not reported here. The other tasks in the brief battery of neuropsychological tests were: an emotional face recognition task and an emotional memory task both taken from the Emotional Test Battery ; and a r2.4www.truecolours.nhs.uk; Participants were invited to enrol in the OXTEXT programme only if their medical notes indicated mood stability over several months. All participants were registered to submit mood ratings on a weekly basis by answering text or email prompts from the True Colours self-monitoring system  by regressing diagnosis along with age, gender, years of education, mood (both depression and mood elevation scores) and age of illness onset against performance score for each of the five outcome measures. Years of education was used as a proxy for pre-morbid IQ as these variables have been previously shown to be highly correlated . We covaIn order to investigate potential drug effects on subtype performance differences, patients were coded for six binary (yes/no) drug status variables: lithium, anticonvulsants, antipsychotics, antidepressants, benzodiazepines and drug free. Each drug status variable together with diagnosis, age, gender, years of education, mood and age of onset were then regressed against performance score for each of the five outcome measures except for drug free as this had less than 10% of patients in one of the drug categories. Drug data was available for between 82% and 85% of our sample depending on the drug type.Similarly, in order to investigate potential effects of illness severity measures on cognitive performance, number of depressed episodes, number of episodes of mood elevation, total number of episodes, number of hospitalisations due to depression, number of hospitalisations due to mania and total number of hospitalisations were each fitted separately into the regression model with diagnosis, age, gender, years of education, mood and age of onset for each of the five outcome measures.Statistical analysis was conducted in SPSS version 21 and all statistical tests were two-tailed.3χ2(1)=.19, p=.66 ], age , years of education , mood elevation score , and age of onset . However, the groups did differ in depression score  with BDII having a significantly higher level of residual depression. Similarly, the groups differed on the prevalence of antidepressant treatment  with 32% of BDI patients and 48% of BDII patients on antidepressants. There was a trend for a difference in prevalence of Lithium treatment  with BDI patients more likely to be taking lithium (37% BDI vs 25% BDII). However, the groups did not differ on prevalence of antipsychotic treatment , anticonvulsant treatment , benzodiazepine treatment , or drug free status .t(238)=1.5, p=.13] but did on number of depressive episodes  and total episodes , with BDII patients having more depressive episodes and consequently more total episodes. In contrast, the groups did not differ on number of depressive hospitalisations . By definition, none of the BDII patients had any manic hospitalisations and because the BDI patients had significantly more manic hospitalisations than zero , total hospitalisations were also more common for BDI .The groups did not differ on number of episodes of mood elevation  with early age of onset associated with poorer performance.The covariant age of onset significantly predicted performance on three of the five VLT measures   with taking benzodiazepines being related to poorer performance but had no effect on any of the other performance measures .The regression analysis comparing the performance of the patients on Lithium and those Lithium free on the five outcome measures whilst also accounting for the effects of diagnosis, age, gender, years of education, mood, and age of onset suggested that lithium did not affect any of the outcome measures  and age of illness onset. This finding is consistent with the results of several primary studies  and a mepost-hoc comparison of our BDII patients with healthy controls taken from two previous studies of VLT performance in bipolar patients recruited from the same geographical area  appear common to the two sub-types, such as right lateral ventricular enlargements  and voluWith respect to possible drug effects on performance, our analysis found no basis for the potential claims that lithium may improve cognitive performance via reduced oxidative stress  nor thatAlthough some studies have suggested that illness variables may be predictive of cognitive decline , our fin4.1As with any clinical study, a major potential limitation is sampling bias. However, it is noted that the BDI and BDII patient groups presented here were well matched for a variety of confounding variables including age, gender, years of education, mood elevation score, and age of onset. These variables were still used as co-regressors as they are known to affect cognitive performance and we wished to estimate the effect size of sub-diagnosis free from such other effects. Unfortunately, the patient groups were not matched for depression mood score  or prevalence of lithium medication and antipsychotics medication (BDI patients were more frequently taking both medications). However, depression mood score was also used as a co-regressor in all sub-type analyses and sub-type diagnosis was also included in the drug effect analysis to attempt to control for these confounds. It is also likely that these group differences were confounds by indication and represent underlying differences in symptom presentation and treatment between the two sub-types rather than simple sampling bias. Similarly, the groups were well matched on two further illness variables  but neither on number of depressive episodes and hence number of total episodes (BDII higher for both) nor on the number of manic hospitalisations and hence number of total hospitalisations (BDI higher for both). Again these are considered to be confounds by indication rather than sampling bias per se.post-hoc analysis using healthy controls from two prior which used a similar duration of test battery studies and recruited from the same geographical area  under its Programme Grants for Applied Research Programme (Reference number RP-PG-0108-10087).This study represents independent research funded by the No conflict declared.This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Reference Number RP-PG-0108-10087). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Guy Goodwin and John Geddes are NIHR Senior Investigators.Additional funding for this work was provided by a Wellcome Trust Strategic Award .


Lower levels of physical activity (PA) and sedentary behaviour (SB) have been associated with increased cardiometabolic risk among children. However, little is known about the independent and combined associations of PA and SB as well as different types of these behaviours with cardiometabolic risk in children. We therefore investigated these relationships among children.The subjects were a population sample of 468 children 6–8 years of age. PA and SB were assessed by a questionnaire administered by parents and validated by a monitor combining heart rate and accelerometry measurements. We assessed body fat percentage, waist circumference, blood glucose, serum insulin, plasma lipids and lipoproteins and blood pressure and calculated a cardiometabolic risk score using population-specific Z-scores and a formula waist circumference + insulin + glucose + triglycerides - HDL cholesterol + mean of systolic and diastolic blood pressure. We analysed data using multivariate linear regression models.Total PA was inversely associated with the cardiometabolic risk score , body fat percentage , insulin , triglycerides , VLDL triglycerides , VLDL cholesterol , LDL cholesterol  and HDL triglycerides  and directly related to HDL cholesterol  adjusted for age and gender. Unstructured PA was inversely associated with the cardiometabolic risk score , body fat percentage , insulin , triglycerides , VLDL triglycerides  and VLDL cholesterol  and directly related to HDL cholesterol . Watching TV and videos was directly related to the cardiometabolic risk score , body fat percentage , waist circumference  and systolic blood pressure . Resting was directly associated with the cardiometabolic risk score , triglycerides , VLDL triglycerides , VLDL cholesterol  and LDL cholesterol . Other types of PA and SB had less consistent associations with cardiometabolic risk factors.The results of our study emphasise increasing total and unstructured PA and decreasing watching TV and videos and other sedentary behaviours to reduce cardiometabolic risk among children.NCT01803776.ClinicalTrials.gov Identifier: Overweight and obesity among children are a major public health problem in developed countries including Finland-3. The eThe metabolic syndrome represents a cluster of cardiometabolic abnormalities, including abdominal obesity, insulin resistance, glucose intolerance, dyslipidaemia and elevated blood pressure,9. The dLower levels of physical activity (PA) and higher levels of sedentary behaviour (SB) have been associated with an increased overall cardiometabolic risk,13,16,17We investigated the independent and combined associations of PA and SB as well as different types of these behaviours with overall cardiometabolic risk using cardiometabolic risk score and with individual cardiometabolic risk factors.The present study is based on the baseline data from the Physical Activity and Nutrition in Children (PANIC) Study, which is an ongoing exercise and diet intervention study in a population sample of primary school children from the city of Kuopio, Finland. Altogether 736 children aged 6–8 years who started first grade in primary schools in 2007–2009 were invited to participate in the baseline examinations between October 2007 and November 2009. Of the invited children, 512 (70%) participated. Complete data on variables used in the analyses were available for 468. The study protocol was approved by the Research Ethics Committee of the Hospital District of Northern Savo. All participating children and their parents gave informed written consent.Habitual PA during a usual week was assessed by the PANIC Physical Activity Questionnaire administered by the parents at home. The types of PA included organised sports, structured exercise, unstructured PA, commuting to and from school and PA during recess. The frequency of each type of PA, expressed in sessions per week, and the duration of a single session of each type of PA, expressed in hours per session to accuracy of half an hour, were asked. The amount of each PA type was calculated by multiplying frequency with duration and was expressed in minutes per day. The amount of total PA was calculated by summing the amounts of each PA type and was expressed in minutes per day. All children in the first grade had 90 minutes of physical education per week that was included in total PA.Habitual SB during usual five weekdays and two weekend days was also assessed by the PANIC Physical Activity Questionnaire administered by the parents at home. The types of SB included watching TV and videos, using a computer and playing video games, using a mobile phone and playing mobile games, listening to music, playing a musical instrument, reading, writing, drawing, doing arts and crafts, playing board games and resting. Electronic media time (EMT) was calculated by summing watching TV and videos, using a computer and playing video games and using a mobile phone and playing mobile games. The amount of total SB was calculated by summing the times spent in each SB and was expressed in minutes per day weighted by the number of weekdays and weekend days.We validated the PANIC Physical Activity Questionnaire using the Actiheart monitor combining heart rate and accelerometry measurements  in a subsample of 38 children examined at baseline of the PANIC Study. Total PA measured by the questionnaire correlated positively with total PA measured by the Actiheart monitor .The number of meals and snacks per day, food consumption and nutrient intake were assessed by food records on four consecutive days.Body composition and blood pressure were assessed by a research nurse at Institute of Biomedicine, University of Eastern Finland. Body height was measured by a wall-mounted stadiometer and body weight by the Inbody 720® bioimpedance device. Body maVenous blood samples were taken after a 12-hour overnight fast by a laboratory nurse at Institute of Biomedicine, University of Eastern Finland. The blood samples were analysed at Laboratory of Clinical Chemistry at University Hospital of Kuopio. The assessment of plasma glucose, total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol and triglycerides as well as serum insulin from 12-hour fasting samples has been explained previously. Very loA continuous cardiometabolic risk score variable was calculated as the sum of Z-scores of waist circumference, insulin, glucose, triglycerides, HDL cholesterol and the mean of systolic and diastolic blood pressure that are specific for the PANIC study population. The Z-score of HDL cholesterol was multiplied by -1, because HDL cholesterol is inversely associated with cardiometabolic risk. A higher cardiometabolic risk score indicates a less favourable cardiometabolic risk profile.T-test for independent samples. The associations of different types of PA and SB with cardiometabolic risk score and individual cardiometabolic risk factors were analysed using linear regression models and standardised regression coefficients (β) adjusted for age and gender. Total PA and EMT were divided into three groups of similar size at tertiles of the distribution of these variables (thirds). Cardiometabolic risk score and individual cardiometabolic risk factors were compared across the thirds of PA and EMT using general linear models (GLM) adjusted for age and gender to explore possible nonlinear associations. The combined associations of PA and EMT with cardiometabolic risk factors were analysed by dichotomising PA and EMT at the median and comparing cardiometabolic risk factors in the four groups using GLM adjusted for age and gender. Associations with a P-value <0.05 were considered statistically significant.Statistical analyses were performed with the SPSS software, Version 21.0 . To normalise skewed distributions, a natural logarithmic transformation was performed for waist circumference and triglycerides, VLDL triglycerides, VLDL cholesterol and HDL triglycerides and a square-root transformation was performed for insulin. Differences in basic characteristics betweengenders were tested with the The girls had lower levels of PA and EMT, higher levels of most other types of SB, a poorer cardiorespiratory fitness and less favourable levels of most cardiometabolic risk factors than the boys Table .Total PA was inversely associated with cardiometabolic risk score, body fat percentage, insulin, triglycerides, VLDL triglycerides, VLDL cholesterol, LDL cholesterol and HDL triglycerides and directly related to HDL cholesterol adjusted for age and gender Table , total SUnstructured PA was inversely associated with the cardiometabolic risk score, body fat percentage, insulin, triglycerides, VLDL triglycerides and VLDL cholesterol and directly related to HDL cholesterol adjusted for age and gender Table , total SOrganised sports were inversely associated with body fat percentage and LDL cholesterol and directly related to HDL cholesterol and diastolic blood pressure adjusted for age and gender Table , total SPA during recess was inversely related to the cardiometabolic risk score, body fat percentage, waist circumference, insulin and systolic and diastolic blood pressure adjusted for age and gender Table , total SPA during commuting to and from school was inversely associated with HDL triglycerides adjusted for age and gender Table , total STotal SB was directly associated with triglycerides adjusted for age and gender Table , total PEMT was directly associated with the cardiometabolic risk score and triglycerides adjusted for age and gender Table . The assWatching TV and videos was directly related to the cardiometabolic risk score, body fat percentage, waist circumference and systolic blood pressure adjusted for age and gender Table . The assUsing a computer and playing video games was directly associated with triglycerides and VLDL cholesterol adjusted for age and gender Table  as well Resting was directly associated with the cardiometabolic risk score, triglycerides, VLDL triglycerides, VLDL cholesterol and LDL cholesterol adjusted for age and gender Table  as well Listening to music was directly related to HDL cholesterol and HDL triglycerides adjusted for age and gender Table  as well The cardiometabolic risk score decreased with increasing thirds of total PA after controlling for age and gender Figure . Also boWe found that lower levels of total PA, particularly unstructured PA, and higher levels of SB, especially watching TV and videos and resting, were associated with an increased cardiometabolic risk. The combination of lower levels of total PA and higher levels of EMT was related to the highest cardiometabolic risk.There are a number of studies on the associations of PA and SB with overall cardiometabolic risk and overweight among children,13,16-20We found that total, unstructured and recess PA were inversely associated with fasting insulin independent of total SB, but the relationship between total PA and fasting insulin was largely explained by body adiposity. These results are consistent with the observation that PA improves insulin sensitivity by reducing body adiposity. PA has Our findings suggest that lower levels of total and unstructured PA and higher levels of total SB and resting are most consistently associated with unfavourable levels of lipids and lipoproteins and that most of these relationships were independent of eating behaviours and body adiposity. PA has been inversely associated with triglycerides and LDL cholesterol and directly related to HDL cholesterol in some studies among children,32-35. HWe found that only PA during recess was inversely associated with systolic and diastolic blood pressure among children. Organised sports were directly associated with diastolic blood pressure, although they were inversely related to body adiposity. Moreover, watching TV and videos was directly associated with systolic blood pressure. One explanation for our observations is that recess PA may relief emotional stress and thereby reduce sympathetic activity and lower blood pressure and that organised sports and watching TV and videos may have opposite effects among children. In previous studies, evidence on the association of PA with blood pressure among children has been limited and inconclusive.Children in our study sample spent on average six hours per week in unstructured PA and two hours per week in PA during recess. Both of these common types of PA were inversely associated with cardiometabolic risk, suggesting that an increase in unstructured and recess PA could reduce cardiometabolic risk at the population level. Children in our study sample spent almost two hours per day watching TV and videos and with other electronic media. EMT was also directly related to cardiometabolic risk. Therefore, more attention should be paid to the reduction of screen time, particularly if it tends to reduce time spent in PA.The strengths of our study include a rather large population sample of healthy girls and boys and comprehensive and detailed assessments of cardiometabolic risk factors and possible confounding factors. We used a continuous cardiometabolic risk score, because it is a more sensitive way to describe cardiometabolic risk than dichotomous definitions for metabolic syndrome,15,39,40The results of our study emphasise increasing total and unstructured PA, decreasing watching TV and videos and other sedentary behaviours and avoiding unhealthy eating to reduce cardiometabolic risk among children.PA: Physical activity; SB: Sedentary behaviour; EMT: Electronic media time.The authors declare that they have no competing interests.JV participated in the collection of data, conducted the statistical analyses and drafted the manuscript. AME, AV, TT, NL, PK, EKL, JA and HML participated in the data collection and drafted the manuscript. DEL helped in the data analysis and drafted the manuscript. VL helped in obtaining funding, participated in the data collection and drafted the manuscript. TAL planned and conceived the study, was responsible for obtaining funding and lead drafting of the manuscript. All authors read and approved the final manuscript.