The number of vaccines available to low-income countries has increased dramatically over the last decade. Overall infant immunization coverage in the WHO African region has stagnated in the past few years while countries’ ability to maintain high immunization coverage rates following introduction of new vaccines has been uneven. This case study examines post-introduction coverage among African countries that introduced PCV between 2008 and 2013 and the factors affecting Pneumococcal Conjugate Vaccine (PCV) introduction. Nearly one-third of countries did not achieve 80% infant PCV3 coverage by two years post-introduction and 58% of countries experienced a decline in coverage between post introduction years two and four. Major factors affecting coverage rates included introduction without adequate preparation, insufficient supply chain capacity and management, poor communication between organizations and with the public, and data collection systems that were insufficient to meet information needs. Deliberately addressing these issues as well as longstanding weaknesses during new vaccine introduction can strengthen the immunization and broader health system. Further study is required to identify and address factors that affect maintenance of high coverage following introduction of new vaccines in the African region. Immunization with PCV is one of the most important interventions protecting against pneumonia, the second leading cause of death for children under five globally. The last ten years have seen a massive surge in vaccine products and many African children and adults have gained access to life-saving immunization against deadly diseases. A global increase in innovative financing and advances in the production of new vaccines have allowed low-income countries to introduce new vaccines faster than ever before. Between 2000 and 2015, 73 Gavi eligible countries introduced a pentavalent vaccine, 54 introduced pneumococcal conjugate vaccine, 37 introduced rotavirus vaccine, 40 introduced inactivated polio vaccine, 20 introduced measles vaccine second dose, two introduced HPV vaccine nationally and one introduced Japanese encephalitis vaccine  also proIn conducting this case study, we collected information on dates of nation-wide introduction as reported in Gavi annual progress reports. We examined PCV 3 coverage data from the WHO/UNICEF Joint Reporting Form  and usedPCV had been introduced in 129 countries worldwide by the end of 2015. PCV was introduced in 22 of 45 countries in the WHO African Region between 2008 and 2013  7]. How. How7]. Despite high coverage within the immediate introduction period, more than half of the countries experienced some decline by post-introduction year two. Some further decline was seen in some countries two to four years after introduction of the vaccines. Comparing PCV rates with those of diphtheria, pertussis and tetanus (DPT) vaccine, which is given at the same age, in countries with over 80% one year post-introduction, PCV 3 was at similar levels of coverage as the third dose of DPT within two years for most countries. However, in Mauritania, Cameroon, Madagascar, Ethiopia, Tanzania and Malawi, PCV3 coverage remained slightly below that of DPT 3. Further comparison in post-introduction year four shows that Mali, Cameroon and Kenya reported lower PCV3 coverage rates than DPT3, with Mali reporting as much as 13 percentage points less. Factors that enabled high coverage included robust planning and forecasting with sufficient stock levels, strong partnership and coordination amongst government agencies and partners, and adequate and timely disbursement of funds.Oversight by country Interagency Coordinating Committees (ICCs) and partnership between the Ministry of Health and key stakeholders, strengthened by regular meetings and good communication from the National Immunization Program, were major enablers in a number of countries such as Mozambique, Zimbabwe, Uganda and Zambia . A phaseZimbabwe avoided national stock out in the first year by ordering the second quarter´s shipment early and requesting additional vaccine from Gavi, while Malawi also received large initial stock amounts , 11. FolLargely through the support of Gavi, low-income countries in Africa now have greater access to new vaccines impacting major causes of death. Overall child mortality fell by over 53% in Africa between 1990 and 2012 . BetweenNew vaccine introductions posed particular challenges to timely procurement and supply chain management. Cold chain capacity was expanded in many countries with acquisition of equipment and devices; however, cold chain repair and continued preventive maintenance were often neglected. In some instances waste management was given inadequate attention with several challenges in the management and disposal of the increased volume of medical sharps waste generated by the additional injectable vaccines. New vaccines are generally accepted by the population and generate demand for immunization, but this increase in demand also highlights the importance of good communication with the public. Opportunity to build health worker capacity to address parental and health worker concerns about the new and unfamiliar vaccines was at times not utilized and the eligibility criteria was not always clearly explained. This resulted in mixed messages being communicated and, in some instances, stock-out of vaccines, particularly in the year of introduction. Finally, vaccine introduction programs must place an early emphasis on the updating of data collection and storage procedures in order to adequately monitor coverage and predict supply needs. Paper records and electronic information systems should be adjusted and made available before introduction and must be available as soon as rollout begins. Unfortunately, the development and strengthening of AEFI and surveillance systems has been inadequate in many countries, and continues to lag behind the new vaccines introduced. When detailed technical guidance and adequate funding is available, new vaccine introduction can present an opportunity to make system-wide improvements that address problems such as surveillance, training, cold chain and logistical capacity, and injection safety system-wide. However, it has been shown that these opportunities are frequently missed due to poor planning around financial and human resources needs . In a coThe introduction of new vaccines such as PCV (13) not only provides a major opportunity to reduce childhood deaths from one of the major causes of mortality in children, but can also provide a platform to strengthen immunization and health systems, particularly in the areas of health worker capacity, service delivery, recording tools, information management, logistics and vaccine supply systems, communications, community engagement, coordination and partnership. Leveraging the political will to address chronic systemic issues related to low immunization rates and strengthen the broader health system remains a potential but often under-utilized opportunity. In future, regular reviews, updating of guidelines and application of the lessons learned through country experience in not only introducing, but sustaining high and equitable performance will go a long way towards increasing the uptake of new vaccines in the years ahead. Consistently, country experiences draw attention to the essential role of health systems in countries’ ability to achieve and sustain high coverage years following the introduction of new vaccines. Given that several introductions of new vaccines are planned in the coming years in the African region, more detailed study will be required to identify these factors and how they interrelate with sustained immunization uptake of new vaccines beyond the introductory period.The authors declare no competing interest.


Titin stiffness appears to increase with muscle force production, providing a mechanism that explains two fundamental properties of eccentric contractions: their high force and low energetic cost. The high force and low energy cost of eccentric contractions makes them particularly well suited for athletic training and rehabilitation. Eccentric exercise is commonly prescribed for treatment of a variety of conditions including sarcopenia, osteoporosis, and tendinosis. Use of eccentric exercise in rehabilitation and athletic training has exploded to include treatment for the elderly, as well as muscle and bone density maintenance for astronauts during long-term space travel. For exercise intolerance and many types of sports injuries, experimental evidence suggests that interventions involving eccentric exercise are demonstrably superior to conventional concentric interventions. Future work promises to advance our understanding of the molecular mechanisms that confer high force and low energy cost to eccentric contraction, as well as signaling mechanisms responsible for the beneficial effects of eccentric exercise in athletic training and rehabilitation.When active muscles are stretched, our understanding of muscle function is stretched as well. Our understanding of the molecular mechanisms of concentric contraction has advanced considerably since the advent of the sliding filament theory, whereas mechanisms for increased force production during eccentric contraction are only now becoming clearer. Eccentric contractions play an important role in everyday human movements, including mobility, stability, and muscle strength. Shortly after the sliding filament theory of muscle contraction was introduced, there was a reluctant recognition that muscle behaved as if it contained an “elastic” filament. Jean Hanson and Hugh Huxley referred to this structure as the “S-filament,” though their concept gained little traction. This additional filament, the giant titin protein, was identified several decades later, and its roles in muscle contraction are still being discovered. Recent research has demonstrated that, like activation of thin filaments by calcium, titin is also activated in muscle sarcomeres by mechanisms only now being elucidated. The  Effectively, the measurements had defined the perception of how muscles operate.Nearly a century ago, critical experiments conducted largely by A. V. Hill and his students Hill, , 1938, dHowever, when the magnitude of a force applied to a muscle exceeds that produced by the muscle, the muscle will lengthen as work is done on it . The history of investigations into lengthening, or eccentric, muscle contraction is anything but straight forward. Even the term “eccentric” , is due to cross-bridges detaching from actin. They propose that the extra tension that remains after stretch to lengths >18 nm per half sarcomere is due to titin. Because the operating length of muscles are generally much larger than 1.1 L0, ~10% L0, , the force of myofibrils increases more rapidly with stretch than it does in passive myofibrils  tandem immunoglobulin (Ig) domains and (2) the PEVK segment  titin stiffness increases in activated skeletal muscle prior to development of force  the N2A region of titin binds to actin; and (2) because the cross-bridges not only translate but also rotate the thin filaments, the PEVK segment of titin “winds” on the thin filaments during force development  in cardiac muscle, and cardiac muscle titin is much stiffer passively than titin in skeletal muscle . Once accepted, any observed cause-effect relationship becomes the paradigm within which future experiments are designed and interpreted. In fact, we have learned a great deal about how muscle responds to damage/injury through this valuable model of high-force, acute eccentric contractions  include changes in the recruitment of motor units with subsequent exposures to eccentric contractions, the elimination of weak areas of muscle fibers after an initial exercise bout, and the development of more resilient muscle structures Stauber, . What isA unique advantage of high-intensity eccentric training is shorter recovery times for some of the most common, long-lasting, and debilitating sports injuries  muscle contractions, though acknowledged, were rarely considered to be more than an oddity or perhaps a method for inducing muscle injury. Because eccentric contractions were not easily explained by conventional theories, several hypotheses were developed that attempted to explain eccentric contractions. Neither cross-bridge mechanisms nor sarcomere or half-sarcomere length non-uniformities can adequately account for the observations. Earlier suggestions that a structural elastic element might develop upon muscle activation were confirmed by recent findings that the stiffness of the giant titin protein increases upon activation in skeletal muscle. Incorporation of titin as a “third filament” in our concept of muscle sarcomeres has led to a profusion of new proposals for a role in active muscles. The “winding filament hypothesis” in particular explains several enigmatic muscle properties, including the high force and low cost of eccentric contractions. Ongoing experiments in single molecules, myofibrils, and intact muscles should soon provide the information necessary for critical tests of alternative hypotheses for titin-actin and titin-myosin interactions in skeletal muscle. New evidence suggests that giant sarcomeric proteins play an important role in the length dependence of force, not only in vertebrate skeletal muscles, but also in the Frank-Starling effect in cardiac muscle and catch tension in muscles of invertebrate animals. Recent research also demonstrates the benefits of eccentric training for numerous practical applications. These include rehabilitation for sports injuries, rehabilitation for persons who are intolerant of traditional exercise, elite athletic training, and training for astronauts during space travel when the risks of muscle and bone atrophy are high and a premium is placed on energy efficiency. High-intensity eccentric exercise results not only in muscle hypertrophy and increased bone mineralization, but also appears to improve tendon remodeling after injury. Elucidating the signaling mechanisms responsible for these beneficial effects of eccentric training should be a major priority for future research.Studies involving human participants were performed in accordance with relevant institutional and national guidelines, with the approval of Northern Arizona University's Institutional Review Board for research involving human subjects, and with informed written consent from all human subjects involved in the study. Studies involving animals were carried out in accordance with the recommendations of the United States Department of Agriculture (USDA) Animal Welfare Act and Regulations (AWA), the Guide for the Care and Use of Laboratory Animals, Public Health Services Policy on Humane Care and Use of Laboratory Animals, Occupational Safety and Health Administration (OSHA), and Environmental Protection Agency (EPA) regulations, Northern Arizona University's Institutional Animal Care and Use Committee policies and procedures. The research was approved by Northern Arizona University's Institutional Animal Care and Use Committee.All authors contributed to the development, writing and editing of this paper. KN also provided final edits and collection of figures.This work was supported in part by the W. M. Keck Foundation to KN, the National Science Foundation  to KN, and the Achievement Rewards for College Scientists Foundation to AH.One of the authors (SL) is a co-inventor of an ergometer licensed to Eccentron; BTE Technologies, Inc., Hanover, MD, USA. Neither SL nor any of the other authors have received any financial incentives  from the company stemming from the contents of this manuscript or any related published papers. The other 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.


Merluccius merluccius), red mullet (Mullus barbatus), annular seabream (Diplodus annularis), common pandora (Pagellus erythrinus), European anchovy (Engraulis encrasicolus), European pilchard (Sardina pilchardus) and bogue (Boops boops) were the most studied species, while sharks and rays were among the least studied ones. Only 25 species were fully studied, i.e. there was available information on all their biological characteristics. The knowledge gaps per characteristic varied among the western, central and eastern Mediterranean subregions. The number of available records per species was positively related to total landings, while no relationship emerged with its maximum reported length, trophic level and commercial value. Future research priorities that should be focused on less studied species (e.g. sharks and rays) and mortality/fecundity instead of length-weight relationships, as well as the economy of scientific sampling  are discussed.We estimated the current level of knowledge concerning several biological characteristics of the Mediterranean marine fishes by carrying out a gap analysis based on information extracted from the literature, aiming to identify research trends and future needs in the field of Mediterranean fish biology that can be used in stock assessments, ecosystem modeling and fisheries management. Based on the datasets that emerged from the literature review, there is no information on any biological characteristic for 43% (n = 310) of the Mediterranean fish species, whereas for an additional 15% (n = 109) of them there is information about just one characteristic. The gap between current and desired knowledge  is smaller in length-weight relationships, which have been studied for 43% of the species, followed by spawning (39%), diet (29%), growth (25%), maturity (24%), lifespan (19%) and fecundity (17%). The gap is larger in natural mortality for which information is very scarce (8%). European hake ( Mullus spp.) and annular seabream (Diplodus annularis), among other species [Ichthyology and fish biology were born in the Mediterranean Sea with Aristotle 384–322 BC) being the first to describe aspects of the life history of fishes  with his2 BC bein species . Concern species  with the species . To that species , onset a species , length  species  and age  species , growth  species , 14 and  species  of MeditA detailed knowledge of biological characteristics  of marine fishes and invertebrates is important in age-based models used in stock assessments that provide the basis for decision-making in fisheries management . The bioIn addition, the ecosystem approach to fisheries management requires that decision making should be based not only on the characteristics of a particular stock, but on all components of the ecosystem . This isThe objective of the present work was to record the available information on key biological characteristics of the Mediterranean marine fishes, aiming at identifying data gaps in the available knowledge. Also to examine the hypotheses that the number of available records per species depends on the commercial value of the species or its landings and if it is related to its size and position in the marine food web. Finally, to provide some recommendations for future research targets for fisheries science and management based on the actual needs (i.e. information gaps and missing data) and discuss how these targets can be achieved through the maximum economy of scientific sampling. Once gaps are minimized, the ecosystem indicators and species description will be improved and will in turn contribute to the better understanding of their biology and interactions within the ecosystem perspective.Gap analysis, as used in management literature , clearlWe revealed this gap by estimating the proportion of species and biological characteristics that has been fully or partially studied, including the most/least studied species, as well as the most/least studied biological characteristics. We collected data on all fish species that have been recorded in the Mediterranean Sea large marine ecosystem as they are listed in FishBase . Overall∞) and the rate at which it is approached (K), and for lifespan (A) records with the maximum age (tmax). The onset and duration of spawning (Spawn) and length at maturity (Lm) were considered to identify spawning and maturity records, respectively, while absolute and relative number of oocytes produced per female were considered for fecundity (Fec). The prey items and feeding preferences were used as records for diet (Diet), whereas for natural mortality (M) the natural mortality rate regardless its estimation method.For length-weight relationships (LWR) we considered records with both the slope (b) and intercept (a) of the relationship, for somatic growth (G) records with the asymptotic length (Lmax) and trophic level (τ) for all species as well as their commercial value , shown as price category in FishBase . We also extracted their total Mediterranean landings averaged for the last five years (2010–2014) from the FAO-GFCM database [To examine whether the number of records per species depends on the species size, position in the food web or commercial value, we also extracted from FishBase the maximum reported length , while for 109 (15%) of them there is information for only one characteristic. As far as the individual biological characteristics are concerned, the gap is smaller for length-weight relationships which are the most common characteristic as they have been studied for 310 (43%) species, followed by spawning , diet , growth , maturity , lifespan , and fecundity . The gap is larger in natural mortality  for which information is scarce (The percentage of studied species that are listed under the categories near threatened (NT), vulnerable (VU), endangered (EN) and critically endangered (CR) of the IUCN Red List (n = 83) compared to all species listed was lower for all biological characteristics except for maturity and fecundity (Merluccius merluccius), red mullet (Mullus barbatus barbatus), annular seabream (Diplodus annularis), common pandora (Pagellus erythrinus), European anchovy (Engraulis encrasicolus), European pilchard (Sardina pilchardus), bogue (Boops boops), common two-banded seabream (Diplodus vulgaris), tub gurnard (Chelidonichthys lucerna), Atlantic horse mackerel (Trachurus trachurus), axillary seabream (Pagellus acarne), white seabream (Diplodus sargus sargus), Mediterranean horse mackerel (Trachurus mediterraneus), picarel (Spicara smaris), big-scale sand smelt (Atherina boyeri), Atlantic bluefin tuna (Thunnus thynnus), garfish (Belone belone), stargazer (Uranoscopus scaber), large-scaled gurnard (Lepidotrigla cavillone), brown meagre (Sciaena umbra), dusky grouper (Epinephelus marginatus), Atlantic chub mackerel (Scomber colias), brown ray , grass goby  and transparent goby (Aphia minuta). For these twenty-five species there is available information for all the biological characteristics considered in the present work  , annular seabream , common pandora , European anchovy , European pilchard  and bogue .In terms of number of records, the most studied Mediterranean fish species  were EurAlthough the general pattern on the studied characteristics and the most studied species holds among the western, central and eastern Mediterranean, there are some spatial variations within each biological characteristic . In the Cetorhinus maximus), thresher (Alopias vulpinus), and great white shark (Carcharodon carcharias). Among the least studied rays were also the stingrays of the family Dasyatidae, and most skates and rays of the family Rajidae, while among the least studies sharks were the members of the families Hexanchidae and Squatinidae. Finfishes with atypical reproductive strategies, such as most gobies (Family Gobiidae) and pipefish (Family Syngnathidae) (Lampris guttatus), the first known warm-blooded fish [Mola mola), which is the most fecund fish with each female producing over 300 million eggs per spawning act [Prionace glauca) and devil fish (Mobula mobular).Our analysis showed that a large number of highly commercial fishes were understudied with available information on less than half of their biological characteristics . Severalathidae) . There ided fish , and thening act , have noFor Mediterranean fish species with at least one studied biological characteristic and with available landings data, the number of records was positively correlated to total landings  . In contGobius niger) and bluespotted cornetfish (Fistularia commersonii), and the highest number of records per cm of somatic length (records/cm) was observed for the annular seabream (4.08 records/cm), anchovy (3.56 records/cm), red mullet (3.18 records/cm), Mediterranean banded killifish (Aphanius fasciatus) (3.00 records/cm), European pilchard (2.44 records/cm), and giant goby (Gobius cobitis) (2.33 records/cm).The highest number of records per ton of production (records/t) was observed for the black goby (ca. 21–30%) have been studied per characteristic but an asymptote has not been reached yet , European pilchard (Sardina pilchardus), annular seabream (Diplodus annularis) and common pandora (Pagellus erythrinus), but also surmullet (Mullus surmuletus) and red mullet (Mullus barbatus barbatus), belong to the most well-studied fish families in the Mediterranean [Parapeneaus longirostris) and Norway lobster (Nephrops norvegicus) are among the stocks that are routinely assessed in many Mediterranean areas [The most studied Mediterranean fish species , as showerranean . Becausean areas . Red mulan areas .The knowledge gaps vary among regions but the general pattern of studied characteristics and species per subregion is similar to the total, with length-weight relationships and spawning being the best studied features and hake, red mullet, and common pandora, being the best studied species . The remGadus morhua) and European pilchard are the most studied species [Worldwide, Salmonidae is the most frequently and well studied family (contrary to our results because the marine species of this family are not inhabiting the Mediterranean Sea), whereas Atlantic cod  and of the lessepsian bluespotted cornetfish (Fistularia commersonii) as the most studied species per ton of catch can be explained if part of the catch of these species remains unreported or aggregated [Aphanius fasciatus) and giant goby (Gobius cobitis) among the most studied species per cm of somatic length is certainly surprising and unexpected, but confirms the occasional scientific interest towards species with no commercial value but with atypical behavioural or biological characteristics. In the case of the Mediterranean banded killifish, which is protected by international conventions, one PhD thesis [The presence of black goby (gregated , as it iD thesis  and the Our results are in general agreement with those of  and poinAlthough the cumulative number of new marine fish species studied per year in the Mediterranean increases, it has not yet reached an asymptote, which implies that there are still many species to be studied, at least regarding their reproductive biology and feeding . The cumWe believe that future research priorities should focus on the biological characteristics for which the gap from desired knowledge is large, especially on mortality and fecundity, whereas length-weight relationships should be studied only for species with no data in FishBase . ConcernBased on the above, sharks and rays that are long-lived, slow growing, late maturing, produce only a few oocytes and are therefore more susceptible to overfishing , are amo


Distributions of haplotypes revealed that selection for pleiotropic genes or interactive genes controlling different traits focused on genotypes with weak effect or on those balancing two traits that maximized production but sometimes their utilization strategies depend on the traits and environment. Detection of pQTLs and interactive genes and associated molecular markers will provide an ability to overcome disadvantageous correlations and to utilize the advantageous correlations among traits through marker-assisted selection in breeding.Avoidance of disadvantageous genetic correlations among growth duration and yield traits is critical in developing crop varieties that efficiently use light and energy resources and produce high yields. To understand the genetic basis underlying the correlations among heading date and three major yield traits in rice, we investigated the four traits in a diverse and representative core collection of 266 cultivated rice accessions in both long-day and short-day environments, and conducted the genome-wide association study using 4.6 million single nucleotide polymorphisms (SNPs). There were clear positive correlation between heading date and grain number per panicle, and negative correlation between grain number per panicle and panicle number, as well as different degrees of correlations among other traits in different subspecies and environments. We detected 47 pleiotropic genes in 15 pleiotropic quantitative trait loci (pQTLs), 18 pleiotropic genes containing 37 pleiotropic SNPs in 8 pQTLs, 27 pQTLs with  Oryza sativa L.) is the staple food of a large proportion of the world population. Development of elite varieties that use light and soil resources efficiently to produce high yield is an important way to eliminate food shortages resulting from population growth and reductions in the area of arable land . Thus it is feasible to balance the relationships among traits by breaking constraints and to uncover the genetic basis underlying correlations among HD and yield.Rice (http://www.gramene.org/), which densely distributing across the 12 chromosomes  has revealed many pleiotropic QTLs (pQTLs) that contributing to the correlations among HD and yield traits at the genomic level. Approximately 734, 209, 239, and 223 widely dispersed QTLs for HD, GNP, PN, and KGW were mapped using different segregating populations respectively  using high quality single nucleotide polymorphisms (SNPs) has been proved to be a good approach to explain the genetic basis of complex quantitative traits , the whole genome sequence of the entire MCC, was carried out using high-throughput sequencing on the HiSeq2000 platform of BGI-Shenzhen Li, . Clean rindica, japonica and full populations on traits HD, GNP, PN and KGW were separately implemented using the compressed mixed linear model (CMLM) that took into account population structure estimated by principal component (PC) and kinship so as to reduce false positives  available as part of the GAPIT software package (version 3.0.2)  was higher than -log10(P_perm), where P_perm was the lowest P-value in 1,000 permutation tests, was considered to be real association between the SNP and the original phenotype in the GWAS.Given that most of multi-test adjustment methods especially the Bonferroni correction are too stringent because not all markers are independent due to linkage disequilibrium (LD) among markers, missing QTL with small effect usually makes GWAS not as straightforward as previously thought  of all pairs between significant SNPs in HD QTL and significant SNPs in GNP QTL using HAPLOVIEW, the detail is demonstrated in the schematic diagram  between average r2 of LD and differences between phenotypic variance contributions (PVC) to GNP for HD QTL and GNP QTL . This rHD2GNP thus accounted for the hitch-hiking effect of HD QTL on GNP. Similarly, we also calculated the hitch-hiking effect of GNP QTL on HD QTL, rGNP2HD, and other combinations.To investigate the role of LD on phenotypic correlation (such as HD vs. GNP) through hitch-hiking effects of QTL controlling one trait (such as HD) with other traits (such as GNP), we firstly calculated the average indica landraces, improved indica varieties, japonica landraces, and improved japonica varieties.We investigated the significance of effects on related traits of alleles of each pleiotropic SNP , haplotypes of pQTLs, and interactive genes  by multiple comparison analysis of GLM in SPSS (version 19.0). Alleles with significantly higher effect on some traits such as HD were denoted as increased effect alleles for that trait, and those with significantly lower effect were denoted as decreased effect alleles. For pSNPs or haplotypes, for example, pleiotropy between HD and GNP, we classified their effects into four types: the same direction (SD) with both increased effect on HD and GNP, or SD with both decreased effect on HD and GNP, the opposite direction (OD) with increased effect on HD but decreased effect on GNP, or OD with decreased effect on HD but increased effect on GNP. We then calculated the distribution of alleles with different kinds of effects among four types of varieties, including japonica had longer HD, more GNP and PN, and lower KGW than indica in both environments. Pearson's correlation analysis  and each subspecies, the differences of which contributed to 94% of population structure and differentiation using CMLM  was reported to control the chlorophyll levels and chloroplast number, and to further affect plant biomass including GNP and PN  between QTLs of two traits belonging to the same pQTL. Among 46 pQTLs, the LD of approximately 5% of combinations exceeded 0.6  levels   of pQTLs showed that the interplay influence decreased along with the LD decay in one pQTL, indicating the contribution of LD to the phenotypic correlation. The effect of these pQTLs on different traits  for all cloned genes and significantly associated genes related to the four traits, we discovered 15 pathways in which two or more genes were involved in regulation of multiple traits and in which at least one of them was cloned. In the 15 pathways (Supplementary Table OsCCD7 (LOC_Os04g46470) and CYP97A4 (LOC_Os02g57290) interactively control PN and GNP by determining the production of carotenoid, i.e., strigolactone or abscisic acid. It has been shown that ABA is a regulator of strigolactone biosynthesis  was reported to negatively control tiller number, PN and GNP  also showed high expression level of CYP97A4 in inflorescences of Nipponbare. The above results suggest that OsCCD7 (LOC_Os04g46470) and CYP97A4 (LOC_Os02g57290) might jointly control GNP and PN by interaction in the carotenoid biosynthetic pathway. The effect of haplotypes for each pair of iGenes on the traits , which is a key enzyme in the sucrose biosynthesis pathway  and CYP97A4 (LOC_Os02g57290) might together control GNP and PN by interaction in carotenoid biosynthetic pathway. The contributions of these three genetic bases to correlations among traits varied. Percentages of SD and OD indicated that in general the contributions of pSNPs or pGenes were the strongest, followed by iGenes within pathways, and linkage between genes was the lowest. The number of pSNPs, pQTLs and iGenes among different traits (Supplementary Table Previous study supported at least two genetic bases underlying correlations among traits in rice, i.e., pGenes (Supplementary Figures japonica (Xue et al., indica varieties in low latitudes and altitudes (Khush, Disadvantageous correlations among agronomic traits are important constraints to maximizing the potential of each trait. Therefore, breaking or weakening correlations is one of the problems faced by breeders. Our results reveal the diverse genetic bases of phenotypic correlation in rice and different strategies for improving the related traits. It is a difficult task to develop varieties with short growth duration and more GNP due to the high proportion of pGenes, pQTLs and interactions in the same pathways, in which the genotype with short growth duration is accompanied by few GNP in majority of the cases. To overcome the contradictory effect of pGenes or iGenes, farmers and breeders tend to utilize genotypes with weak sensitivity to day-length so as to develop the varieties that adapt the long-day environment with the cost of moderately decreased GNP during the domestication of s Khush, . Our ress Khush, , 9, 10, In summary, phenotypic correlations among growth duration and yield traits can be advantageous or disadvantageous depending on variety types and environments. Selection for pGenes or iGenes needs to focus on the genotypes with weak effects when two traits show disadvantageous negative correlations or on genotypes with strong effect when two traits have advantageous positive correlations. Discovery of pQTLs attributed to different genes with strong LD or iGenes will provide breeders the opportunities to overcome the disadvantageous phenotypic correlations among traits by breaking the disadvantageous linkages or genotype combination for two genes, and also provide the opportunities to improve the breeding efficiency by simultaneously selecting two trait pairs with advantageous phenotypic correlation through MAS.FL and HZ designed the experiments. FL wrote the manuscript and performed data analysis. JX, XZ, XW, XM, ZhiZ, LZ, and SZ helped in data analysis. YZ, ZhaZ, and MR helped to prepare the manuscript. HZ, ZL, and JL conceived and supervised the project. HZ and ZL conceptualized and guided the study.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.


The present study aimed to find gender differences for arterial stiffness and arterial aging in smokers. A total of 147 smokers  were explored using an Arteriograph in a cross-sectional survey. Pulse wave velocity (PWV), arterial age (AA), brachial and aortic augmentation index , and blood pressure variables were assessed. Data about smoking intensity, such as the number of cigarettes smoked daily, smoking period, and smoking pack years (SPY) were used. No significant differences were found for PWV, AA, AixBrach and AixAo. Significant correlations were found between SPY and PWV, augmentation indices, and AA, respectively. The cut-off values for SPY were higher for an increased arterial stiffness in male compared to female smokers . SPY is significantly associated with an increased arterial stiffness in smokers regardless of gender, and with an increased SBPAo only in female smokers. The results of our study indicate gender differences for arterial stiffness and arterial age in smokers. Public health programs and legislation significantly decreased the prevalence of tobacco smoking and secondhand tobacco smoke exposure in several countries . SmokingArterial stiffness is a marker of arteriosclerosis and subclinical atherosclerosis, and provides information beyond standard cardiovascular risk factors in the prediction of future cardiovascular events . CurrentAll-cause and cardiovascular mortality are higher in men than in women, but there is a higher increase of cardiovascular mortality in women with age, especially after menopause, due to estrogen deficiency . Gender In Romania, the percentage of declared smokers was 30% in 2010, easily exceeding the European average in percentage of smokers, and the average number of cigarettes smoked daily was 15 [It was the aim of the present study to explore gender differences of arterial stiffness, endothelial function, and arterial aging in smokers.Study population: A total of 147 consecutive volunteer smokers  recruited from a general practitioner’s office were explored using an Arteriograph in a cross-sectional survey. Data about smoking habits were collected. All clinical and biological parameters were evaluated on the day of Arteriograph examination. The investigations conformed to the principles outlined in the Declaration of Helsinki, and were approved by the “Victor Babes” University (2743/9 March 2016). Written informed consent was obtained from each study participant. The purpose and procedures of the study were explained to each participant.Exclusion criteria: patients with atrial fibrillation, diabetes mellitus, history of coronary heart disease, myocardial infarction, stroke, transient ischemic attack or peripheral arterial disease, and therapy with drugs known to influence arterial stiffness  were excluded.Arteriograph: An Arteriograph—an oscillometric, noninvasive, validated, operator-independent device —was used to assess central and peripheral blood pressure variables, pulse wave velocity (PWV), augmentation indices , and arterial age (AA) in each study participant. PWV is a measure of arterial stiffness, and assesses the velocity of the movement of the pulse wave generated during ejection of the left ventricle, along the arterial tree. As the pulse wave travels from the aortic root to the peripheral vessels, a first systolic direct wave results, and due to diameter changes and bifurcations, a second reflected wave occurs. The augmentation index was automatically calculated from the blood pressure waveform as the difference between the amplitude of the reflected (late systolic) and direct (first systolic) wave, divided by the pulse pressure and multiplied by 100. The pulse pressure is the difference between systolic and diastolic blood pressure. Arterial age is a measurement of aortic PWV, which depends on age and was automatically calculated by the Arteriograph.The methodology and the significance of the variables were previously described . RecordiSmoking variables: The study participants were interviewed to determine smoking status and data about smoking habits (self-reported): the number of cigarettes smoked daily and smoking period. Smoking pack years (SPY) was calculated as an expression of lifetime tobacco exposure. One “pack year” is 20 cigarettes smoked/day for 1 year ,19.Other variables: Data about cardiovascular family history, diagnosis, and therapy were also collected from medical records.Statistical analysis: Categorical data are given as numbers and percentages; continuous data as means ± standard deviation. Standard deviations were calculated from the unbiased estimator of the variance. Binary logistic regression analysis with a single categorical predictor, Bravais-Pearson correlation coefficient, Wilcoxon test, ANOVA, and receiver-operating characteristic (ROC) curve analysis were used as statistical methods. Analyses were performed using Excel 2016, IBM SPSS Statistics Free trial, the STATS package from The Comprehensive R Archive Network (R for the Wilcoxon test), and a self-programmed algorithm with Python) (ANOVA). Wilcoxon test and ANOVA were used to report significant differences between male and female smokers. Logistic regression analysis and Bravais–Pearson correlation assessed the relationship between SPY and variables obtained during oscillometric measurements. ROC curve analysis allowed a complete sensitivity/specificity report of SPY for an increased AixBrach, systolic blood pressure in the aorta (SBPAo), and PWV.The power analysis conducted to determine the sample size needed for the present study showed a minimum sample size required for Bravais–Pearson correlations of 29 participants . The required sample size for an area under the curve (AUC) of 0.8, 95% confidence interval, 80% power, and a marginal error of 0.12 was 61.The characteristics of the male and female study population and the obtained variables are included in Men had significantly higher values for SPY, number of cigarettes smoked/day, BMI, and blood pressure values compared to female smokers. Brachial augmentation index was more severely impaired in female compared to male smokers, but the differences were statistically significant only after adjusting for heart rate . No signMore important correlations were found between SPY and arterial age, AixAo and AixBrach, respectively , in maleBinary logistic regression analysis was performed separately for male and female smokers. SPY was associated with an increased arterial stiffness in both male and female patients .ROC curve analysis revealed SPY as a diagnostic test for AixBrach ˃ 10% and increased arterial stiffness (PWV ˃ 9.7 m/s), regardless of gender. SPY was also a significant diagnostic tool for an increased systolic blood pressure in the aorta (˃130 mmHg) in female smokers. The cut-off values for SPY—related to an increased arterial stiffness—were higher in male compared to female smokers .The present study shows gender differences for the vascular consequences of smoking—especially for arterial stiffness. SPY was significantly associated with an increased arterial stiffness regardless of gender, but a lower exposure to cigarette smoke is needed in order to increase arterial stiffness in female compared to male smokers. SPY affects arterial age more severely in male smokers.Smoking has been defined as a chemical toxicosis, and several harmful compounds were found in tobacco, such as nicotine, tar, thiocyanate, and carbon monoxide ,21. MainPrevious studies reported higher aortic systolic blood pressure and augmentation index in chronic smokers compared to nonsmokers—regardless of gender—and increase of blood pressure, augmentation index, and pulse wave velocity after smoking of one cigarette, regardless of smoking status . The incThe strengths of the present study lie in the recruitment of real-world participants free of severe cardiovascular comorbidities and drugs able to influence aortic elastic properties. As far as we know, our study shows for the first time using ROC curve analysis gender differences related to the vascular effects of smoking, demonstrating a lower SPY cutoff value for increased arterial stiffness in female compared to male smokers in two groups of male and female smokers, respectively, matched for age, PWV, and arterial age. SPY more severely impaired arterial age in male compared to female smokers, probably related to the cardiovascular protective anti-atherogenic effects of estrogens in young and middle-aged women included in the present study. Brachial and aortic augmentation indices were significantly higher in female smokers only after adjusting for heart rate, probably related to the higher heart rates recorded in this group. The findings of the present study have clinical implications, considering the prognostic importance of increased arterial stiffness for cardiovascular risk.Cardiovascular screening using an Arteriograph may be beneficial in smokers. Monitoring of brachial augmentation index and pulse wave velocity and early detection of increased arterial stiffness are especially important in female smokers, in order to reclassify patients to higher or lower risk groups and avoid severe cardiovascular events. The Arteriograph provides a simple method to assess PWV, augmentation indices, and arterial age in daily clinical practice, similar to the conventional measurement of blood pressure. The present study encourages lifestyle changes in smokers, emphasizing the importance of smoking cessation—especially in women—for positive vascular outcomes in order to reduce the burden of cardiovascular disease. Smokers are aware of the harmful effect of smoking, but they continue due to the addiction and the belief of improved stress management, but the beneficial effect on stress reduction was questioned by a recent study .Study limitations: The most important limitations of the present study are the cross-sectional study design, the observational nature of the study, the small patient number, self-reported data about smoking habits, the use of arterial stiffness and arterial age as surrogate markers of cardiovascular risk, and missing data related to lipid profile, fasting blood glucose, and serum creatinine. The cross-sectional study design does not provide data about a cause–effect relationship between the variables. Aortic PWV measurement provided by the Arteriograph has also been questioned, but it has been previously validated against invasive methods . There eFurther larger follow up studies are needed in male and female smokers to confirm the findings of the present study and to compare the collagen content of the arterial wall considering gender.SPY is significantly associated with an increased arterial stiffness, regardless of gender and with an increased systolic blood pressure in the aorta in female smokers. The present study shows gender differences for arterial stiffness and arterial age in smokers. A lower exposure to cigarette smoke is needed to increase arterial stiffness in female compared to male smokers.


The aims of this study were to provide a comprehensive summary of the body of research disseminated by Cerebral Palsy (CP) registries and surveillance programs from January 2009 through May 2014 in order to describe the influence their results have on our overall understanding of CP. Secondly, registries/surveillance programs and the work they produced were evaluated and grouped using standardized definitions and classification systems.A systematic review search in PubMed, CINAH and Embase for original articles published from 1 January 2009 to 20 May 2014 originating from or supported by population based CP registries and surveillance programs or population based national registries including CP were included. Articles were grouped by 2009 World CP Registry Congress aim, registry/surveillance program classification, geographical region, and the International Classification of Function, Disability and Health (ICF) domain. Registry variables were assessed using the ICF-CY classification.Literature searches returned 177 articles meeting inclusion criteria. The majority (69%) of registry/surveillance program productivity was related to contributions as a Resource for CP Research. Prevention (23%) and Surveillance (22%) articles were other areas of achievement, but fewer articles were published in the areas of Planning (17%) and Raising the Profile of CP (2%). There was a range of registry/surveillance program classifications contributing to this productivity, and representation from multiple areas of the globe, although most of the articles originated in Europe, Australia, and Canada. The domains of the ICF that were primarily covered included body structures and function at the early stages of life. Encouragingly, a variety of CP registry/surveillance program initiatives included additional ICF domains of participation and environmental and personal factors.CP registries and surveillance programs, including novel non-traditional ones, have significantly contributed to the understanding of how CP affects individuals, families and society. Moving forward, the global CP registry/surveillance program community should continue to strive for uniformity in CP definitions, variables collected and consistency with international initiatives like the ICF so that databases can be consolidated for research use. Adaptation to new technologies can improve access, reduce cost and facilitate information transfer between registrants, researchers and registries/surveillance programs. Finally, increased efforts in documenting variables of individuals with CP into adulthood should be made in order to expand our understanding of CP across the lifespan. Cerebral palsy (CP) is a neuromuscular disorder caused by an injury to the fetal or infant brain that affects the development of movement and posture and causes activity limitations. The motor disorders of CP are often accompanied by disturbances of sensation, perception, cognition, communication, and behavior; by epilepsy; and by secondary musculoskeletal problems . This coTo understand the complexity of cerebral palsy, registries using total population of a geographically defined area as the denominator were established and became instrumental in the contribution to our understanding about prevalence –7, risk Over time, the quest to understand CP, its prevalence and prevention grew globally. Funding mechanisms, government healthcare, and social service programs differ between and within countries, necessitating innovative ways to collect data and perform population-based CP research –23. New At the 3rd International Cerebral Palsy Conference , the Research Foundation of the Cerebral Palsy Alliance hosted a World CP Register Congress, providing an opportunity for global CP registries and surveillance programs to meet and discuss practices and strategies . This CoAlthough the scientific community has seen a diversification in structure and characteristics of CP registries/surveillance programs over the past decades, there have also been international initiatives to standardize language used to define and classify CP and frameworks to conceptualize health conditions and disorders. One such initiative to unify domains in which clinicians and researchers think about health status in a broad sense was the 2001 World Health Organization’s (WHO) International Classification of Functioning, Disability and Health (ICF). This model acknowledges the body structure and function aspects of a condition, but also examines how it impacts activities of daily life, participation within society and influence of environmental and personal factors .The purpose of this systematic review was to examine and evaluate the research productivity of international CP registries/surveillance programs since the 2009 World CP Register Congress, as it relates to registry characteristics. Specifically, articles were evaluated using established CP registry and surveillance programs’ aims, the type of registry/surveillance program that produced the data and region where it is located. The ICF domains represented in the articles as well as in database variables of known CP registries/surveillance programs were also examined.A systematic search was conducted by one author (DSH) in collaboration with a medical librarian in MEDLINE (PubMed), Embase, (embase.com) and CINAHL (EBSCO) for original articles published in peer reviewed journals between January 1, 2009 and May 20, 2014. The year of the World CP Register Congress was chosen as a starting date because this is when aims were defined. Controlled vocabulary terms specific to each database were used, based on the terms profiled in the Congress report , includiInclusion criteria for this systematic review were as follows: (1) full length research articles; (2) written in English; (3) published January 2009 – May 20, 2014; (4) pertaining to cerebral palsy either as a primary patient population or as a primary outcome or endpoint; and (5) participant recruitment or data extracted from a population-based database from a defined region.Exclusion criteria for this study were as follows: (1) conference abstracts/presentations; (2) editorials, letters to the editor; (3) CP not a primary aim or endpoint of the study; (4) databases that were limited to non-total population such as individual hospitals, clinics, private insurance companies; (5) recruitment from only the general population, convenience and population cohort groups; (6) articles describing future studies (protocols); (7) non-English articles; (8) systematic reviews, Cochrane systematic reviews and meta-analysis papers.The search resulted in 1,618 abstracts with an additional 14 articles found through incidental discovery . All Cochrane systematic reviews, systematic reviews and meta-analyses (n=42) were reviewed by three authors  for additional articles (n=1) that had potential to fit inclusion criteria. Duplicates were removed and the remaining 788 abstracts were screened for inclusion. These were reviewed independently by two authors  using a data abstraction criteria sheet that was comprised of inclusion/exclusion criteria. Abstracts were retained for full review if they met the inclusion criteria or if more information was needed from the full text to ascertain inclusion. A summary PRISMA flow chart ,27 of thFrom the 788-screened abstracts, 177 met the inclusion criteria for this study. Using decision guidelines, two independent reviewers  categorized each article by primary aim(s), type of CP registry/surveillance program as classified by the CP registry/surveillance program classification system, geographical region captured, and ICF domains represented. Discrepancies were discussed and a final decision was made without requiring an additional independent reviewer. Further details on these categorizations are in the following sections.Consensus was reached at the 2009 World CP Register Congress24 regarding aims and purposes that CP registries should aspire towards. In summary, the CP Registry and Surveillance Program Aims24 include:This aim asserts that CP registries/surveillance programs, through their research data, can assist families and professionals with the development and planning of medical, social and educational services.CP registries/surveillance programs have a unique position to assist with determining etiological understanding and prevention by using the framework of multiple causal pathways to CP.This aim focuses on the potential for CP registries/surveillance programs to increase awareness of CP among community and professional groups through publications, advocacy and social media.This aim asserts that CP registries/surveillance programs are able to use their registered cases as a source of subjects for etiological or management research in several ways. Firstly, they can be used to investigate the generalizability of research results generated from more limited samples of persons with CP. Secondly, databases can be used as a means of identifying CP as an outcome in long term follow up studies. Thirdly, registry observations can be used as a source of hypothesis-generating preliminary evidence concerning causal pathways or management approaches. When these hypotheses are further tested, registered cases can form a sampling frame.CP registries/surveillance programs can be used to monitor trends over time and determine prevalence of the diagnosis within a defined population.Two additional uses for CP registries/surveillance programs emerged during abstract screening that were not identified in the original 2009 CP registry aims description. These were CP registries have been used as (1) a recruitment source for independent studies and (2) as a cross-validation tool to confirm or identify the diagnosis of CP within a different sample set. We included these additional purposes within the Resource for CP Research aim.Journal articles were assigned either one or two aims, depending on the use of CP registry/surveillance program data and stated purpose or outcomes of the study. Those with one aim aligned closely to just one of the stated aims above. Instances where two aims were assigned included prevention and surveillance studies that used CP registry/surveillance program enrollees’ clinical data as a resource or when a study’s conclusions could be used for planning or raising the profile of CP. It also occurred when the paper reported an independent, non-CP registry/surveillance program study that used a CP registry/surveillance program for subject recruitment, confirmation of a CP diagnosis or to link data with government datasets.In addition to long-established CP registry/surveillance programs, additional avenues researchers used to obtain population data were identified. Therefore, CP registries/surveillance programs were classified in a new, novel way using dictionary definitions and registry/surveillance program descriptions referred to in the literature.These are registries that maintain databases using the total population of a specific geographical region as their denominator, and are often able to link enrollees through government agencies. Examples include the Victorian CP registry and the Danish National CP Registry –30.Traditional CP registries from multiple regions merging data to establish a collaborative database using common language and variables in order to expand CP research efforts. Examples include the Surveillance of CP Europe (SCPE) and the Australian CP Register (ACPR) ,32.Collaborative CP registry subgroups leverage existing collaborative CP registry data and enrollees for research studies, often adding ICF domains not commonly found in traditional CP registries . An example is the Study of Participation of Children with Cerebral Palsy Living in Europe (SPARCLE) .CP Surveillance programs use methodical, multi-source data collection of variables for a regional CP population when government registry data is unavailable or unattainable. An example includes the Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) .Health care programs have been established for children with CP in certain geographic regions. These surveillance programs aim to prevent hip dislocation, scoliosis and severe contracture deformities and collect and store longitudinal data on children with CP in their databases. Examples include CP Uppföljnings Program (CPUP) in Sweden  and CP OGovernment sponsored total population datasets with indicators of CP and other related neurodevelopmental disabilities can be used independently or linked with CP registries/surveillance programs for research purposes. Examples include the use of Hospital and Patient Registers and the California Department of Developmental Services ,37.These types of programs obtain a total population denominator for CP prevalence in a targeted geographical area through various methods such as door-to-door interviews and population surveys. Examples include prevalence studies in defined areas of Egypt, Pakistan and India ,21,22.Regions were divided into six global areas based on geographical boundaries: Africa, Asia, Australia, Canada, Europe and the United States.One or more ICF domains were identified and categorized for each article according to the World Health Organization International Classification of Functioning, Disability and Health (ICF) definitions for health condition, body structure and function, activities, participation, environmental factors, and personal factors ,38.Of note, articles focusing primarily on surveillance and identification of CP as a diagnosis were categorized as health condition, and those focusing on risk factors related to prenatal influences (in vitro fertilization status or pre-eclampsia for example) were identified as environmental factors because these issues were external to the child with the CP diagnosis.In order to put the productivity of CP registries related to the ICF domains into context, we also compared database variables of 14 global CP registries that were compiled for the 2009 World CP Register Congress with the ICF for Children and Youth (ICF-CY) developmental code sets published by Ellingsen and Simeonsson ,40. The For each of the registries available , we compared their database variables 24 with the ICF-CY code sets ,40. We iDescriptive statistics were compiled for the regions of the world, registry/surveillance program classification, ICF variables, and aims. Further, themes were identified among research studies within each of the established registry/surveillance program aims.In this systematic review, we evaluated the productivity of global CP registries/surveillance programs through peer-reviewed publications on a number of features, including registry/surveillance program aims addressed, registry/surveillance program classification, global region, and ICF domains covered. A total of 177 articles met the criteria for this review . CP regiCP registries/surveillance programs have shown consistent productivity in the years reviewed and are trending upwards, with 27 articles in 2009, increasing to 38 articles in 2013 . The regIn contrast, the articles identified as coming from the Unites States (n=11), Asia (n=4) and Africa (n=1) were significantly fewer in numbers. These regions do not have traditional CP registries in place and instead must rely on surveillance programs, government databases and census methods to ascertain the impact of CP within their countries and regions. No articles were identified in Central or South America or the Middle East.Research productivity showed an unexpected distribution within the registry classification system. Although the registry classification most frequently responsible for production of research articles were traditional CP registries (n=87), there has been substantial productivity from other types of registries as well. More than half of the identified articles came from a combination of other sources, including collaborative registry databases (n=11) and their subgroups (n=14), surveillance programs (n=7), government CP health programs (n=17), government registries and programs (n=35) and population-based surveillance through local surveillance and census techniques (n=6) . Most reArticle aims were categorized using the CP Registry and Surveillance Groups aims described previously. Of the 177 identified articles, 114 addressed one aim, and 63 accomplished two aims. These results and the linkages between aims are summarized in Resource for CP Research was identified as a single aim in 63 studies , coverinThe remaining 60 studies in this aim were classified as two-aim studies because their central theme fulfilled a different aim, but the way the CP registry/surveillance program was used fit into the Resource for CP Research aim. In these two-aim articles, researchers used a CP registry/surveillance program for study subject recruitment, analysis of the CP registry/surveillance program data, linkage of CP registry/surveillance program data with one or more government registries, or to confirm or identify a CP diagnosis for cases found in government registries data. Central themes of these two-aim articles are discussed in the following, respective sections.The Prevention aim had 41 articles, 29 of which addressed two aims. The 12 articles addressing Prevention alone  includinTwenty-seven of the 29 dual-aim articles were shared with Resource for CP Research . Risk faPrevention is a complex issue to address, and there was evidence of a multi-faceted approached to information gathering in the studies reviewed, with extensive linking of multiple sources to obtain study data. Cross-referencing databases increases the validity and confidence of research studies. Most studies used either a traditional CP registry (n=25) or government registry and program dataset(s) (n=14) as one of the sources. Examples of additional data sources include hospital/physician medical records, birth/death registries and insurance databases, with some papers using as many as 4 different resources to compile study data .The Surveillance aim had 39 articles, 32 of which were focused on this aim alone . PrevaleThe 7 Surveillance articles that addressed two aims were generated from traditional CP registries (n=3), collaborative CP registries (n=2), national health surveillance programs for CP (n=1), and CP surveillance programs (n=1) . Six of The 30 articles in the Planning aim addressed planning for current and future needs of children with CP and their families, and how communities can promote social and environmental changes for the success of this group. Data for the Planning articles were obtained from traditional CP registries (n=11), government registries and programs (n=4), national health surveillance programs for CP (n=6), CP surveillance programs (n=5), collaborative CP registries subgroups (n=3), and collaborative CP registries (n=1) .Single aim Planning articles  emphasizTwenty-one dual aim articles shared this aim (Planning) with the Resource for CP Research aim  and emphOnly 7 articles in this review were classified as Raising the Profile of CP. The single-aim article in this aim  describeData elements from 14 registries were reported in the 2009 World CP Register Congress survey , represeThis systematic review provides a comprehensive summary of research disseminated by cerebral palsy registries and surveillance programs, and demonstrates the influence these programs have on our overall understanding of Cerebral Palsy (CP) through research themes and within the ICF framework. CP registries/surveillance programs were characterized by their, region, classification, and when known, how their data elements fulfilled ICF-CY developmental code sets.Establishment of the first CP registries/surveillance programs was done with strict regard to epidemiological considerations. They interfaced with supportive government health care infrastructure to fully ascertain a total CP population within their defined region, and used this cohort as their denominator . This deThere are many areas of the globe that are grossly under-represented in population-based studies of CP. As international research productivity expands, it is unknown if the findings of the studies presented in this review can be appropriately applied to the under-represented regions that have different genetic makeup and cultural values. Developing CP registries/surveillance programs in these uncharted regions and then comparing data with established registries/surveillance programs would be a highly effective way of accelerating discovery of the role of genotype and environment.While there remain strengths and weaknesses with each CP registry/surveillance program classification that are outside of the scope of this review, it is significant to note that research in the field is no longer dependent on any one type of registry/surveillance program, and there may be room for additional strategies in the future as well. Agreement on common language, establishing common data elements for CP –216 and The standardized collection of investigational data is a method for facilitation of data captures, comparison of results across studies and aggregation of information into significant metadata results. This effort has been undertaken in other neurological disorders through a process facilitated by the National Institute of Neurological Disorders and Stroke  in the UThe advantage of adopting international initiatives such as the ICF is that they provide the opportunity to achieve a comprehensive and holistic understanding of individuals with CP. With the ICF-CY, it was found that less than half of the relevant codes were collected after early childhood. This decline in variables by age reflects poorly on how CP registries/surveillance programs are equipped to research adolescent and adult issues. Variables that capture information on aging with CP, such as medical and developmental associated conditions, quality of life issues and education, employment and housing opportunities should be incorporated into data collection. Similarly, the use of the ICF in research articles reviewed remains consistently high in the health condition and body function and structure domains and low in the participation and personal factors domains. Additional focus also needs to be placed on categories of the ICF other than body function and structure in order to provide holistic care and planning for individuals with CP throughout all stages of their life. Comprehensive data will lead to a better understanding of the complex trajectories this heterogeneous and complicated condition presents with, and can be beneficial with planning for the future of newly diagnosed individuals.Interesting findings were discovered in each of the CP Registry and Surveillance Groups Aims. Within Resource for CP Research, new ways research utilized CP registries/surveillance programs were identified. Extensive linking of multiple data sources in the Prevention aim resulted in integrated study data. In the Surveillance aim, traditional CP registries were not contributors of the highest number of articles on prevalence. Government datasets and collaborative CP registries were strong contributors to this aim, demonstrating successful alternative ways on gathering population-based data for CP research. The Planning aim addressed planning for current and future needs of children with CP and their families, and how communities can promote social and environmental changes for the success of this group. The poor representation of the Raise the Profile of Cerebral Palsy aim makes one question if there really is a serious lack of progress in this area or if traditional peer-reviewed journals are the best avenue for promotion and advocacy for CP. For example, international collaborations that include CP registries/surveillance programs have played a role in creating World CP Day .While success of current CP registry/surveillance programs is commendable, adaptation to new technologies can improve access, reduce cost, and facilitate information transfer between registrants and registries, as well as between registries/surveillance programs. New and creative technology solutions can be adopted to reach participants on a regular basis, and facilitate researcher-health professional dialogue. In this era of social media and big data, we have the opportunity to improve the accuracy of information captured in real time, thus allowing for a better understanding of successful support strategies that maximize functioning, participation and well being for those with CP.The main strength of this study was performing a systematic search of several key literature databases using both standardized terminology and keywords (see Search Method for details). All steps of the review  were performed independently by two authors to minimize error. Further, the systematic review has been completed as per PRISMA guidelines. Finally, we focused on several factors that influence CP registry research  with the goal of providing a thorough understanding of the relationship between CP registries/surveillance programs and the research they publish.The main limitation to our study is that reference lists from the final 177 papers were not used as an additional resource for additional articles; therefore the results in this study might be under represented. Nevertheless, regions throughout the world were well represented in the search and a large number of publications were reviewed.CP registries/surveillance programs have made steady contributions of significant research discoveries over the past six years. Through the continued growth and collaboration between international CP registries/surveillance programs for research and epidemiological purposes, CP registries/surveillance programs can further impact surveillance and prevention of CP as well as promote public awareness, programming, and social change so as to improve life course outcomes for all individuals with cerebral palsy across the globe. Key stakeholders within CP research and healthcare delivery should encourage funding agencies to prioritize CP registries/surveillance programs as part of the agenda to accelerate discovery and care for this condition.S1Supp


Women’s participation in medicine and the need for gender equality in healthcare are increasingly recognised, yet little attention is paid to leadership and management positions in large publicly funded academic health centres. This study illustrates such a need, taking the case of four large European centres: Charité – Universitätsmedizin Berlin (Germany), Karolinska Institutet (Sweden), Medizinische Universität Wien (Austria), and Oxford Academic Health Science Centre (United Kingdom).The percentage of female medical students and doctors in all four countries is now well within the 40–60% gender balance zone. Women are less well represented among specialists and remain significantly under-represented among senior doctors and full professors. All four centres have made progress in closing the gender leadership gap on boards and other top-level decision-making bodies, but a gender leadership gap remains relevant. The level of achieved gender balance varies significantly between the centres and largely mirrors country-specific welfare state models, with more equal gender relations in Sweden than in the other countries. Notably, there are also similar trends across countries and centres: gender inequality is stronger within academic enterprises than within hospital enterprises and stronger in middle management than at the top level. These novel findings reveal fissures in the ‘glass ceiling’ effects at top-level management, while the barriers for women shift to middle-level management and remain strong in academic positions. The uneven shifts in the leadership gap are highly relevant and have policy implications.Setting gender balance objectives exclusively for top-level decision-making bodies may not effectively promote a wider goal of gender equality. Academic health centres should pay greater attention to gender equality as an issue of organisational performance and good leadership at all levels of management, with particular attention to academic enterprises and newly created management structures. Developing comprehensive gender-sensitive health workforce monitoring systems and comparing progress across academic health centres in Europe could help to identify the gender leadership gap and utilise health human resources more effectively. Women’s participation in medicine and the need for gender equality in healthcare are increasingly recognised, yet little attention is paid to leadership and management positions in large publicly funded academic health centres. Greater involvement of women in leadership and management is not only an issue of equality and human rights but also an important strategy towards effective utilisation of women’s qualifications, greater creativity and innovation, and improved organisational performance –3.International evidence indicates persisting gender inequality and under-utilisation of women’s expertise in leadership and management positions in academic medicine. For example, in the United States, 47% of medical school matriculants but only 21% of full professors, 15% of permanent department chairs, and 16% of medical school deans are women . While gCharité – Universitätsmedizin Berlin , Karolinska Institutet , Medizinische Universität Wien , and Oxford Academic Health Science Centre —use our own institutions as case studies. Throughout this article, we refer to them collectively as ‘academic health centres’.This study sets out to critically explore and compare the representation of women in leadership and management in European academic health centres. As systematic data are lacking, we—academic and clinical leaders, researchers, and gender equality practitioners from Similarities between the four centres and different country-specific contexts make multi-centre cross-national comparison an important tool to reveal general trends and factors affecting gender equality, yet a framework for comparison is lacking. To take a first step towards developing a common analytical framework and indicators for data collection and analysis, we held a half-day workshop in October 2015 at Charité. Following a bottom-up and context-sensitive approach, we started with describing the management structure of each of the four centres and explaining and translating formal management and leadership positions into English. Next, we explored similarities and differences and tried to identify categories and indicators for comparison. On the backdrop of numerous differences, we decided to reduce the complexity of management structure to three levels  and to use these levels for comparison. The top level includes the boards and senior leaders, while ‘middle’ refers to large units and ‘low’ to smaller units. Then, we jointly assigned the management positions within the four individual cases to these three levels and refined the assessment framework  across eight domains including work, money, knowledge, time, power, health, violence, and intersecting inequalities—ranges from high in Sweden (74.2) to medium in the United Kingdom (58.0), Germany (55.3), and Austria (50.2) . In the Our institutions are large academic health centres characterised by a shared commitment to the integration of university and hospital missions of research, education, and patient care , 12. TheThe current gender breakdown of medical students, doctors, and specialists in Germany, Sweden, United Kingdom, and Austria is compared in Fig. Although medicine in the EU has largely become a gender-balanced profession at the junior level, in all four academic health centres but Karolinska Institutet, women remain under-represented among senior doctors Fig. . No exacThe under-representation of women among full professors and senior doctors creates a leadership gap in the organisational units but in different and uneven ways Table . For exaThe findings indicate important shifts in the gender leadership gap, which challenge the focus of gender policies and research on top-level positions. Remarkably, hospital management now seems to be more permeable for women than academic management. Although changes in gender equality are driven by many different factors , 17–22, Notwithstanding differences in governance and management arrangements as well as in gender equality policies, all centres have taken action to improve gender equality. Major tools include equal opportunity recruitment, anti-discriminatory practices, monitoring of gender equality, career development workshops and seminars, gender-sensitive appointment and promotion criteria, support for parents and carers, flexible and part-time working arrangements, mentoring programmes and networking for women, unconscious bias and diversity training for all staff, and inclusion of gender issues in teaching curricula . While tTo begin with, the Federal State of Berlin makes legal provisions for the position of Central Representatives for Equal Opportunities, and Charité has established a comprehensive policy and action plan . The CenKarolinska Institutet has established a Council for Equal Treatment at the central level and Equal Treatment representatives at the level of departments and developed a comprehensive action plan for equal treatment, which is periodically revised , 29. No At Oxford and elsewhere in the United Kingdom, the Athena Project and the Scientific Women’s Academic Network (Athena SWAN) Charter for Women in Science provides a common framework for advancing gender equality in science and medicine. Every university medical sciences department and the Medical Sciences Division as a whole have Athena SWAN committees and coordinators who develop and implement action plans. The Charter recognises the efforts of participating institutions with institutional and departmental bronze, silver, and gold awards . The ChaAt Vienna Medical University, according to the Austrian Universities Act of 2002, there is a compulsory quota of 40% women on university boards and decision-making committees. This quota is monitored and enforced by the Federal Ministry for Science, Research and Economy on a yearly basis . MoreoveOverall, our case study material illustrates important steps taken at all centres to reduce the gender leadership gap. Although policy frameworks and action plans are usually broad and stretch across organisational levels, gender equality policies focus on top-level positions, especially appointment of professors. In all centres, this is complemented with a range of activities on the individual level such as mentoring programmes for women, and training seminars and workshops to improve the gender-sensitivity of managers. Less attention has been paid so far to the improvement of organisational performance and management, but recent connections between gender equality goals and performance incentives at the level of departments and institutes (middle management) might indicate a move in this direction. There are also no specific education programmes for gender-sensitive clinical leadership, such as modules in Masters’ and Ph.D. courses.In the course of data collection for our comparison, we found that gender-disaggregated data are not systematically collected from a management approach, although each of our centres has well-established organisational structures for human resources and equality. Such data are especially poor for middle and lower organisational levels. This is alarming, because academic health centres with devolved and decentralised organisational structures make important health human resources and funding decisions precisely at these levels. We also found a lack of standardised indicators and efforts to compare the levels of gender equality in academic health centres across the EU member states.In this multi-centre cross-country comparison, we set out to explore a gender gap in leadership and management positions in large publicly funded academic health centres, taking four centres in the EU as case studies. While approximately half of current medical students are women, significantly fewer women than men hold leadership and management positions within academic health centres. Two important patterns can be identified across our centres and countries. First, gender inequality is strongest at the middle level of leadership and management as well as among full professors. Second, the gender leadership gap tends to be narrower within the hospital than within the academic enterprise. Also of importance is that new forms of management  may embody new risks for gender equality and therefore need careful gender assessment. These findings reveal novel and uneven shifts in the gender leadership gap towards the less-well-monitored middle-level management positions.The findings suggest that clear targets and action plans to increase the representation of women in top-level decision-making positions are important but not sufficient. A focus on top-level decision-making bodies is not sustainable, because the inequality gap may move down to middle-management positions that are less well monitored. Furthermore, stronger inequality in the academic enterprise is especially alarming, because it compromises commitment to high-quality medical education and negatively effects the future generation of doctors. Action should be taken to assess the effects of changing clinical management through the lens of gender and to develop comprehensive gender-monitoring systems based on standardised indicators, which enable comparison across academic health centres. This could help to identify and close the gender leadership gap and to utilise health human resources more effectively.