Jenny Hill and colleagues discuss the importance of antenatal care services in providing pregnant women with a long-lasting insecticide treated net for the prevention of malaria in both the mother and infant.Please see later in the article for the Editors' Summary Long-lasting insecticide treated nets (LLINs) are a powerful public health tool and, when used by pregnant women, contribute to improving maternal, neonatal, and infant health, with lasting benefits to the developing child.Use of LLINs among pregnant women is well below national and international targets; the median use of an insecticide treated net (ITN) the previous night among pregnant women across 37 countries for 2009–2011 was 35.3% ; ITN use was higher in areas with both a high disbursement of funds for malaria control and a lower per-head gross domestic product.Routine antenatal care (ANC) services constitute an important delivery channel that ensures pregnant women who attend an ANC clinic at least once (77% in sub-Saharan Africa) are covered with a LLIN from their first ANC visit in each pregnancy and plays an important role in maintaining population-level coverage between campaigns, particularly for women who become pregnant between campaigns and for infants born outside of campaign years.The majority of LLINs delivered from 2010–2012 in sub-Saharan Africa were through mass campaigns as countries sought to reach the 80% coverage target, and some of the LLINs used in these campaigns were re-allocated from routine ANC delivery.Going forward, national malaria programmes and donors alike will have to make difficult decisions to balance costs with the benefits and impact of investments in LLINs. Where choices must be made, high-risk groups (pregnant women and children under 5 years of age) should be prioritized for the same reason these groups were targeted under the pre-universal coverage WHO strategy.The use of insecticide treated nets (ITNs), and subsequently the new generation of long-lasting insecticide treated nets (LLINs), has been a core malaria prevention strategy for more than two decades The strategy for achieving and maintaining universal coverage outlined by the RBM Partnership involves a combination of strategies based on mass campaigns, either target-specific or population-wide, to rapidly scale up coverage (“catch up”), complemented by continuous distribution through routine health services, including antenatal clinics, child health clinics, and expanded programme on immunisation (EPI) services (“keep up”) Use of ITNs among pregnant women is well below national and international targets; a recent meta-analysis of national survey data in 37 countries for the years 2009–2011 estimated the median use of an ITN the previous night among pregnant women was 35.3% (range 5.2%–75.5%) Plasmodium falciparum infections in pregnancy P. falciparum placental infection at some stage of pregnancy, accounting for 41% of the estimated 27.6 million live births in sub-Saharan Africa in 2010 LLINs are a powerful public health tool and, when used by pregnant women, contribute to improving maternal, neonatal, and infant health, with long-lasting benefits to the developing child. Worldwide, an estimated 125 million pregnancies are at risk from malaria each year LLINs have been proven in clinical trials and in field programs to substantially reduce the adverse consequences of malaria in pregnancy, reducing maternal anaemia, severe anaemia, peripheral and placental malaria, and low birth weight The delivery of free or subsidized LLINs (or vouchers) to pregnant women through ANC services is a key strategy for controlling malaria and increases coverage and use by both pregnant women Routine ANC services constitute an important delivery channel that ensures pregnant women who attend ANC at least once (77% in sub-Saharan Africa) In addition, campaign delivery of LLINs to households with pregnant women In short, the distribution of LLINs through routine services, ANC services included, is an important strategy and will require a sustained commitment to health systems strengthening; and neglecting this strategy will impede a country's ability to maintain universal coverage over the longer term. Delivery of LLINs through ANC has been observed to increase pregnant women's attendance at ANC clinics The policy shift towards universal coverage reflects huge progress in malaria control and is a laudable goal that has injected enthusiasm into the global malaria community and has attracted calls for elimination. Notwithstanding, funding for malaria control peaked at $US2 billion in 2011 Despite recent encouraging statistics on funding for continuous delivery systems, including ANC, increasing from 22% in 2008–2010 of all funding commitments to 42% for the 2012–2016 funding interval These trends prompted a policy recommendation from the WHO Vector Control Technical Expert Group to the Malaria Policy Advisory Committee (MPAC) noting that, although universal coverage was still the priority, LLINs distributed through routine channels such as ANC and EPI should continue regardless of mass campaign timing, and that nets for routine distribution should not be diverted to campaigns. This recommendation has been approved by MPAC The shortfall in funding for malaria, generally, and for LLINs, in particular, calls for endemic country programs, malaria donors, implementing agencies, and partners to adopt the most cost-effective strategies to deliver this life-saving intervention. The challenge will be to ensure that population-wide coverage does not fall while maintaining highest priority for pregnant women and children. The arguments for maintaining the ANC distribution mechanism are strong. This mechanism reaches the highest risk population of mothers and their newborns, takes advantage of the fact that most pregnant women visit ANC clinics, is the only antenatal malaria prevention intervention that provides protection in the first trimester of pregnancy, and adds an important benefit to the focused ANC delivery system as it serves to encourage ANC attendance.Going forward, national malaria programmes and donors alike will have to make difficult decisions to balance costs with the benefits and impact of investments in LLINs. WHO's MPAC has recommended that routine LLIN distribution (through ANC and the EPI) continue “before, during, and after” campaigns, and that recommendation needs to be adopted by Ministries of Health and donors


Alternatives to traditional hospital acute care for medical disorders address to benefits for the Health Systems, which experience budget constraints . The comPPPM experience and proposed models need to be monitored and assessed not only on the basis of financial sustainability and patient’s satisfaction, as currently is done by public and private institutions, but also by carefully designed research projects. These should be independently supported (such as EU funding). These must have the goal of overcoming the gap among predictive, preventive and personalized medicine mainly within a comprehensive urban daily life scenario. Calls must encompass the actual pre-requisite and promotion of the professional quality of staff skilled 1) in sustainable non-invasive diagnostic procedures, 2) in non-pharmacological intervention , 3) in translational research and 4) in timely dissemination of the most high impact information. An effective training of professionals toward these PPPM directives and planned articulated collaborations with of Academy, Health Institutions, Cities, non-profit organization and SMEs should be included in any project.


The phenomenon of keystone actors represents an increasingly important feature of the human-dominated world. Sustainable leadership by keystone actors could result in cascading effects throughout the entire seafood industry and enable a critical transition towards improved management of marine living resources and ecosystems.Keystone species have a disproportionate influence on the structure and function of ecosystems. Here we analyze whether a keystone-like pattern can be observed in the relationship between transnational corporations and marine ecosystems globally. We show how thirteen corporations control 11-16% of the global marine catch (9-13 million tons) and 19-40% of the largest and most valuable stocks, including species that play important roles in their respective ecosystem. They dominate all segments of seafood production, operate through an extensive global network of subsidiaries and are profoundly involved in fisheries and aquaculture decision-making. Based on our findings, we define these companies as  Globalization is increasing the economic power of transnational corporations in relation to national governments, but the effects of this gradual shift are largely unknown . The worGlobally increasing demand for seafood, a critical source of protein for human wellbeing, is shaping marine ecosystems and the harvest of wild capture fisheries and aquaculture production worldwide , 11. GloThe interplay of transnational corporations and ecosystems across geographical scales may represent an important feature of the global social-ecological system , 20. AltIn this paper, we analyze whether or not a keystone pattern  can be oIn order to investigate the pattern of revenues for seafood companies, we examined two recent global fishing industry reports , 13 and In the following, we describe; how we documented the global activities of these companies, including their catch of wild species and production of aquaculture species and the economic value of these species; how these catch and production volumes were linked to global volumes; and the extent to which these companies participate in fisheries and aquaculture policy and management processes.IntraFish (Fishing News), FIS, Undercurrentnews, and Minato-Tsukiji , OECD (France), the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR) Secretariat  and the Marine Stewardship Council , as well as with fisheries management agencies , journalists , environmental NGOs  and scientists  for further company specific information. We also used additional data from shsource  as well We systematically documented the number of species handled by each company and the number of countries and territories to which they are connected , using the information sources described above and in Engraulis ringens and the stocks with the 2nd largest , and the 3rd and 6th largest  catch volumes. Atlantic herring Clupea harengus was the species with the 4th largest catch volume in 2012, but as this species is widely dispersed over the entire North Atlantic, and was often reported together with other small pelagic species by the investigated companies, we instead pooled information on small pelagic species  from the entire North East Atlantic region . Due to a lack of data availability and ambiguity in the use of the name “mackerel”, we were unable to include Chub mackerel Scomber japonicas (the stock with the fifth largest catch volume in 2012).To estimate the role of these largest companies in global fisheries catches, we investigated their activities in relation to the largest and economically most important wild-capture stocks, representing whitefish, tuna, and small pelagic species . We collMerluccius spp, and toothfish (Patagonian toothfish Dissostichus eleginoides and Antarctic toothfish D. mawsoni combined). Namibian hake is (together with Argentinean hake) the second largest (by volume) white fish species [These selected stocks include species that, by volume and value, dominate their respective segments of seafood production , or whiteleg shrimp, the largest component of shrimp aquaculture  global salmon production , b) shr in 2010 ) and c)  species ). AquacuThe economic value of the investigated wild fish stocks and aquaculture species in 2012 was determined using species specific values (USD/ton), derived from a seafood investment report , expert We used data on quotas and catches produced in 2012 (or 2013 in one case) by the respective company and its present subsidiaries, accounting for known overlap between companies, to avoid double counting the proportion of each stock caught or produced. We exclusively relied on published and official data, combined with information provided directly by the respective companies, without accounting for estimates of illegal or underreported catches or production volumes, for any of the species included. Some companies were also involved in the production of feeds for terrestrial animals, but these volumes were not included in our analysis. Company specific volumes were compared to global and regional volumes, using data from the FAO –45, or oWe studied participation in globally relevant institutions as a proxy for the potential of the companies to influence fisheries and aquaculture policy and management. We quantified the number of occasions that a company was registered as a participant during the meetings of the thirteen Regional Fisheries Management Organizations (RFMOs). These organisations together represent an established mechanism for managing fisheries, including stocks of tuna, pollock, toothfish and some small pelagic species. We used the most recent meeting documents from the main governing body of these RFMOs, including five tuna RFMOs: the Commission for the Conservation of Southern Bluefin Tuna (CCSBT), Inter-American Tropical Tuna Commission (IATTC), International Commission for the Conservation of Atlantic Tunas (ICCAT), Indian Ocean Tuna Commission (IOTC) and the Western and Central Pacific Fisheries Commission (WCPFC), and eight non-tuna RFMOs: Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR), Convention on the Conservation and Management of Pollock Resources in the Central Bering Sea (CCBSP), General Fisheries Commission for the Mediterranean (GFCM), North East Atlantic Fisheries Commission (NEAFC), North Atlantic Salmon Conservation Organization (NASCO), Northwest Atlantic Fisheries Organization (NAFO), South-East Atlantic Fisheries Organization (SEAFO) and South Pacific Regional Fisheries Management Organization (SPRFMO) . We alsoIn addition we evaluated the role of the investigated companies in establishing, or the extent they were members in three international organizations identified as important industry initiatives for aquaculture management and certification —namely, keystone actors.The investigated companies were all identified as playing a disproportionate role in marine social-ecological systems. They a) dominate global seafood volumes and revenues, b) are globally connected through subsidiaries and other networks of operations, c) dominate globally relevant segments of seafood production, and d) are represented in global fisheries and aquaculture policy and management. When combined, these aspects provide them with a disproportionate role in the global seafood production industry and a disproportionate ability to influence the dynamics of marine ecosystems worldwide. We label these corporations The average annual revenues of the 160 largest companies in 2012  exhibit Thirteen of the sixteen largest companies operate directly in marine ecosystems through their harvesting and farming activities around the world, with headquarters in Norway (four companies), Japan (three), Thailand (two), Hong Kong, Korea, Spain and the USA (one each), see . The comThese transnational corporations are catching, farming and handling more than 208 species from 974 subsidiaries and associates operating in 102 countries and territories . They arWe conservatively estimate that these companies combined handle between 9 and 13 million tons of wild-caught fish annually (shellfish included), corresponding to 11–16% of the total global marine catch . The catThe keystone actors together control 19–40% of several of the world’s largest or most valuable capture fisheries , includiSeveral of the companies produce high value predatory species in aquaculture, including 35% of global salmon and trout volumes and 38% of farmed bluefin tuna . The stuWe investigated to what extent the globally connected actors participated in policy processes and found that three of the investigated companies were among the few  that were identified as active in more than one regional fisheries management organization (RFMO). They were active either as observers or as members of national delegations. The Korean company was the most active company overall, participating in six RFMOs. In addition to direct representation by the parent company and its subsidiaries, keystone actors are also indirectly participating in RFMOs through influential industry organizations . KeystonEleven out of the thirteen companies were also actively engaged in the development of aquaculture management and certification processes, through their central role in one or several industry organizations that are actively working to influence the global context of aquaculture production .keystone actors that together dominate global seafood revenues. These companies play a critical role in increasing the connectivity in seafood networks and thereby operate as key nodes in what we here refer to as a global social-ecological system. This increasing connectivity is a recent and rapidly evolving phenomenon  and contribute to the structure, function and resilience of their respective ecosystems. Fishing for such species can have both direct and indirect effects on associated species and ecosystems. Skipjack and yellowfin tuna fishing using fish aggregation devices (FADs) or long-lines generates bycatch of juveniles and associated vulnerable species, including bigeye tuna seabirds , 56. Fisseabirds  and largseabirds , 58. Addseabirds –40.The production of predatory fish in aquaculture is directly connected to marine ecosystems through the inclusion of wild fish in feeds . Salmon and shrimp are major consumers of aqua feeds . HoweveNot only do keystone actors have the ability to shape ecosystems—they also actively participate in policy-making. The ability of non-state actors, such as transnational corporations, to influence policies has been directly correlated to their degree of participation in global governance . We haveGlobally networked and vertically integrated companies, with an ability to influence policy-making, are resilient to disturbances that critically affect the survival of smaller companies, including financial system crises and instability, currency fluctuations, increasing fuel prices or changing fish stock dynamics . The gloPescanova, the 7th largest company in 2012, went bankrupt in 2013, but was, due to the resilience resulting from its global connectivity and diversification of activities (active in wild capture fisheries worldwide as well as in aquaculture), able to maintain its operations and trading activities despite the bankruptcy [As an example, nkruptcy . Other enkruptcy ).The current global sustainability challenge in fisheries  is thereNation states have traditionally formed the basis for governance of fisheries resources and the majority of existing institutions are designed around this assumed reality, as are global fisheries statistics. Our study reframes the responsibility for fishing in terms of transnational corporations, illustrating that 13 companies handled around 10 million tons of wild capture fish in 2012, whereas only 23 countries caught >1 million tons of wild fish that year . SeveralFishing industry firms can play a key role for sustainability  but keyskeystone actors are critical in shaping the future direction of seafood production and as a consequence, the future of marine ecosystems. There is mounting evidence that similar keystone actors exist in other sectors [Globalization has resulted in the emergence of a small number of resilient transnational seafood corporations, operating across the world. Such  sectors , 75. BasS1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.


In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC).Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC . A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7).We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors. Cervical cancer (CC) is the fourth most common cancer among women worldwide with an estimated 528,000 new cases and the fourth most common cause of female death from cancer with an estimated 266,000 deaths in 2012 . HPV genThe EPIC study is a large prospective cohort study including 521,448 participants  recruited between 1992 and 2000 through 23 centres in 10 European countries: Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom. Most of the EPIC participants were between the ages of 35 and 70 years. The study procedures have been described in detail elsewhere ; Italy : Comitato Etico Indipendente, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; Florence: Comitato Etico Locale Azienda Sanitaria di Firenze; Malmo: Ethics Committee of Lundst University; Netherlands (Bilthoven and Utrecht): The Medical Ethical Committee (METC = Medisch Ethische Toetsingscommissie) of the University Medical Center Utrecht (UMCU), Utrecht, the Netherlands; Norway: Regional ethical committee for Northern Norway and the Norwegian Data Inspectorate; Oxford: Scotland A Research Ethics Committee; Potsdam: Ethikkommission der Landesärztekammer Brandenburg Cottbus, Deutschland; Spain : CEIC Comité de Ética de Investigación Clínica; Turin: Human Genetics Foundation Torino: Ethics Committee; Umea: Umea Regional Ethical Review Board) and the Internal Review Board of the International Agency for Research on Cancer.Baseline characteristics for cases and non-cases included in the cohort analysis have been reported previously  11]. In. In11]. When analyses were restricted to parous women and mutually adjusted for number of FTP and age at first FTP, the effect of number of FTP for CIN3/CIS risk was maintained in the full cohort analysis , and was of borderline statistical significance in the nested case-control study . No associations were found for ICC risk.versus never users) and a lack of association for combined formulations (data not shown). The effect of progestin alone could not be assessed due to the low number of exposed subjects. For ICC, most exposed cases used some kind of combination of hormones showing a borderline inverse association . There were not enough cases to assess the effect of estrogen or progestin alone (data not shown). Concerning IUD use, a non significant inverse association with both CIN3/CIS and ICC risk was observed in the nested case-control study.When the combined effect of duration and recency of OC use was evaluated, the risk of CIN3/CIS declined progressively with increasing years since last use (data not shown). This pattern was not observed for ICC risk.In both study designs, the combined effect of number of FTP and duration of OC use was analyzed, and showed a significant increased risk of CIN3/CIS with increasing number of FTP within each category of OC use . Women wConcerning associations by histological type, the risk of SCC showed the same overall pattern: increased risk of CIS with number of FTP and years of OC use and decreased risk with years of HT use, and increased risk of invasive SCC with years of OC use and decreased risk with years of HT use (data not shown). Regarding adenocarcinomas, associations could not be evaluated accurately because of the small number of cases (52 cases in the cohort study and 33 cases in the nested case-control study for both in situ and invasive adenocarcinomas). Nevertheless, these analyses showed non significant and weak positive associations with number of FTP and OC use for invasive adenocarcinoma, and a non significant inverse association with HT use (data not shown).Analyses restricted to countries with screening programs  did not substantially change the magnitude of the associations for the several risk factors (data not shown).versus ICC . Current use and duration of OCs increased the risk of both CIN3/CIS and ICC although the associations were not statistically significant. HT use and duration was inversely and significantly associated with ICC. Finally, IUD use was inversely associated with both CIN3/CIS and ICC risk without statistical significance, although when we combined CIN3/CIS and ICC the significance emerged . Associations were broadly similar in analyses restricted to all cases and high-risk HPV seropositive controls and in analyses including only HPV seropositive cases and controls (data not shown), revealing a significant inverse association between IUD use and ICC among HPV seropositive women .The results of this large prospective cohort study show that certain endogenous and exogenous hormonal factors appear to be related to cervical carcinogenesis. Thus the risk of cervical pre-cancer increased with increasing number of FTP and duration of OC use, and decreased with increasing years since last OC use among past users. For ICC, the risk increased with number of abortions and duration of OC use, and decreased with increasing duration of HT. A reduced risk of ICC was also observed among IUD users in the nested case-control study. Globally the associations were somewhat stronger in the cohort study than in the nested case-control study. The case-control study is useful to support the results obtained in the cohort study since it allowed for the additional adjustment of serological markers of HPV exposure and other STIs.et al. observed a stronger association (OR = 4.0). In line with our findings, these two studies also found a reduced risk of cervical cancer for users who ceased OCs . Other prospective studies did not find associations between OCs and CIN3/CC risk [Consistent with results from previously published pooled analyses ,17, our /CC risk –20. AnalSince HPV is the necessary cause of CC, analyses including some measure of HPV infection are needed to assess potential residual confounding. In our nested case-control study we included the adjustment by HPV serology, and we evaluated OC use and CC risk among all cases and HPV seropositive controls. As already discussed, these results were broadly similar to those obtained in the cohort study, suggesting that we can reasonably rule out a large confounding effect due to HPV infection in our associations. In the last 10 years, most of the published studies have also considered HPV infection in their analyses, and the results were globally comparable to those for all women. On the other hand, the very few studies that have used serology as HPV measurement found contradictory results –23. EvenA possible mechanism to explain the associations between OC use and CC risk is that estrogens and progestogens may interact with hormone receptors, mainly progesterone, present in cervical tissue and influence the natural history of HPV infection. Specifically, sex steroid hormones are thought to enhance the expression of HPV 16 E6 and E7 oncogenes stimulating the degradation of p53 tumor suppressor genes and enhancing the ability of the viral DNA to transform cells and induce carcinogenesis ,25,26. Tet al. [We found contrasting results between parity and risk of CIN3/CIS and ICC. Thus, while women with high parity had a higher risk of CIN3/CIS than nulliparous women, no associations were found with ICC. We also found that this association with high parity was present in each level of OC duration with a synergistic effect between the two variables. These results are in concordance with results from some ,23 but net al. ,19 and aAs discussed in relation to OC use, these associations may be confounded by a number of other factors. However, adjustment by proxy measures of HPV exposure and sexual behavior did not change our risk estimates. In addition, two pooled analyses that adjusted their models by cervical screening practices obtained also similar results ,29.A possible biological mechanism for these associations could be that the elevated levels of estrogen and especially progesterone during pregnancy are responsible for the alterations in the squamo-columnal junction occurring during pregnancy, maintaining the transformation zone on the exocervix for many years. This would facilitate the direct exposure to HPV contributing to HPV persistence and progression to cervical neoplasia and cancer ,20,29. AOur findings provide evidence for a reduction in ICC risk among peri- and postmenopausal women using HT, an effect that was stronger with longer duration of use. We found very few studies evaluating HT and CC ,30. OverAs noted previously, one of the limitations of this study is the lack of accurate individual screening history that may indeed influence the effects of HT use on CC risk. Thus, the inverse associations found with ICC, an outcome more susceptible to screening bias, could be somewhat overestimated. One possible explanation of this effect is that women who take HT are more frequently screened than non users, being consequently diagnosed and treated earlier of pre-cancerous lesions. Nevertheless, when we stratified analyses by proxy measures of screening such as parity and OC use, the inverse association remained (data not shown). The intrinsic mechanisms that might explain the biology of these potential associations are currently unknown. Data from HPV transgenic mouse models suggest that estrogens promote cervical carcinogenesis and progesterone inhibits CC ,28. HoweAn increased risk of ICC and a reduced risk of CIN3/CIS were found among women reporting an induced abortion. Globally, the literature with regard to cervical cancer and pre-cancer risk and induced abortions is inconclusive and our results were in line with some ,34–36 buWe observed a decreased risk of both CIN3/CIS and ICC risk with increasing cumulative years of menstrual cycles. Longer menstrual lifespan is implicitly associated with shorter OC use duration and lower parity. However, the advantage of using menstrual lifespan is that includes in a single indicator combined information on the cumulative exposure to some endogenous and exogenous hormones taking into account the actual hormonal lifespan of the woman, providing thus more robustness in the risk estimates. It is interesting to note that even though this variable has been used in studies of other hormone-related cancers such as breast, ovarian and endometrial, no previous studies of CC have been identified in the literature.We found a non significant decreased risk of both CIN3/CIS and ICC among IUD users in the nested case-control study that reached statistical significance in the analyses restricted to all cases and HPV seropositive controls when combining CIN3/CIS and ICC cases  and in the analyses restricted to HPV seropositive women for ICC risk . The full case-control study and the different stratified analyses consistently found that IUD use was inversely associated with both CIN3/CIS and ICC risk. Few studies have evaluated associations between IUD use and CC risk with inconsistent results ,23,37,39Globally, the associations found between both exogenous and endogenous hormones and SCC risk were comparable to those obtained in models evaluating CIN3/CIS and ICC risk (data not shown). Concerning the risk of invasive adenocarcinoma, even though there were very few cases, an association was found with increasing number of FTP, in addition to OC use and HT, in the cohort study (data not shown). In concordance with our study, the IARC collaborative reanalysis evaluating risk factors for SCC and adenocarcinoma obtained an increased risk for each histological type with increasing duration of OC use . ContrarOur study has several strengths including its prospective, population-based design in most of the countries, a large sample size that embraces various regions in Europe, and the inclusion of two disease outcomes: CIN3/CIS and ICC. In addition, our inclusion of a nested case-control study within the cohort allowed us to determine and take into account biomarkers of past exposure to STIs such as HPV, CT and HHV-2.Nevertheless, our study design failed to consider direct markers of HPV infection, cervical cancer screening practices or sexual behavior, not only at recruitment but also during follow-up, as none of the assessed risk factors or potential confounding variables was reassessed after recruitment. Since these risk factors could and most likely did change in an unknown direction during follow-up, our associations may have led to under- or overestimation of the real effects on CC risk. Another limitation was the low sensitivity of the HPV serology technique, as only half of infected women seroconvert, and a potential misclassification cannot be totally ruled out .This study contributes strong evidence to consider high parity and long-term OC use important risk factors for cervical cancer and pre-cancer. These risk factors would act not independently but rather as cofactors that interact with HPV to induce cervical carcinogenesis. Our study also provides some evidence that IUD use and HT confer a reduced risk of cervical cancer, but these findings need further confirmation. Despite the clear involvement of hormones in cervical carcinogenesis, and from a public health point of view, adherence to current screening recommendations will certainly minimize the potential increased risk of CC associated with some of these hormonal risk factors.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Text(DOC)Click here for additional data file.


The International Society for Computational Biology (ISCB) is gearing up for its flagship meeting, ISMB.  The conference is the world’s largest gathering of computational biology and bioinformatics researchers. The ISMB 2016 pre-conference program will feature 17 special interest group and satellite meetings over the course of two days. This article previews those special meetings at ISCB’s flagship meeting, ISMB. As in the past, satellite meetings and special interest group (SIGs) meetings, will be held on Friday, July 8th and Saturday, July 9th, prior to the main conference at the main meeting venue, the Swan and Dolphin Hotel. Several applied knowledge exchange sessions (AKEs) have also been scheduled for Saturday and are smaller in size in order to provide a more intimate meeting environment. Check out this year’s3DSig: Structural Bioinformatics & Computational Biophysics will be holding its 12th meeting and has become one of the largest meetings that brings together world class scientists studying structural computational biology. Keynote speakers include David E. Shaw of Columbia University, Ruben Abagyan of UCSD and Molsoft LLC, Heather Carlson of the University of Michigan, Bruce Donald of Duke University, Koby Levy of the Weizmann Institute, Rafael Najmanovich of the Université de Sherbrooke, and Shoshana Wodak of the Free University of Brussels.This year, two popular satellite meetings are convening once again for two days on Friday, July 8th and Saturday July 9th.three data analysis challenges for its annual contest. Scientists present their analyses of these data set challenges and prizes are awarded for best analyses/presentations.The 15th annual International Conference on the Critical Assessment of Massive Data Analysis (CAMDA) is the other major satellite meeting being held on July 8th and 9th. CAMDA focuses on the analysis and integration of massive data sets, and the scientific committee of CAMDA has postedCOSIs). These SIGs span all topic areas in the field of computational biology including bio-ontologies, high-throughput sequencing, open source bioinformatics software, data visualization, and RNA biology. There really is a SIG for everyone, and these smaller meetings provide an atmosphere conducive to scientific discussion and exchanges. Two new SIGs are debuting this year: SysMod: Computational modeling of biological systems and TransMed 2016: Translational Medicine Informatics & Applications. SysMod aims to close the gap between bioinformatics and systems biology modeling and will include talks on modeling metabolism and modeling biochemistry. TransMed will cover topics related to the burgeoning field of translational medicine informatics, including clinical and molecular data storage and integration infrastructure, curation and harmonization of clinical, ‘omics and imaging data, and computational approaches for target selection and drug discovery, as well as other related topics.ISMB is fortunate to host numerous one- and two-day SIGs prior to the main meeting. Many of the SIGs are organized by ISCB’s Communities of Special Interest  - Opportunities and Challenges for Integrating Bioinformatics into the Clinical Realm•AKES05: Cytoscape 3 User Tutorial: Introduction to network visualization and analysis using CytoscapeMake sure you consider all of these pre-meeting sessions during your conference planning and make the most of your time at ISMB 2016.


Hodgins.See related article by Global Health: Science and Practice editorial, Hodgins identified key steps to “take a big chunk out of the wedge of maternal, newborn, and stillbirth mortality attributable to eclampsia/pre-eclampsia,” calling for early case identification with more frequent antenatal care (ANC) contacts, effective management of complications in pregnant women that progress to life-threatening states, and timely delivery.In a recent The editorial is an important call to action and we agree with its proposals; however, there are complementary programmatic issues that must also be considered in crafting an integrated strategy for addressing the burden of perinatal morbidity and mortality attributable to hypertensive disorders in pregnancy in Africa. These include: (a) strengthening management of preterm neonates, (b) strengthening delivery of secondary prevention through ANC, and (c) integrating primary prevention into ANC delivery.,Effective surveillance and timely delivery as a strategy to address the burden of pre-eclampsia will likely increase incidence of medically indicated preterm births. Without concomitant action to strengthen the system to care for babies born too soon, the reduction in perinatal mortality might be limited. Preterm birth remains the single leading cause of neonatal mortality globally,,We agree with Hodgins that revisiting the policy on the recommended number of ANC visits in the third trimester is important, and we furthermore suggest that addressing current challenges and quality issues in pre-eclampsia screening and diagnosis in primary health care facilities is essential. Improving community demand for ANC should be emphasized. Regular and accurate blood pressure and proteinuria measurement in ANC is still the mainstay of pre-eclampsia detection and surveillance, but there are important coverage and quality gaps in these procedures in Africa, even when women present for ANC. Only 57% of pregnant women who had up to 4 ANC visits had urine samples collected, according to Demographic and Health Survey (DHS) data from 29 African countries (calculated from Hodgins 2014incidence of pre-eclampsia, without the risk of increasing the burden of preterm delivery, particularly in communities with inadequate dietary calcium intake, as is the case in many African communities.Integrating programs for primary prevention of pre-eclampsia into ANC, i.e., preventive calcium supplementation and low-dose aspirin in pregnancy, is essential. Primary preventive programs hold the promise of reducing the By integrating primary preventive programming with strengthened capacity for case detection, timely patient transfer and delivery, and effective management of preterm neonates, maternal, stillbirth, and perinatal health indicators can be improved simultaneously.


Characterizing the community structure of naturally occurring microbes through marker gene amplicons has gained widespread acceptance for profiling microbial populations. The 16S ribosomal RNA (rRNA) gene provides a suitable target for most studies since (1) it meets the criteria for robust markers of evolution, e.g., both conserved and rapidly evolving regions that do not undergo horizontal gene transfer, (2) microbial ecologists have identified widely adopted primers and protocols for generating amplicons for sequencing, (3) analyses of both cultivars and environmental DNA have generated well-curated databases for taxonomic profiling, and (4) bioinformaticians and computational biologists have published comprehensive software tools for interpreting the data and generating publication-ready figures. Since the initial descriptions of high-throughput sequencing of 16S rRNA gene amplicons to survey microbial diversity, we have witnessed an explosion of association-based inferences of interactions between microbes and their environment.Despite these advances, the field of microbial ecology faces numerous technical challenges. Sampling and storage strategies, DNA extraction protocols, limitations of the so called “universal” PCR primers, random sequencing errors, and the identification of ecologically relevant units can bias interpretations of observations based on 16S rRNA gene data. Although microbiologists comprehend most of these challenges, the need for handling large number of sequences, and to partition these complex data into appropriate proxies for environmental genomes caught almost everyone off-guard.De novo clustering of short reads into operational taxonomic units (OTUs) based on “pairwise sequence similarities” quickly became the primary way to partition sequencing data into ecological units as this approach significantly out-performed analyses that relied strictly upon taxonomy. On the other hand, as random sequencing errors can dramatically increase the number of mismatches between two aligned reads, the underlying principle of most de novo clustering algorithms that rely on the edit distance was prone to inflating the diversity estimations. The use of 97% sequence similarity threshold emerged as a de facto standard, and has successfully reduced the impact of erroneous OTUs on diversity estimations. However, the computational convenience this arbitrary threshold offers has been at the expense of accurate ecological inference, as 3% OTUs are often phylogenetically mixed, and inconsistent , mammalian guts , deep-sea sediments (Buttigieg and Ramette), as well as freshwater (Newton and McLellan), sewage , marine , and soil  ecosystems. In a study that cuts across multiple environments, Schmidt et al. uses oligotyping to investigate the Vibrio ecology in environmental, as well as host- and substrate-associated habitats. Ramette and Buttigieg implements an R package for entropy-based decomposition procedures, and their software library contains additional approaches, such as the “broken stick model” procedure to identify low-abundance oligotypes that could be generated by chance alone, and a “one-pass entropy profiling” approach to efficiently identify those OTUs whose decomposition into oligotypes would most likely explain concealed diversity (Ramette and Buttigieg). Finally, Utter et al. reconcile the individuality, stability, and variability of the oral microbial communities in the context of “spatial structure” of microbes in dental plaque by combining high-resolution depiction of microbial community data with high-resolution imaging of multi-taxa microbial consortia in the human oral cavity . The ideal result of a properly partitioned marker gene dataset will have the minimum number of units that contains minimum entropy , which in fact can be achieved through multiple ways. Indeed, the search for algorithms that can provide single-nucleotide resolution without relying on arbitrary percent similarity thresholds is not limited to entropy-based approaches: studies that aim to address the same issue include distribution-based clustering (Preheim et al., While oligotyping demonstrates the efficacy of an entropy-based concept to partition closely related taxa, the algorithm minimum entropy decomposition suggests that the use of information theory can be generalized to analyze entire sets of marker gene data (Eren et al., Potential new directions for a more accurate depiction of microbial communities through marker gene amplicons come with new questions. What should microbial ecologists do with all the data they have generated, and plan to generate during the years to come? What are the computational and ecological issues that will need to be addressed for new methods to be more accessible in the field? Although our collection does not promise answers to these questions, we hope it will further stimulate the community of microbial ecologists and the developers of widely used software platforms to move beyond the use of OTUs that require arbitrary percent similarity cut-offs.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.AME was supported by the University of Chicago and the Marine Biological Laboratory collaboration award.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.


Pharmacological thromboprophylaxis in the peri-operative period involves a trade-off between reduction in venous thromboembolism (VTE) and an increase in bleeding. Baseline risks, in the absence of prophylaxis, for VTE and bleeding are known to vary widely between urological procedures, but their magnitude is highly uncertain. Systematic reviews and meta-analyses addressing baseline risks are uncommon, needed, and require methodological innovation. In this article, we describe the rationale and methods for a series of systematic reviews of the risks of symptomatic VTE and bleeding requiring reoperation in urological surgery.We searched MEDLINE from January 1, 2000 until April 10, 2014 for observational studies reporting on symptomatic VTE or bleeding after urological procedures. Additional studies known to experts and studies cited in relevant review articles were added. Teams of two reviewers, independently assessed articles for eligibility, evaluated risk of bias, and abstracted data. We derived best estimates of risk from the median estimates among studies rated at the lowest risk of bias. The primary endpoints were 30-day post-operative risk estimates of symptomatic VTE and bleeding requiring reoperation, stratified by procedure and patient risk factors.This series of systematic reviews will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding. Our work advances standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at best estimates of risk , dealing with subgroups at higher and lower risk of bias, and use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate certainty in estimates of risk. The results will be incorporated in the upcoming European Association Urology Guideline on Thromboprophylaxis.CRD42014010342.PROSPERO The online version of this article (doi:10.1186/2046-4053-3-150) contains supplementary material, which is available to authorized users. Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), represents a serious, and sometimes fatal, complication of urological surgery. A systematic review and meta-analysis including gastrointestinal, urological, gynecological, and general surgical procedures has demonstrated that pharmacological prophylaxis decreases the risk of VTE in surgical patients by approximately 50% but increases the risk of post-operative major bleeding by approximately 50% . The decThe crucial issue in making this decision is the risk of VTE and bleeding in those not receiving anticoagulants, which we will refer to as ‘baseline risk’. Baseline risks, in the absence of prophylaxis, for VTE and bleeding are known to vary widely between urological procedures , but theThus, the decision regarding thromboprophylaxis is critically dependent on the baseline risks of both VTE and bleeding. Reliable estimates of these risks require systematic summaries of the best available evidence, which have thus far been unavailable . ConsequOur series of systematic reviews aims to fill this critical gap in knowledge by addressing the risks of VTE and bleeding requiring reoperation in patients undergoing urological surgery but not receiving prophylaxis. Each review summarizes the evidence regarding the frequency of VTE and bleeding requiring reoperation for procedures for diseases of the urinary tract and  genital system. In this article, we outline the specific methods used in our reviews and familiarize readers with the methodology of systematic reviews and meta-analysis of observational studies of complications and their strengths and limitations.Systematic reviews are summaries of a body of evidence, and meta-analysis is a quantitative, statistical method to summarize the results. Preparing a systematic review requires a number of decisions including determining the focus; identifying, selecting, and critically appraising the relevant primary studies; collecting and synthesizing the relevant information; and drawing conclusions from the evidence. Typically, investigators addressing questions of therapy frame their research questions in accord with the Patient, Intervention, Comparator and Outcome (PICO) format with associated eligibility criteria . This faConventional systematic reviews that compare one treatment against another or against a non-treatment control are common and the methods are well established . SystemaOne reason for the dearth of such reviews is the multiple challenges they present. First, indexing of observational research is less well established than for randomized controlled trials (RCTs), making it harder to identify the relevant studies . Second,Third, even when articles report risks of VTE and bleeding, key information is often missing. Such information includes the use of prophylaxis , the timing of the events of interest, and diagnostic criteria for the events of interest. Fourth, risk of bias criteria, as well as criteria for overall certainty in estimates , well esIn these reviews, we address these challenges with the goal of providing precedents for optimal methodology. For the overall certainty in estimates of effect, we used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, which has provided detailed methodological guidance for systematic reviews , and iniWe included studies published in English language medical journals that enrolled adult male or female patients undergoing procedures for diseases of the urinary tract and  genital system, including kidneys, ureters, bladder, prostate, seminal vesicles, urethra, scrotum, testicles, penis, and vagina . Absolute estimates include the percentage , proportions , natural units or natural frequency , and natural frequency per time  but do not include relative estimates, such as risk ratio or odds ratio.We used two search strategies. First, we used the MEDLINE database to search for potentially eligible articles published from January 1, 2000 until April 10, 2014. A combination of keyword and medical subject headings search included the ‘urological procedures’  term family combined with the ‘thrombosis’ term family , as well as other missing or unclear information.Primary outcomes were the absolute risks of symptomatic VTE and bleeding requiring reoperation (including exploration and angioembolization). Secondary outcomes were the absolute risks of fatal PE and fatal bleeding. All outcomes were extracted and analyzed separately for each procedure .We also extracted the length of follow-up regarding VTE and bleeding outcomes. When authors presented the frequency of events at more than one time point, we recorded the number of events up to 3 months and used the absolute risk closest to 4 weeks (our primary outcome). We did not collect data on events of questionable importance to patients , in partWe assessed design features that could potentially bias the estimates of VTE or bleeding risk. These include the representativeness of the recruited patient population, study type, losses to follow-up, explicitness of criteria for VTE diagnosis, thromboprophylaxis documentation, and data source Table . We alsoTo assess applicability and representativeness of each study and to assess heterogeneity between estimates, we recorded the mean age of the study population and proportion of patients with malignant disease. When there were clear outliers, with atypical populations for either of these factors, we excluded those studies.We used the median value of estimates from studies with the lowest risk of bias to estimate baseline risk of VTE and bleeding requiring reoperation. The reason we chose the median as opposed to the pooled estimates across studies is that even the largest studies are likely to have factors idiosyncratic to that population and setting that will influence risks of both thrombosis and bleeding. There is little reason, given these idiosyncratic factors, that larger studies should have more weight than smaller studies. Under these circumstances, the median is likely to provide better estimates of typical risk than is the pooled estimate .We provided procedure-stratified estimates for both risk of VTE and bleeding requiring reoperation in urological surgery. We chose one and four-week time frames for estimates of risks of thrombosis and bleeding because these are feasible and frequently chosen time frames for, respectively, shorter and longer term prophylaxis. For studies that did not report VTE estimates using these intervals, we modeled estimates—based on a literature search  showed a VTE risk of 1%, assuming that the relative risk reduction with prophylaxis is approximately 50%, we inferred that the included patients would have experienced a 2% risk of VTE had they not received prophylaxis.Similarly, in the same study, the bleeding risk was 3%, because anticoagulant prophylaxis increases the risk of bleeding by approximately 50%, we inferred a bleeding risk of 2% without prophylaxis. Thromboprophylaxis was often used for less than 4 weeks. In those circumstances, we estimated its impact using same rationale but also considered the duration of thromboprophylaxis by using our models  from these studies. We then applied the degree of overlap to estimate VTE frequency in trials that provided only separate reports of DVT and/or PE.After assessing the baseline risk of VTE for each procedure, we stratified the risk by patient risk factors. We conducted a literature search addressing VTE risk factors in the context of urology, general surgery, gynecology, and gastrointestinal surgery , and assessed risk of bias using criteria specific to this review. In addition, teams of two reviewers independently assessed eligibility and risk of bias and extracted data, a third reviewer adjudicated discrepancies, and we sent our consensus of data extraction to the original authors of each article for confirmation or correction. We considered, for the first time in urology, risk of VTE and bleeding separately for each procedure including surgical technique . We took into account length of follow-up, use of thromboprophylaxis, and patient risk factors.ad hoc, it is possible that literature is biased towards underreporting of events. This is especially true regarding single-surgeon series: individual surgeons experiencing high rates of complications are unlikely to publish their results. Secondly, due to poor reporting standards (both indexing and abstract information), our search likely missed some relevant studies.Our reviews have limitations. Our analyses reflect published data and we cannot completely exclude publication bias. Because reporting of surgical complications is sporadic and We have carefully addressed the many challenges involved in generating best estimates of risk of VTE and bleeding in the absence of antithrombotic prophylaxis in patients undergoing urological surgery. Clinicians can therefore look to the systematic reviews in this series as providing the best current estimates of the risk of both symptomatic VTE and bleeding requiring reoperation in urological procedures. Guideline panels will find these estimates helpful when formulating recommendations for VTE prophylaxis in urological surgery. Moreover, these reviews provide guidance for best practices in systematic reviews of observational data—particularly with regard to surgical complications.Search history for baseline risk of VTE.(DOCX 32 KB)Additional file 1:Search history for baseline risk of major bleeding/bleeding requiring reoperation.(DOCX 32 KB)Additional file 2:Search history for modeling of risk for venous thromboembolism after surgery.(DOCX 29 KB)Additional file 3:Search history for patient related risk factors of venous thromboembolism after surgery.(DOCX 29 KB)Additional file 4:Search history for patient related risk factors of major bleeding/bleeding requiring reoperation after surgery.(DOCX 29 KB)Additional file 5:


We introduce our active experts’ communications and reviews (Part II) of 2015 Korea-China Joint Symposium on Biomimetic Medical Materials in Republic of Korea, which reflect their perspectives on current research trends of biomimetic medical materials for tissue regeneration in both Korea and China. The communications covered three topics of biomimetics, i.e., 1) hydrogel for therapeutics and extracellular matrix environments, 2) design of electrical polymers for communications between electrical sources and biological systems and 3) design of biomaterials for nerve tissue engineering. The reviews in the Part II will cover biomimetics of 3D bioprinting materials, surface modifications, nano/micro-technology as well as clinical aspects of biomaterials for cartilage. An invitation-based, bilateral symposium on biomimetic medical materials was held from October 22 to 26 in Seoul, Korea, towards building strong relationships among established leaders and emerging young scientists in Korea and China. Numerous breakthrough achievements in biomedical materials and nano-biotechnology research on regenerative medicine have been made in the two countries throughout successful series of the previous Korea-China Joint Symposium on Biomaterials and Nano-biotechnology pioneered by professors Inseop Lee in Yonsei University of Korea and Fu-Zhai Cui in Tsinghua University of China over more than 10 years.Biomaterials science and technology have recently evolved into a new stage of tissue engineering research through the modeling of characteristics of the extracellular matrix (ECM) of defect tissues as well as the advancement of new fabrication methods of 3D bio-printings of functional biomaterials. The symposium focused on recent scientific progress on biomimetics and regenerative medical materials for tissue engineering, particularly bone, cartilage and nerve, and provided a platform for the academic cooperation between Korea and China.During the discussion session about two countries’ scientific collaboration led by key scientists, diverse issues were mainly discussed on how to upgrade our scientific relationship of this new research area. Other topics also raised how to contribute to improve the relationships among the National Research Foundation (NRF) of Korea and the National Natural Science Foundation of China (NSFC), Korean Society for Biomaterials (KSBM) and Chinese Society for Biomaterials (CSBM) and how to improve partnerships in research and industrial aspects.The key members of both Korean and Chinese Societies for Biomaterials agreed on holding a biannual exchange forum of young scientists during each society’s annual meeting. The first forum was held on November 20, 2015 in Hainan, China, and the second one is scheduled to be held in Korea in 2016.Herein, we introduce our active experts’ communications and reviews, which reflect their perspectives on current research trends of biomimetic medical materials for tissue regeneration. The communications covered three topics of biomimetics, i.e., 1) hydrogel for therapeutics and extracellular matrix environments, 2) design of electrical polymers for communications between electrical sources and biological systems and 3) design of biomaterials for nerve tissue engineering. The reviews will cover biomimetics of 3D bioprinting materials, surface modifications, nano/micro-technology as well as clinical aspects of biomaterials for cartilage.Polymeric hydrogels have received substantial attentions in various biomedical applications due to their structural similarities to the native extracellular matrix (ECM) as well as multi-tunable properties. Up to date, various kinds of polymeric hydrogels have been developed through physical- or chemical-cross linking mechanisms, which can be applied as either therapeutic implants or therapeutic vehicles for controlled drug delivery and tissue regeneration . SpecifiIn the past decade, polymeric hydrogels have been used as a carrier to deliver therapeutic agents  for tissue regeneration . RecentlRecently, many researchers are interested in utilizing the artificial extracellular microenvironment using bio-mimetic hydrogel materials to support cell growth. These engineered cellular microenvironments are created by tailoring the polymeric backbone with cellular response molecules , which are critical for supporting 3D cell growth . In addiTissues and cells in our body are strongly affected by electrical signals, such as electrical field and current, and at the same time utilize electrical signals as important factors that control physiological conditions . For exaNative tissue and its environments are highly organized and their properties are harmonized to permit cues modulating biological activities. Depending on the physiological and pathological states, native environments actively respond and dynamically change their composition, structures, and bioactivities . TherefoFirst, in comparison with the rigidity of conductive polymers (> MPa), the most tissues are softness with a few Pa (brain tissues) to kPa except bone . This meAnother important property is a structure, which can serve as biomimetic features of extracellular matrices including porosity, nano-/micro-structures, and orientation . AdvanceLastly, various biological active molecules are to be immobilized in/or conductive polymers by physical or chemical fashions. Since the effect interactions are often mediated by receptor-ligand binding, it will be critical to fabricate biologically active conductive materials by immobilizing ECM proteins, polysaccharides, and growth factors. In particular, anioinic proteins and mucopolysaccharides can be doped into oxidized conductive polymers, which can be easily produced during polymerization processes of conductive polymers . CovalenIn summary, biomimetic conductive polymers can offer great promise to actively modulate biological systems. Still, better mimicry of characteristics of the target tissues and their demonstration will be desirable. High performance conductive polymer-based biomaterials will be greatly beneficial for applications of tissue engineering, drug delivery, and biocompatible bioelectrodes.The design of optimal biomaterials for regenerating injured human tissues and organs plays a crucial role in tissue engineering and regenerative medicine, especially for highly complex nerve system , 34. BioPrevious studies indicate that biophysical properties of biomaterials are very important design parameters in preparing artificial regenerative niche for nerve regeneration. For example, the stiffness/elasticity of the underlying substrate could direct stem cell fate and even regulate their lineage differentiation , 37. AduIn our study, a hierarchically aligned fibrillar fibrin hydrogel that was fabricated through electrospinning and the concurrent molecule self-assembly process mimics the soft and oriented features of nerve tissue simultaneously, thus providing hybrid biophysical cues to instruct cell behavior in vitro and in vivo. We found that the low elasticity and aligned topography of AFG had co-effects on promoting the neurogenic differentiation of human umbilical cord mesenchymal stem cells (hUMSCs), and also inducing dorsal root ganglions neurons to project numerous long neurite outgrowths longitudinally along the fibers rapidly for total migration distance of 1.96 mm in three days without the supplement of neurotrophic factors. Moreover, the aligned fibrin hydrogel implanted in a rat T9 dorsal hemisection spinal cord injury model was found to promote endogenous neural cells fast migration and axonal invasion along the fibers constructing aligned tissue cable in vivo. Our results suggest that matrix stiffness and aligned topography could synergistically instruct stem cell neurogenic differentiation and rapid neurite outgrowth, providing great promising in biomaterials design for applications in nerve regeneration.


As human populations expand, there is increasing demand and pressure for land. Under this scenario, behavioural flexibility and adaptation become important processes leading to the persistence of large carnivores in human-dominated landscapes such as agroecosystems. A growing interest has recently emerged on the outcome of the coexistence between wolves and humans in these systems. It has been suggested that spatial heterogeneity in human activities would be a major environmental factor modulating vulnerability and persistence of this contentious species in agroecosystems. Here, we combined information from 35 den sites detected between 2011 and 2012 in agroecosystems of western Iran (Hamedan province), a set of environmental variables measured at landscape and fine spatial scales, and generalized linear models to identify patterns of den site selection by wolves in a highly-modified agroecosystem. On a landscape level, wolves selected a mixture of rangelands with scattered dry-farms on hillsides (showing a low human use) to locate their dens, avoiding areas with high densities of settlements and primary roads. On a fine spatial scale, wolves primarily excavated dens into the sides of elevated steep-slope hills with availability of water bodies in the vicinity of den sites, and wolves were relegated to dig in places with coarse-soil particles. Our results suggest that vulnerability of wolves in human-dominated landscapes could be compensated by the existence of spatial heterogeneity in human activities. Such heterogeneity would favor wolf persistence in agroecosystems favoring a land sharing model of coexistence between wolves and people. As human populations expand, there is increasing demand and pressure for land  and, consequently, different impacts on wildlife are expected. Under this scenario, behavioural flexibility and adaptation are important processes leading to the persistence of viable animal populations in human-dominated landscapes, including urban environments  are able to persist in contrasting human-dominated landscapes Existing evidence shows how wolves , and provide insights into the behavioural response of wolves to the spatial heterogeneity in human activities. Since large-scale approaches may disregard fine-scale patterns affecting different components of the selection processes we were interested, we evaluated the requirements of denning wolves at large (den area) and fine (den site) spatial scales. In particular, we hypothesized that wolves are able to assess the type and intensity of human activities over a wide geographic range selecting den areas with low human use, minimizing the risk of mortality. Thus, on a landscape level, we first expect that wolves will avoid areas with high densities of infrastructures and humans and, second, we also predict that, in absence of natural dense vegetated areas in this agroecosystem acting as refuge and where to locate the den sites, wolves will select farmlands with the lowest intensity of human activity. On a fine scale, we expect that although wolves will select for den sites fulfilling previous known environmental requirements for the species , Dogwood  or Cherry plum (Prunus divaricata) This study was carried out in Hamedan province, a human-dominated landscape located in western Iran  strongly determine the use of the landscape by local people. Thus, while flat areas (slope <10 degrees) are the most preferred landscape for settlements, development and human activities (84.5% of the study area), rugged landscapes (slope> 10 degrees) only encompass 15.5% of the whole landscape and is mainly used as rangelands and, sometimes, dry-farms. As a result, human activities are heterogeneously distributed across different types of farmlands. Based on cultivation and livestock practices and land use, intensity of human activities differ across farmlands as follow: irrigated farms> dry farms> rangeland with scattered farms> rangelands. For example, in irrigated farmlands , the use of heavy equipment and mechanized cultivation is quite common and these type of crops requires a continuous human presence during many months of the year, including the peak of reproductive activity of denning wolves. On the other hand, cultivation strategies of other types of farms such as dry-farms require human presence only in two specific periods, plant and harvest, resulting in low human presence especially during denning activities and rearing of immature pups.We used information from 35 den sites detected between 2011 and 2012 . Wolf dens were located using information from local sources in the rural areas, especially observations from sheepherders and game guards of the Department of Environment of Hamedan province, as well as field patrols conducted by motorcycle in those areas where we expected to find wolf dens according to previous local knowledge in the area. Since all issues subject to wildlife care and animal welfare regulations is handled by Department of Environment (DOE) In Iran, as well as the study was in collaborated with Hamedan Provincial Bureau of Department of Environment (43106/140), all our fieldwork procedures was adhered to the animal welfare regulations. Our data sampling was carried on after confirming that wolf packs left their dens. Our field survey did not involve chasing the wolves to locate their dens. We also did not destroy or damage wolf dens. Since the breeding season is the most sensitive period for wolves 2; landscape scale), where environmental variables were measured by using GIS; and ii) den site , where variables were measured in situ. On a landscape level, we estimated the spatial heterogeneity in human activities around den areas using a 2 km circular buffer centered on the den sites. The lack of information on wolf territory size in the study area confined us to consider a 2 km buffer size based on literature review Data sampling and measurement of environmental variables were performed in two different spatial scales and using different protocols: i) den area , we measured thirteen variables related to the vulnerability of wolves , ease to dig  testing for significant differences between wolf den areas/sites and non-wolf den areas/sites for all the explanatory variables, excepting for the proportion of den sites with water bodies and farmlands within 100 m radius, where Z-proportions tests were used , Table 2anova” function of the “car” package for R 2 and Wald χ2 in order to evaluate the significance level of each interaction. Akaike's Information Criterion corrected for small sample sizes (AICc) wi) For both spatial scales, we built separate Generalized Linear Models (GLMs) with binomial error distribution and logit link to assess the influence of human activities on den site selection patterns by wolves in this semi-arid agroecosystem. For each spatial scale, Pearson correlation coefficients were used to test for multicollinearity among predictors, but no significant correlation between any pair of explanatory variables was detected. At the landscape scale, because of the inherent relationship between topographic contexts with land use, we first examined the possible interactions between elevation and roughness against land use types and length of primary and secondary roads , and sigP <0.05; P <0.001; P <0.0001; roughness: Mann–Whitney U-test, P = 0.022; P = 0.017; settlements: Mann–Whitney U-test, P = 0.016; Den areas were located in agricultural matrix with a significantly less proportion of irrigated farms  Based on the comparison of human land use between den areas, random areas and the whole study area (Hamedan province) we found that the mixture of rangelands with scattered dry-farms Click here for additional data file.Figure S2Fine-scale pictures showing the environment around den sites in rangelands of Hamedan province, Iran.(JPG)Click here for additional data file.Table S1Results from Generalized Linear Models testing for significant effects of the pairwise interactions between land use and type of roads with elevation and roughness.(DOC)Click here for additional data file.Table S2Results of the assessment of goodness-of-fit and discrimination capacity of selected candidate models explaining the selection of den areas/sites by wolves in Hamedan, Iran.(DOC)Click here for additional data file.


Genetically encoded indicators are fluorescent proteins engineered to change their optical properties and report the dynamics of intracellular molecules or voltage. Encoded in a relatively compact size of DNA , they are readily compatible with standard gene delivery techniques, including viral vectors and transgenesis. They can be thus expressed in specific types of cells with the use of cell type-specific promoters and/or Cre-loxP recombination system, which makes them beneficial for disentangling the complex mammalian neural circuitry. Another unique advantage of genetically encoded indicators is that they can be stably expressed for a long period, which allows chronic tracking of the same neuronal ensemble by longitudinal imaging, and offers unprecedented opportunities to investigate the neural basis of development, learning, and disease.2+ indicators (GECIs) were reported for the first time , as well as genetically encoded indicators of voltage and synaptic activity . Griesbeck and colleagues present an overall review of GECIs, covering from the basics of Ca2+ imaging in neurons to the description of latest variants, and also discuss recent studies where GECIs were applied to neuronal population imaging in awake head-restrained mice . The article by Nagai and colleagues focuses on affinity variants, color variants and photoactivatable variants of GECIs, the last two of which are of considerable importance for simultaneous use with optogenetic tools . Lin and colleagues then provide a review, for the first time to our knowledge, on a rapidly growing subfamily of optogenetic tools—a group of photoactivatable effector proteins that control the dynamics of intracellular molecules, rather than the membrane voltage .Since the prototypical genetically encoded CaIt is also noteworthy that an important update of red GECI, R-CaMP2 was recently published . Tsutsui and colleagues present their attempts to turn a GFP variant into a genetically encoded chromophore optimized for second harmonic generation microscopy, which can be used for voltage imaging . White and colleagues describe a set of in utero electroporation vectors carrying genetically encoded Ca2+ indicators (GCaMP), and investigate Ca2+ dyanamics of astrocytes in rat organotypic slice culture .More specific technical advances are also reported in this Research Topic. Knöpfel and colleagues characterize a new series of genetically encoded voltage indicators, with a chimeric voltage sensing-domain (fragments from the Ci-VSP and the Kv3.1 potassium channel) sandwiched by a FRET donor and acceptor . Ohki and colleagues perform wide-field Ca2+ imaging in transgenic mice expressing GCaMP broadly across the cortex, and identify two visual association areas that respond to drifting gratings, where they further examine the cellular responses by 2-photon imaging . Fletcher and colleagues also perform wide-field Ca2+ imaging in transgenic mice expressing GCaMP in excitatory output neurons in the olfactory bulb, and examine the circuit element responsible for olfactory habituation .The improved performance and rich repertoire of genetically encoded indicators have stimulated their widespread application to biologically relevant questions. Tvrdik and colleagues demonstrate 2-photon CaWe thank all the authors and reviewers for their valuable contributions to our Research Topic, and sincerely hope that it will provide readers with useful information and inspiration for further innovation in the field.YY and KM conceived the overall plan of Research Topic, recruited contributors, and wrote the manuscript.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.


Cross-sector collaboration on child obesity prevention is common, yet littleresearch has examined the context of collaboration at the state level. Thisstudy describes secular trends in collaboration between state agency staffresponsible for school nutrition and physical education activities and otherorganizations from 2000 to 2012.Data from the School Health Policies and Practices Study were used todescribe collaboration between state agency staff and 13 types of public,private, and nonprofit organizations. Breadth of collaboration in 2012 wasexamined across political, social, and economic conditions.Collaboration between state agency staff and other organization typesincreased from 2000 to 2006 and decreased or stabilized from 2006 to 2012.Breadth of collaboration was greater in states with a physical educationcoordinator, higher levels of poverty, higher prevalence of childhoodobesity, and more public health funding. Breadth was similar across statesby census region, political party of governor, majority party in statelegislature, percentage non-Hispanic white population, high schoolgraduation rate, and unemployment rate.Cross-sector collaboration on school nutrition and physical education waswidespread and did not vary substantially across most political, social, andeconomic measures. Expanded monitoring and surveillance of state-levelcollaboration would assist efforts to understand how state agencies workacross sectors and whether this collaboration affects the support theyprovide to schools. The multifactorial nature of childhood obesity has led to calls for increasedcollaboration across multiple sectors of society to address the environmental,social, and policy factors driving the epidemic –4. CrossCollaborative partnerships are theorized to be more effective in achieving broadsocial change than single-sector efforts  because they leveragethe skills, knowledge, resources, and power of their member organizations ,8.CrossPartnership breadth (the number of sectors or organization types participating in thepartnership) is one structural feature that is theorized to allow partnerships totake on broad, comprehensive activities and increase the likelihood of effectingpositive change ,8,17. ThCollaboration was measured by using data from the nutrition services and physicalactivity questionnaires in the School Health Policies and Practices Study(SHPPS) , a surveIn the nutrition services questionnaire in 2000, a series of 8 questions askedwhether state-level child nutrition or food service (CNFS) staff worked onschool food service or nutrition activities during the previous 12 months withstate-level school health education staff; school health services staff; schoolmental health or social services staff; PE staff; staff or members of astate-level health organization such as the American Heart Association or theAmerican Cancer Society; a food commodity organization such as the Dairy Councilor state produce growers association; businesses; or colleges or universities.In 2006 and 2012, five questions were added .A similar series was asked in the physical activity questionnaire. In 2000, tenquestions asked whether state-level PE staff worked on PE activities during theprevious 12 months with state-level school health education staff; school healthservices staff; school mental health or social services staff; school nutritionor food service staff; or staff or members of the state parks or recreationdepartment; the state-level American Alliance of Health, Physical Education,Recreation and Dance (AAHPERD); a state-level health organization such as theAmerican Heart Association or the American Cancer Society; the Governor’sCouncil on Physical Fitness and Sports; businesses; or colleges or universities.In 2006 and 2012, three questions were added .All questions were developed and reviewed by CDC staff, subjected to cognitivetesting, and reviewed by external reviewers before their inclusion . ResponsPolitical, social, and economic characteristics found to predict statelegislative activity on childhood obesity were examined as correlates ofcollaboration breadth ,22. BecaWe counted the number of states collaborating with each organization type for2000, 2006, and 2012 and calculated changes that occurred from 2000 to 2006 andfrom 2006 to 2012 using the comparable questions asked in both years. We definedcollaboration breadth in each state as the sum of the number of organizationtypes collaborating with 1) CNFS staff on school nutrition activities and 2) PEstaff on PE activities. We examined average collaboration breadth in 2012overall and stratified by state characteristics. To facilitate comparisons, wecategorized continuous measures of state characteristics into tertiles. Wereported means and 95% confidence intervals for collaboration breadth acrossstrata of state characteristics. We did not conduct statistical tests for thisdescriptive analysis.From 2000 to 2006, the number of states in which CNFS staff collaborated with otherstate-level school health staff increased . In 2000The number of states in which CNFS staff reported collaborating with staff or membersof businesses and academic institutions increased from 2000 to 2006 and decreasedfrom 2006 to 2012, leaving overall collaboration unchanged from 2000 to 2012. From2006 to 2012, we found decreases in the number of states in which CNFS staffreported collaborating with nonprofit organizations, including state-level healthorganizations (−8 states), Action for Healthy Kids (−7 states), andstate-level physicians organizations (−13 states). The only notable increaseduring this later period was the number of states in which CNFS staff reportedcollaborating with staff from the state department of agriculture (+16 states).In 2006 and 2012, CNFS staff in most states reported collaborating with allorganization types except school mental health or social services staff and staff ormembers of a state-level physicians organization. The most common collaboratorsthroughout the study period were state-level health education staff (40–48states), academic institutions (45–48 states), Action for Healthy Kids(41–48 states), state school nutrition associations (48–50 states),and food commodity organizations (48–49 states).From 2000 to 2006, the number of states in which PE staff reported collaborating witheach organization type increased by 7 to 24 states . The greCompared with CNFS staff, PE staff were less likely to report collaborating with thefollowing organization types in 2000: state-level staff from school healtheducation, health services, and mental health or social services, and staff ormembers of businesses, academic institutions, or state-level health organizations.However, after the larger increases in collaboration reported by PE staff comparedto CNFS staff from 2000 to 2012, collaboration with most organization types wassimilar for PE activities and school nutrition activities in 2012.In 2012, the number of organization types working with CNFS staff on school nutritionactivities (collaboration breadth) ranged from 4 to 13 of 13 organization typesmeasured , with a Collaboration breadth for both school nutrition and PE activities did not varysubstantially across most state characteristics . In statOur study is the first to quantify the extent to which various organization types areinvolved in state-level school nutrition and PE activities across the country.Collaboration between CNFS and PE staff and other organization types increased from2000 to 2006, and decreased or stabilized from 2006 to 2012 for all organizationtypes except state departments of agriculture. This trend is consistent withtheories and research on collaborative partnerships, which posit that the breadth ofcollaborative networks expands as they mature ,28 but mThe economic recession that began in 2008 had substantial impacts on state budgets,possibly reducing state agencies’ capacity to engage large numbers ofstakeholders. On the other hand, federal stimulus funding through the AmericanRecovery and Reinvestment Act of 2009 and CDC’Our study also sheds light on the most common organization types engaged instate-level school nutrition and PE activities during the past decade. Theseorganizations include school nutrition and PE professional associations and foodcommodity organizations, which have a self-interest in school policies andpractices, and academic institutions, which may partner on research and evaluation.In contrast, physicians associations and mental health and social service staff wereamong the least frequently reported collaborators; states may be missingopportunities to integrate school nutrition and PE activities with the activities ofexperts in such areas as weight stigma and eating disorders. Knowing whichorganizations are involved in obesity-related collaborative activities is importantwhen designing and interpreting studies of collaboration impact becauseorganizations may have different or even contradictory interests in the outcomes ofcollaborative activities. For example, public health advocacy organizations may havean interest in developing stronger state policies on obesity prevention, whereasorganizations representing the food and beverage industry may have an interest inlimiting the impact of these policies on sales of their products. Of particular interest to public health practitioners is the expansion across thecountry in collaboration between state-level school health staff from diversedisciplines, especially the large increases in the number of states in whichstate-level CNFS and PE staff work with each other on both topics. State agencystaff are often responsible for coordinating implementation activities, includingproviding resources, training, and technical assistance to schools and districts, and greSeveral patterns in collaboration across state characteristics warrant discussion.States with a state-level PE coordinator engaged in collaboration with an average of3.4 more organization types than states without a coordinator. Although we cannotdetermine from the SHPPS data the role of state-level PE coordinators in developingand managing cross-sector collaboration, theory and practice suggest that having anindividual or organization act as a convener or coordinator is an importantcomponent of collaboration formation and effectiveness, and these are natural rolesfor state PE coordinators .InteresStates with higher levels of poverty and childhood obesity also had broadercollaboration on PE activities, which could indicate greater mobilization of diversesectors for childhood obesity prevention in states where the rate of childhoodobesity is highest. A complex health problem is a strong motivator for cross-sectorcollaboration; however, poverty, lack of funding, and other social issues may limitthe effectiveness of collaboration .This study illustrates both the strengths and limitations of using surveillance datato conduct research studies. Few data sources exist that enable examination of howpartnerships change over time. The use of surveillance data in this study enabled anationally representative descriptive analysis of organizations that worked togetherin each state in the country, providing insight into how our society and governmentare responding to the societal challenge of childhood obesity. Examining thesequestions is an important first step in identifying potential missed opportunitiesfor partnership and generating hypotheses on the impact of these partnerships. Thecollaboration variables generated by the SHPPS may also be used as predictors orcovariates in future studies investigating the relationships among collaboration,state policies, state agency support, and student health outcomes.However, surveillance data are generally not collected with the same frequency orintensity as data collected for a specific research question and may be subject tomeasurement error resulting from respondents’ incomplete or inaccuratereports. The SHPPS data did not include measures of the strength or quality ofrelationships between organization types, and the survey had a limited list ofpotential collaborating organizations. SHPPS should consider adding questions on thefrequency of interactions and purpose of collaboration  to assist in evaluating the impact of collaboration.Cross-sector collaboration on school nutrition and PE was widespread and did not varysubstantially across most political, social, and economic measures. Expandedmonitoring and surveillance of state-level collaboration would assist inunderstanding how state agencies and departments work across sectors on obesityprevention activities and the impact collaboration may have on the types of supportthey provide to schools.