There is a consensus that cancer care should go beyond physical care as cancer patients and their family caregivers experience psychological burden, financial difficulty, as well as social relation issues. The current study aimed to investigate the moderating impact of social support on depression and anxiety of cancer patients and their family caregivers.Gastric cancer patients and their family caregivers who visited a university medical center in Seoul were approached for participation in the study. Fifty-two pairs of adult patients and caregivers participated in the study. Along with demographic information and the physical condition of the patients, such as pre-operation cancer stage and the type of gastrectomy, social support, depression, and anxiety were measured for patients and caregivers, respectively.In the first round of analysis, patients’ depression was associated with age, while patients’ anxiety was related to income. On the other hand, caregivers’ depression was not associated with patients’ health and living arrangement. In the second round of analysis to examine the moderating effect of social support, patients’ income and social support were related to depression and anxiety, but the interaction of income and social support was only observed for anxiety. For caregivers, no interaction effects were found. Social support decreased the negative effects of low income status on the patients.While the income of the families with cancer cannot be adjusted in the short-term, their experience of social support can be managed by a proper support system. Diverse implications in medical settings are discussed. Cancer has been a leading cause of death across continents. 14 million new cases and 8.2 million deaths were related to cancer worldwide , and morCancer patients with relatively good prognosis, however, might lose attention and support from those in their social network. This can leave the family caregivers as the sole source of support during the long process of treatment and survivorship. Caregivers of cancer patients are reported to experience physical and psychological difficulties and are vulnerable to developing depression due to the stressors related to caregiving –7.In this regard, the current study aimed to investigate the moderating role of social support on psychological well-being of both cancer patients and family caregivers.The Institutional Review Board of the research site, a university medical center in Seoul, South Korea, approved the study (IRB Number 4-2014-0861). The opportunity for research participation was advertised in the gastric cancer division of its cancer center. Adult gastric cancer patients who were 18 or older and able to communicate in both oral and written Korean language were recruited. In addition, patients were recruited at least one month after surgery; by that point in time patients start experiencing minimal pain and physical strength to the degree that they can perform daily activities with almost no difficulty, including eating regular foods. Patients who expressed their interest in the study met with the research nurse to complete the informed consent. Then the patient was administered the survey in a quiet room. It took about 20–35 minutes to complete the cross-sectional survey.In order to recruit family caregivers, the family members who accompanied the patients to the clinic were included. Caregivers who were 18 or older and had no barrier to communicate in Korean were recruited. When the caregiver expressed their interest, the research nurse administered the survey after gaining the informed consent. Each participant of the dyads completed the survey individually in a quiet space in the medical center. Fifty-two dyads of adult patients and family caregivers, 104 persons in total, participated in the study. There were no withdrawals during the course of the survey. All individuals who volunteered to participate completed the survey.Demographic variables, including age, gender, marital status, education, religion, income, and living arrangement, were included in the patient and family caregiver questionnaires. These factors have been examined in previous studies of predictors of anxiety and/or depression among cancer patients –9. To meDuke-UNC Functional Social Support Questionnaire  was usedThe Hospital Anxiety and Depression Scale (HADS from below) was employed to measure the depression and anxiety of the participants . Seven oHierarchical multiple regression analyses were conducted to test the shared variance among the variables of interest. In the first round of analysis, we aimed to identify the significant predictors of depression and anxiety out of patients’ age, income, living arrangement, type of surgery, and cancer stage. In Model II, patients’ and caregivers’ social support were entered as predictors to see the effects on depression and anxiety of patients and caregivers, respectively.The predictors shown to have significant main effects in the first round of analysis were selected to be entered in the second round of analysis to see the interaction effect with social support. In Model I, age and income were entered as predictors; in Model II, patients’ social support was entered as a predictor of patients’ depression and anxiety; and in Model III, the product terms of social support with age and income, respectively, were entered as predictors to investigate the moderating effect of social support.As In the first round of analysis, Model I showed marginally significant effect of patients’ income on patients’ anxiety . On the We proceeded to investigate the main effects of age, income, and social support, as well as their interaction effects. In the second round of hierarchical multiple regression analyses, patients’ depression was explained by patients’ income and patients’ anxiety was explained by income, social support, and their interaction . For carThe interaction effect of patients’ income and social support on patients’ anxiety was found . When thIn sum, the predictors that explained patients’ depression and anxiety were different from those that explained caregivers’ depression and anxiety. There were tendencies that older patients and patients with less income felt more depressed; and that patients with less income and patients with less social support felt more anxious. For caregivers, only caregivers’ social support explained their depression and anxiety: caregivers with less social support felt more depressed and anxious.With respect to the interaction effect of social support and patients’ status, only patients’ anxiety was significantly explained by the interaction of patients’ income and their social support . More specifically, patients with less income was influenced more strongly by their social support or the lack thereof. By the same token, patients with more social support could be influenced less strongly by their income or the lack thereof.It is well documented that people in low income households have higher likelihood to experience depression and anxiety, generally speaking –13. For On the other hand, management of financial status of all families in a society might need plans on a larger scheme. While cancer patients go through psychological hardships, along with the physical pain and difficulties, social support provided by their family and friends can have rather direct effects. Social support can buffer the psychological burden of the lack of monetary resources in the treatment process. Notwithstanding the positive effects that social support can have, cancer patients and caregivers are reluctant to seek support from others because of the perceived stigma related to cancer . TherefoSimilarly, methods to educate medical professionals to provide support to their patients could potentially promote the well-being of everyone involved as well. Even though we know that discussions about the illness, prognosis, plausible treatment plans between patient and the medical team enhance the psychological well-being of cancer patients , it is tWith a set of 52 patient and caregiver dyads, it is hard to generalize the findings to other populations. The small number of participants might account for the lack of consistent results with other literature. For example, Given and colleagues’ study identified the most vulnerable family caregivers of cancer patients, according to their gender, age, employment status, and relationship to the patient . HoweverAlso the dataset was composed of gastric cancer only. Results cannot be generalized to other types of cancer, particularly if the prognosis is not as good, as in the case of lung or pancreatic cancer. For types of cancer that have lower survival rates, one of the biggest sources of concern for both patients and caregivers is the anxiety about relapse . FurtherDespite limitations, the current study provides insight on the moderating role of social support when it comes to the effect of income on patient’s anxiety. Cancer patients will benefit from social support to overcome their anxiety related to the medical condition, more so with those of low income than of high income. This provides perspective for the efforts to mobilize resources to support cancer patients.S1 File(SAV)Click here for additional data file.


Vaccination is considered to be one of the greatest public health achievements in the 20th century, which has helped to build a society free of vaccine preventable diseases and save lives of millions children across the globe . However2013 and 2015 were marked by an outbreak of vaccine-preventable diseases such as measles and pertussis -11. ThesReligion influences decisions on vaccination -16, and In this article we would like to explore whether different religious beliefs are, in itself, real exception for vaccination or they are just a parents’ excuse to avoid vaccination.extrema ratio,” that is in the case of extreme situations such as saving the lives of children. The document also suggests to parents to oppose participation in such medical procedures by their appeal by “objection of conscience” or to seek alternative sources of effective vaccines. Besides this document, the Catholic Church's Magisterium discusses bioethical issues with respect to forbidden sources of human biological materials in two further documents. Dignitas personae  aum Vitae . In the um Vitae .The Catechism of the Catholic Church  does notTo clarify the Orthodox view on the vaccination process, we chose the example of Russia, a country where the orthodox religion is the leading religion and where historical perspective plays a special role in public, social, and cultural life. The Russian Orthodox Church absolutely acknowledges that vaccination is the main way to achieve progress. However, according to official statistics in Russia, annually 3%-5% of the population refuse to be vaccinated.At present, the tribune of the anti-vaccination movement is the internet, which can provide access to the general population without demanding a true scientific assessment of efficiency and risks of vaccination. One of the motives used by opponents of vaccination is speculation in religious beliefs. Recently the anti-vaccination movement began to spread actively in monasteries, churches, and through a video production. An essentially medical question became “a bone of contention” among the believing people.Refusal of vaccination and its causes cannot be clear without being familiar with the history of the anti-vaccination lobby. This history begins in 1988 with the article “Well, You Will Think, That It Is Only a Prick?” . This arThis all prompted the official Russian Church to issue an opinion about the topic of vaccination. In September 2008, the department of church charity and social service, the Synod organized a round table “Vaccine’s Prevention of Paediatric Problems and Ways of Making the Decision” ,28. The The position of orthodox doctors and philosophers was reflected in the statement of Church Public Council on Biomedical Ethics of the Moscow Patriarchy and in the statement of the Department of Church Charity and social service of the Moscow Patriarchy and the Ministry of Health and Social Development of the Russian Federation . These dAt the same time it was noted that some aspects of vaccination demand additional attention. The Russian public has shown concern regarding vaccines against rubella, hepatitis A, and chicken pox, which are produced from the diploidic cells from aborted embryos. There are alternative  rubella vaccines received from the cellular line of a rabbit (Japan), hepatitis A vaccines, made from the cellular culture of the monkey . However, application of these vaccines is only beginning and it is not widely available, so the diploidic vaccines against these diseases are mostly used.In Protestantism, there are various denominations without a supreme leading moral figure, such as the Pope in the Catholic Church. Protestantism accentuates individual freedom and gives parents the right to decide whether to vaccinate their children or not. According to Ruijs ,17, OrthPikuakh nefesh – the act that saves lives . Other animals are licit – halal – depending on how they die . According to Islamic tradition, vaccination serves to protect life, to respect the principle of preventing harm , and public interest . Vaccination protects others, which is why the law of necessity should be considered. It has a purpose in prevention, therefore its components cannot be judged as a diet , Hotoke (Buddha), or Ten (Heaven). This mysterious entity orders and gives people the whole necessary connections of universe, which is called Michi (Tao or Way) or Ri (Logos or Ratio). Based on their religious common sense background, Japanese people accept all relations of things and actions as they are and feel very familiar with everything relating to them. Moreover, with gratitude, they hold memorial services for used tools or for sacrificed laboratory animals , Japanese people have basically acknowledged modern biomedicine, and they have gradually accepted vaccination as its symbol. In 1948, new Japanese government made vaccination mandatory. Thus, after 1962, vaccination has been practiced collectively and compulsory. But, in 1994, it was suddenly proclaimed optional under the pressure of the public taking side effects as dangerous.Vaccination refusal among the parents of pediatric population is emerging globally, regardless of religious or political background or geographical location. In many countries legal systems advise how to react to vaccination refusal . For exaThe number of vaccination refusals based on religious exemption is increasing. The question is whether religious freedom is a threat to public health, in this case to the vaccination system .There are many publications regarding the religious exception of vaccination ,14,15 baAlthough in this paper the authors did not cover all religions, they reflect on religions and social environment of the society which they come from. The majority of religions respect life as a basic value and therefore oppose the use of vaccines derived from aborted human fetuses (Catholicism) or any form of life (Buddhism). But if these vaccines serve to protect many more lives they are permitted. Regarding this, we should not consider vaccination opposed to the theological base and values. Following this idea, religion is not in contradiction with vaccination and public health. It is only individual parents or religious leaders and their questionable interpretation of religious practices that are opposed to vaccination, no religion as such. In order to protect vaccination from the questionable religious interpretation we should bring closer to the public the basic theological perspective. The society of the 21st century, just as many societies and cultures in the history of human civilization, use religion as an excuse for wars, discrimination, and now for vaccination refusal. The question is whether the public is aware of the teachings of their religion on these issues. One of the first steps in resolving the situation should be the appropriate communication -48 to il


Background: The use of complementary and alternative medicine (CAM) therapies has increased in the United States, but little is known about consumers’ perceptions of use of such therapies. The purpose of this study was to assess knowledge, perceptions, and predictors of spice use for health promotion among adults in the Midwestern US.Methods: UUsing a cross-sectional study design, adults in the Midwestern US (n = 703) completed a valid and reliable survey which was pilot tested with a small convenience sample of adults (n = 38). The study variables included demographic profile, spice use behavior, perceptions about efficacy of spices, and willingness to use spices. Data were analyzed using SPSS to compute descriptive (e.g. percent and frequencies) and inferential statistics .Results: Almost half of the participants were interested in learning about health benefits of spices (48%), indicated friends and family members as sources of information on spices (50%),and were willing to use spices as CAM therapies (51%). Most (>50%) of the participants were familiar with or had used eight out of the 10 listed spices. The majority of participants (54%)were currently using one or more spices on a daily basis and believed that ginger (64%), garlic(58%), and cinnamon (56%) could promote good health and wellness. In logistic regression analysis, age, gender (odds ratios [OR] = 1.44 and OR = 1.56), income (OR = 1.77), health status(OR = 2.01), and recommendations from healthcare providers (OR = 5.31 and OR = 3.96) were significant predictors of current spice use and willingness to use spices.Conclusion: Individuals in our study did not use many ethnic spices and were unaware of potential health benefits of spices. Greater awareness of ethnic spices for disease prevention and health promotion are needed in this population. According to the US National Health and Nutrition Examination Survey (NHANES), 5%-10% of adults in the United States utilize botanical supplements such as spices, for health benefits.15 In addition to the adult population use, spices have also been explored in pediatric populations. For example, more than a tenth of the infants and children have used spices, primarily to remedy minor ailments such as fussiness or stomach complications, and cough and cold. Such increased usage could in part be due to lack of side effects from spices, greater availability than traditional medicines, and consideration of known health benefits of spices.16Spices have been used for various purposes and explored for their utility for hundreds of years in various parts of the world, but the interest in spices has grown in the Western world only during recent times.16 Although a handful of studies in the United States have observed the use of herbs and spices, they have several limitations.21 First, the studies are from small convenience samples of individuals. Second, most studies use few itemized questions to examine spice usage without estimating perceptions and predictors of spice usage. Third, studies frequently inquire about CAM usage and do not examine usage of various CAM products such as spices. In addition, the few studies that we found in a comprehensive literature review focused on special groups in the United States such as registered dietitians and dietetics students. Finally, none of the studies looked at general adult population in the Midwestern US. Therefore, the purpose of this study was to assess knowledge, perceptions, and predictors of spice use for health promotion among adults in the Midwestern US.As more Americans are considering the use of spices and herbs for medicinal and therapeutic use, especially to remedy various chronic conditions, reduce disease symptoms, and aid in treatment and management of common health problems, it is prudent to examine consumers’ perceptions about spices and their utility and predictors of spice usage.23A snowball sampling procedure was utilized to recruit a convenience sample of adults in the Midwestern US. The sample was invited to take the valid and reliable survey created for this study. An a-priori power analysis was conducted to determine the sample size, we found that with a conservative 95% confidence level, and 5% margin of error, 354 adult participants would be needed to make inferences to the total population of adults in the Midwestern US .The inclusion criteria were that participants had to be at least 18 years of age, English speaking, and living in the Midwestern US. A recruiting e-mail communication informed participants about the study purpose and overview of the research and approximate time commitment for completion of the survey. Participants in the community and in social networks were sent a link with the informed consent information and the study survey. Participants were also asked to share the survey link with friends, family members, and community acquaintances in the Midwestern US. Preceding the survey distribution, the study protocol was approved by the Institutional Review Board for research involving human subjects.23Based on expert suggestions, changes in format and content were included in the final survey. In addition to the demographic and background information items on the survey, a major component of the study survey was the multi-item Consumers Usage of Ethnic Spices Survey (CUES). The CUES was developed and adapted based on revision of a previous survey that explored the familiarity of spices in registered dietitians and dietetic students.20 CUES has three subscales and the subscale reliabilities were assessed from the final sample of study participants. The first subscale assessed individuals’ usage and familiarity with spices . The second subscale assessed individuals’ perceptions about various spices in promoting good health and wellness . The final subscale of CUES assessed consumers’ perceptions of the efficacy of various spices in preventing 12 disease types .Based on a comprehensive literature review and available questionnaires, a 39-item survey was designed to ensure face validity. The survey was reviewed by experts (n = 5) on survey design and consumer sciences to ensure content validity.23 A total of 38 completed matched pairs of surveys from individuals were used for reliability testing. The stability reliability coefficients for the various CUES subscale items were found to be acceptable and ranged from 0.63 to 0.90.Stability-reliability of the survey instrument items was assessed by collecting data from a convenience sample of adults in the Midwestern US. A random-sample of 50 adults was invited to participate in reliability testing. These individuals were asked to complete the survey twice within a period of 7 days. Kappa statistics (percentage agreement = ĸ) were used for items on the subscales as they were all categorical variables.a-prior at P ≤ 0.05.Survey data were entered into the computer and analyzed using the IBM SPSS Statistics for Windows statistical package . Descriptive statistics (frequencies and percentages) were used to describe the participants in terms of their demographic and background characteristics and responses to the questions about usage of spices and perceived efficacy of spice use. To assess participants’ current usage of spices and willingness to use spices in the future, we conducted univariate logistic regression analysis to compute odds of spice usage in various groups . The outcomes were categorized as binary variables (yes vs. no) for current daily use of spices and intent to use spices in future and demographic characteristics served as independent predictor variables. Statistical significance was established A final sample of 703 eligible individuals completed the survey . The majority of the respondents were females (77%), Whites (88%), above the age of 25 years (52%), and earned more than $35 000 per year . In relaParticipants were asked about their opinion of the effectiveness of spices in promoting health and wellness and the majority believed that ginger (64%), garlic (58%), and cinnamon (56%) could promote good health and wellness. Participants were least likely to believe that curry leaves (15%) and fenugreek (11%) could be effective in health promotion . AdditioSeveral demographic and health related variables were significant predictors of current spice use and willingness to use spices in the future . FemalesIn relation to future spice use, females , individuals older than 55 years , those with a graduate degree , individuals reporting current health status as fair or poor , those who were dissatisfied with current health status , those who cooked at home four or more times , those with an interest in knowing about health benefits of spices , individuals who had ever met a registered dietitian , and those who were ever encouraged by a health professional to consume spices  were statistically significantly more likely to be willing to use spices in the future compared to their counterparts. However, individuals who were eating out of home more than four times a week and those who were disinterested in knowing about health benefits of spices were less likely to be willing to use spices in the future.3 Yet there exists a lack of understanding about usage and perceptions of common ethnic spices in the United States.21 With increasing prevalence of spice usage in the United States as a form of CAM, this study explored consumers’ perceptions and predictors of spice usage in a unique population (adults in the Midwestern US). Several unique findings of this study warrant attention. Majority of the participants reported using a spice on a daily basis, were interested in learning more about the health benefits of spices, and were willing to use spices as CAM. This is interesting given that our sample mostly consisted of people from Midwestern US and may not have the exposure to or cultural diversity in available food items. Along the Western and Eastern regions of the United States, there is greater ethnic and cultural diversity when compared to the Midwestern regions. Furthermore, those with higher income and more education levels had a greater propensity to use spices, which speaks of awareness and affordability that might be low in the Midwestern US. Most of the participants were familiar with and believed in the efficacy of few spices in health promotion and disease prevention. The common spices in this category were garlic, cinnamon, ginger, and chili pepper. This finding is in agreement with studies of US based registered dietitians and dietetic students who reported greater benefits of and familiarity with these few spices, especially as it relates to prevention and reduction of diabetes, cardiovascular disease, and gastrointestinal diseases.20 In addition, these are widely known spices as there is ample evidence from studies to show the utility and health benefits of these commonly used spices.26 Participants were least likely to use or be familiar with fenugreek and curry leaves, which are highly utilized in many Asian and Middle-Eastern cuisines, these cuisines may not be as common in the Midwestern US. This lack of awareness about many spices could also be in part because less than a fifth of study participants saw a registered dietitian or received advice to consume spices from a health professional, highlighting the role of such professionals in advancing the use of CAM approaches.20 Results of this study also revealed that consumers received most of their information about spices from friends, family, and the internet, sources that may not be credible.Ethnic spices have long been studied in various regions around the world as medicinal agents, for culinary use, and as health promotion supplements.27 This can also be related to another finding of our study where those who are dissatisfied with their health are significantly more likely to be willing to consume spices in the future. Given the rising prevalence of chronic diseases in US population and the fact that most individuals who have a chronic disease often have multiple health issues, spices can certainly play a major role in preventing diseases and promoting good health as a CAM approach.26 According to a study conducted with Oregonian dietitians, 80% of them believed that food supplements can play an effective role in preventing and treating chronic diseases; dietitians can therefore, serve as advocates for use of spices as a CAM approach along with other supplements.28Our study has profound implications for future research and health promotion practice. Overall, as majority of participants shared interest in learning about the health benefits of spices, there are avenues for providing knowledge. Evidence-based strategies and resources could be integrated in both culinary, nutrition and allied health courses throughout all phases of educational advancement . Additionally, community garden initiatives, local farmers, and health care professionals could also provide educational opportunities to increase consumers’ awareness of the health benefits of spices and utility as CAM.21 While reasonable evidence exists for the efficacy of spices, further research is needed on the various benefits of spices- such studies should be conducted in larger community and clinic based samples. Some spices could more likely be used or known to consumers because of widespread and consistent evidence about their efficacy in disease prevention and health promotion. Registered dietitians and nutritionists have a key role in research and education related to spices and their uses.30 In addition, they can serve as credible resource persons for information and prescription. In fact, a study of Californian dietitians, most of the dietitians (greater than two-thirds) believed that a dietitian should be proficient in discussing about dietary supplements with clients and be able to inform the public.29 Studies have shown that more Americans suffer from chronic conditions now. As many ethnic spices have potential to aid in not just one, but also multiple chronic disease treatments, the use of ethnic spices could help prevent many co-morbidities simultaneously without precipitation of any side effects.The most interesting and unique finding of this study is the predictors of current usage and future use willingness. Females, more educated, older, those who make higher incomes, and individuals who cook at home more often were significantly more likely to use or willing to use spices. This is logical as women are commonly responsible as primary providers of meals for family and may have better knowledge, those with higher incomes may be more able to afford spices, and those with higher education could possibly know more about health benefits of spices. However, some predictors of spice usage need additional research. For example, those with poor health status were less likely to report current usage of spices, but two times more likely to be willing to use spices compared to those with good health. It could be possible that those currently using spices are in good health and those who have poor health may be willing to use spices for health benefits. There is evidence in published literature to show that individuals with severe chronic illness might be willing to participate in research, experiment with therapies, and look for any possible solutions in the hope of finding treatment of existing disease conditions.23 First, the results may be impacted by all the traditional limitations of survey research . In addition, participants could have given socially desirable responses to study questions. The questionnaire was monothematic in nature and mostly closed format in nature, this could be a threat to internal validity. Our sample was limited to adults in the Midwestern US and cannot be generalized to adults across the United States. However, in spite of these factors, we observed high reliability and validity of the instrument in our unique sample, have the largest sample report to date for general population in the United States, and we also explored various predictors of spice usage, making our study unique.The results of our study should be viewed in light of several potential limitations.This study was an attempt to assess perceptions about and the predictors of spice usage in a sample of adults in the Midwestern US. Individuals in our study did not use many ethnic spices and were unaware of potential health benefits of spices. Greater awareness and marketing of such ethnic spices as complementary and alternative options for disease prevention and health promotion are needed in this population. Given the spice use predictors we found, the information can be used to reach out to individuals who are less likely to use spices and may find it beneficial to use spices for health promotion.The study protocol and procedures were approved by the Institutional Review Board for Human Subjects Research at Ball State University, USA.We declare no conflicts of interest.JI and JayK contributed to the conception and design of the study and the writing and editing of the manuscript. JK analyzed and interpreted the data and wrote the results. JayK and JK provided critical revision of the article. JI, JayK, and JK have approved this submission. All authors contributed equally to the work of the manuscript.The authors did not receive any funding for this study.


Wolf control to reduce cattle depredation is an important issue to ecology and agriculture in the United States. Two recent papers use the same dataset having wolf population characteristics and cattle depredation, but come to opposing conclusions concerning the link between wolf control and cattle depredation. Our paper aims to resolve this issue by using the same dataset and developing a model based on a causal association that would explain the nature of the relationship between wolf control and cattle depredation. We use the data on wolf population, number of cattle, number of wolves killed and number of cattle killed, from the U.S. Fish and Wildlife Services Interagency Annual Wolf Reports over the period of 1987–2012. We find a positive link between wolf control and cattle depredation. However, it would be incorrect to infer that wolf control has a positive effect on the number of cattle depredated. We maintain that this link comes from a growing wolf population, which increases cattle depredation, and in turn, causes an increase in the number of wolves killed. While the wolf population is growing, we see both wolf removal and cattle depredation simultaneously grow. It is not until the wolf population growth nears the steady state, that removal of wolves has a sufficient negative effect to reduce or stabilize the number of cattle depredated. The issue of wolf control to reduce livestock depredation has an important place in agricultural and ecological literature. Removing wolves is generally thought to help ranchers reduce their livestock losses through a reduction in the wolf-cattle interactions. Two recent papers  were essentially extirpated from the western U.S. by the 1930s. In 1973, the gray wolf was given protection under the Endangered Species Act, which also laid the ground work for the required recovery of the species. In the early 1980s, Canadian gray wolves began colonizing the northwestern portion of Montana and by 1987, there were an estimated 10 gray wolves in Montana. In 1995, gray wolves were reintroduced to Yellowstone National Park located at the borders of Montana, Idaho and Wyoming. Seventeen years later, Montana, Wyoming and Idaho had an estimated 625, 277 and 683 wolves, respectively. The rapid recovery of wolves from near extinction in the 1980s to the current level of more than 1,500 wolves in the western US indicates the adaptability of these animals. See the U.S. Department of Justice web page for a brief history of the gray wolf in the western U.S. [Wolf control and its consequences are an important issue in the western United States. In reaction to depredations on livestock and wildlife, gray wolves . While the first two predictors were positively significant, the lagged number of wolves killed was negatively significant. All other predictors were not significant at the 0.05 level. Based on these results, Poudyal et al.  conclude. While t2, Year3, etc.).In this paper, we reanalyze the data presented in Wielgus and Peebles   is represented as a linear function of the state , year, yearsoftware The model form is as follows:The above model does not include the wolf population variable and it is reasonable to ask why? Cattle depredation in a given year is caused by wolves, and is therefore, a function of the existing wolf population in the same year. As stated earlier, cattle are located in most areas of Montana, Wyoming and Idaho, but wolves exist over a much smaller portion of each state; there are areas in each state where cattle exist, but there are no wolves, and there are areas in each state where wolves exist, but there are no cattle. Thus the overall wolf population for a state is not a necessarily the best predictor of the number of cattle depredations.More importantly, because cattle depredations lead directly to removal of the wolves involved , the numIn order to assess the model assumptions, we develop a series of model diagnostics. These include McFadden’s R-squared, Efron’s R-squared, PRESS statistics, VIF, Durbin-Watson statistics and the Pearson residuals plotted against time.Poudyal et al.  use McFath observation computed with the model parameters estimated when the ith observation is removed from the data. PRESS provides information on the quality of model fit for future observations, which R-squared statistics do not necessarily provide [Of course, R-squared statistics do not necessarily indicate whether a model is a good predictor of future observations, only that the model may be a good predictor of the data used to develop the model. PRESS statistics provide a much better indication of a proposed model to predict future observations. PRESS is equivalent to the computed sum of squared errors , but with the predicted response for the i provide .VIF statistics were computed for each predictor variable in order to assess the potential impact of multicollinearity among the predictors. Multicollinearity can have two potentially negative impacts. First, it can adversely affect the variance associated with estimated model parameters and thereby lower the power of associated tests. Secondly, multicollinearity can, but may not necessarily, negatively impact the interpretation of a parameter estimate by changing the sign and size of the parameter estimate. Researchers should determine the sign of the parameters by first assessing the relationship between the response and each predictor individually. In the presence of strong multicollinearity, parameter estimates may vary in significance between similar models with predictors that are common to different models, and may also result in the loss of meaningful interpretation of the parameter estimates. Of greater concern would be a sign change in the parameter estimate between similar models. The authors believe that the strong multicollinearity among model predictors led to the different conclusions of Poudyal et al.  compared2 and year3, the correlations remain moderately high, except that number of cattle in the states becomes nonsignificant. Although not shown, none of the one year lagged predictors had a higher correlation than the current year predictor, indicating that the non-lagged versions of the primary predictors were more highly related to the number of cattle depredated when compared to the lagged version.We begin by estimating the correlations and partial correlations between cattle depredation and the primary predictor variables . The corOur proposed model demonstrates a much improved fit over the models of Wielgus and Peebles  and PoudThe parameter estimates for the proposed model appear in th year the effect of wolves killed on cattle depredation changes from positive to negative. However, this does not tell the entire story. In fact, the truth is somewhat difficult to tease out of this model, or the other models, because of the nonlinear nature of the data that is only being approximated by the proposed model.The results presented in Tables The population of colonizing wolves grew modestly at first (lag phase). During this time there was little interaction between the relatively small population of wolves and cattle. However, a few years into colonization, the wolf population entered the exponential phase of population growth. During this phase, cattle depredation by wolves increased with the strongly increasing wolf population and the removal of the wolves that committed the transgressions subsequently increased. However, the rate of wolf removal was more than offset by the rate of wolf population growth. Although wolves are being removed at ever-increasing numbers, the number of cattle depredated is still increasing (positive relationship between cattle depredation and wolves killed). It is not until the wolf population nears the steady state of population growth at about year 24, that removal of wolves has a sufficient negative effect (negative interaction between wolves killed and year) to reduce the number of cattle depredated relative to prior years. Thus, the appearance that removing wolves has a positive effect on the number of cattle depredated is not true.2  and 2007 removed. The Press statistic for the model of Poudyal et al. [The value of Efron’s R2  for the Poudyal et al.  used misThe VIF values are presented in The model presented in this paper was chosen based on ecological principles and is consistent with the fundamental ecological literature. It also outperforms the models by Wielgus and Peebles  and PoudModeling is as much art as it is statistical science. For designed experiments, where all variables are highly controlled, the correct statistical models are dictated by the design structure. Aside from meeting the model assumptions, the analyses for designed experiments are usually straightforward. On the other hand, developing models where there is no known a priori structure presents the researcher with substantial difficulties. If the goal is to develop models that predict the response well, then standard statistical model building methods, such as forward selection, stepwise selection, or best AIC based models will typically perform well. This is true of the models developed by Wielgus and Peebles , PoudyalThe data set presented in Wielgus and Peebles , and useThe model presented by Wielgus and Peebles  used forOur proposed model was deduced from fundamental ecological principles, although the model only approximates the nonlinear nature of the data, as previously indicated. It has a simple structure that produces the highest predictive value among the three models considered. Because of these two attributes, and because the sign on the parameter estimates for the model remains the same as the sign on the parameter estimates for the models having only a single predictor, interpretation of the estimated model parameters is warranted. Our results show a positive significant link between cattle depredation and the number of wolves killed. This finding is consistent with that of Wielgus and Peebles , althougThe effect of wolf removals on reducing cattle depredations only becomes apparent when the wolf population growth closes in on the steady state. This poses a dilemma for wolf managers. Removing wolves that depredate cattle will slow the relative rate of cattle depredations. However, cattle depredations will increase until the wolf population approaches a stable level. Only an increased removal of wolves well above and beyond the rate used by wildlife managers will reduce the rate of cattle depredations, but this level of removal is likely to increase public reaction to the killing of wolves. In fact, Wielgus and Peebles  did indi


Long-term care (LTC) facilities are an important part of the health care industry, providing care to the fastest-growing group of the population. However, the adoption of electronic health records (EHRs) in LTC facilities lags behind other areas of the health care industry. One of the reasons for the lack of widespread adoption in the United States is that LTC facilities are not eligible for incentives under the Meaningful Use program. Implementation of an EHR system in an LTC facility can potentially enhance the quality of care, provided it is appropriately implemented, used, and maintained. Unfortunately, the lag in adoption of the EHR in LTC creates a paucity of literature on the benefits of EHR implementation in LTC facilities.The objective of this systematic review was to identify the potential benefits of implementing an EHR system in LTC facilities. The study also aims to identify the common conditions and EHR features that received favorable remarks from providers and the discrepancies that needed improvement to build up momentum across LTC settings in adopting this technology.The authors conducted a systematic search of PubMed, Cumulative Index of Nursing and Allied Health (CINAHL), and MEDLINE databases. Papers were analyzed by multiple referees to filter out studies not germane to our research objective. A final sample of 28 papers was selected to be included in the systematic review.Results of this systematic review conclude that EHRs show significant improvement in the management of documentation in LTC facilities and enhanced quality outcomes. Approximately 43% (12/28) of the papers reported a mixed impact of EHRs on the management of documentation, and 33% (9/28) of papers reported positive quality outcomes using EHRs. Surprisingly, very few papers demonstrated an impact on patient satisfaction, physician satisfaction, the length of stay, and productivity using EHRs.Overall, implementation of EHRs has been found to be effective in the few LTC facilities that have implemented them. Implementation of EHRs in LTC facilities caused improved management of clinical documentation that enabled better decision making. While birth rates are falling, life expectancy is rising in many countries, and people are entering an age when they will most likely need care . SeventyPflegeversicherung, to fund for LTC with equal contribution between the insured and their employers [Governments around the world have responded to the rising need for LTC at various echelons of care for a range of acute and emergent illness or disease. Western European countries are underfunding their LTC needs, relying on existing national systems to manage acute and emergent services, but their health systems are not prepared to care for the countries’ dependent population for long periods . For insmployers . With thmployers ,9. The Employers .The Centers for Medicare and Medicaid Services (CMS) defines an EHR as “an electronic version of a patient’s medical history, that is maintained by the provider over time, and may include all the key administrative clinical data relevant to that person’s care under a specific provider, including demographics, progress notes, problems, medications, vital signs, past medical history, immunizations, laboratory data and radiology reports” . AnotherIn the literature, the terms EHR and electronic medical record (EMR) are often used interchangeably. The CMS differentiates these two: the EMR is bound to one organization, and the EHR is compatible across organizational lines. Although we would prefer that all publications kept these distinct, we also realize that it is impractical. Some of the literature analyzed in this review refers to EMRs when they are really analyzing an EHR. In the interest of keeping the authors’ words intact, we will not differentiate between them in our analysis. We are evaluating works about EHRs, EMRs, and some stand-alone components of the EHR or EMR for the same purpose of this review.a continuum of medical and social services designed to support the needs of people living with chronic health problems that affect their ability to perform everyday activities [LTC is tivities . LTC is The EHR enables providers to deliver better medical care to patients because of the availability of complete and accurate information . PreviouThe purpose of this review was to address the knowledge gap and the lack of significant literature accounting for the relationship between an EHR and LTC facilities. Do existing EHR implementations in current LTC facilities have positive outcomes? Do the users of these systems have positive experiences or observations that have been shared? The hypotheses are as follows:Our methods followed a measurement tool for the assessment of multiple systematic reviews (AMSTAR) . The forWe queried three common research databases: MEDLINE  by Web of Science, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and PubMed. We used key terms from the US National Library of Medicine’s Medical Subject Headings (MeSH) separated by Boolean terms. Searches were conducted from April 21 to April 24, 2017. The reason we chose to query MEDLINE by Web of Science is because we received different outputs when we queried MEDLINE in PubMed. We do not have a reason for the disparity. MEDLINE by Web of Science gave us more papers to choose from.Searches in each database were nearly identical:  AND (“long term care” OR “long-term care” OR “nursing home”) AND (outcome OR impact OR effect) NOT “patient portal” NOT “health information exchange.” Due to the differences in indexing methods between the databases, we had to slightly modify the search string and filters for each. An exact listing of the search strings and filters is provided in Reviewers agreed ahead of time what to look for in each abstract. We wanted to focus on papers that explained an experience within an LTC facility of an EHR or a major component of the EHR as defined by the CMS ,11. We aPapers were assigned to reviewers in a way that each paper was read by at least two reviewers. Once again, reviewers recorded independent observations on their copy of the Excel spreadsheet, ensuring to capture the observations in terms of effectiveness, efficiency, or the negatives of the same. Reviewers were also asked to identify possible bias in each paper, loosely following the Cochrane Collaboration’s risk-of-bias tool . All obsThe summary measure used in this analysis was the expression of experience with EHRs or a major stand-alone component of an EHR, in an LTC facility, expressed in terms of effectiveness or efficiency, and a frequency of occurrence of the themes identified by the reviewers. A table of observations was created, and an affinity matrix was created to illustrate potential trends. As illustrated in After the second consensus meeting, the overarching themes recorded by each reviewer were combined. We counted the number of times that a theme occurred in the literature and sorted by frequency of occurrence. These data were placed into an affinity matrix for further analysis see . The totThe broad research criteria encouraged a thorough assessment of the implication of an EHR across various attributes: health outcomes, documentation, quality outcomes, length of stay, productivity, accessibility, medication safety, cost, patient satisfaction, nurses’ working time, physician satisfaction, and time consumption.Among all the attributes, markedly 12 out of 28 papers addressed management of documentations, with approximately 27% of total occurrences of the attributes in the literature ,43,45,48Nine out of 28 papers (32%) reported positive quality outcomes, accounting for 21% of the occurrences ,44,47. FNotably, only three out of 28 papers (11%) reported greater physician satisfaction using EHRs, as it improved working environment and reduced errors ,37,38. AManagement of documentation was identified as a common theme in 13 papers. Studies documented that the time consumed for management of documents in EHR compared with paper-based records was significantly less ,41,48. FFew papers mentioned that they could not observe much difference in the time consumed for documentation after implementing EHRs ,33,45, aQuality outcome was the second most commonly observed theme. Many papers stated that EHRs directly improved the quality of care ,36,44,47Health outcome was another commonly identified theme. Four different papers showed significant improvement in health outcomes by reducing the occurrence of infections, high-risk pressure sores, neurolepsis, improving activities of daily living (ADL), range of motion, and timely medication ,34. One The next most commonly occurring attribute was time consumption. In a few of the studies, the respondents have mentioned that EHR was time consuming because of reasons such as complexity in signing out of an EHR ,36. AnotAccess to patient data was another commonly occurring attribute ,25,27,36Other common factors included cost, patient satisfaction, physician satisfaction, length of stay, and productivity. Studies mentioned that there was a marked increase in the cost incurred by facilities post implementation ,35. The EHRs are known to improve care coordination and health outcomes. Although LTC facilities have been slow to adopt EHR, they continue to be areas where the benefits of implementing EHR can be realized to its fullest potential. This review tries to identify the established outcomes in various LTC facilities that have adopted this technology. For this review, we analyzed papers, studies, and other summaries of experiences relating to our topic of interest. Management of documentation, quality outcome, and health outcomes were identified as the most common themes, which were identified in 60% of all papers reviewed.There were both positive and negatives outcomes reported in this systematic review; however, the former was found in the literature more than the latter. Some reported a boost in productivity only after 23 months; others did not put a time frame on it—they just reported slower processes.The LTC market has been slow to adopt health information technology, in general, and EHRs specifically. The paucity of data on the adoption of the EHR in LTC is similar to the private health care market in the United States before the major legislation in 2009. The adoption rates for EHRs in the United States greatly increased with incentives that helped to offset the steep adoption costs of the technology. Future research could determine the level at which the cost of investing in the EHR is equal or better than the cost of abstaining.The researchers reviewed only those papers that were published between the years 2007 to 2017 and did not include the papers outside the period of study. We thought 10 years’ time was adequate, commensurate with other reviews. There is unavailability of data owing to the slow adoption of EHR in LTC settings. The systematic search process in the three primary databases yielded studies that predominantly focused on the United States’ LTC scenario rather than an international focus. Although selection bias and face validity are concerns, we mitigated these risks by following the AMSTAR standard and using more than one reviewer to opine on the inclusion or exclusion of papers used for analysis [Overall, implementation of EHRs has been found to be more effective than not in LTC facilities. Implementation of EHRs in LTC facilities caused improved management of clinical documentation that enabled better decision making. Negative experiences were observed in workflow and productivity, but it is unclear whether this was because of change management and the general disruption that a major information technology (IT) implementation can exert on the organization. The authors recommend improving the design of EHRs that address issues such as time spent on documentation and enhancing the usability for physicians and nurses. These improvements would address most of the negative experiences and may promote widespread adoption of this essential technology in LTC.


The launch of this new journal is the natural outgrowth of several recent macro trends in our specialty.It is our great pleasure to introduce a new publication devoted exclusively to diseases of the posterior segment of the eye Since its creation as a subspecialty more than 50 years ago , the fieThe goal of IJRV is to provide up-to-date, accurate, and easily understandable information to our readership and to contribute to the body of scholarly work in the area of retina and vitreous. The journal will present original articles on new approaches to diagnosis and treatment that may impact clinical practice. As part of this vision, our aim is for IJRV to focus on articles that directly impact the clinician’s ability to treat patients, and will include special topics of interest such as imaging of the retina, choroid and vitreous especially innovations in optical coherence tomography (OCT) and other imaging systems, small-gauge vitrectomy, retinal detachment repair, chromovitrectomy, electroretinography, microperimetry, other functional tests, intraocular tumors, retinal pharmacotherapy & drug delivery, diabetic retinopathy & other vascular diseases and age-related macular degeneration & other macular entities –5.The peer-review process involves two Editors-in-Chief, seven Associate Editors, and a Board composed of over 50 outstanding international experts in the field of retina . All manFor the science of retina, existing journals serve the field very well and published important research. We hope to supplement the existing journals with a different format. Our aim is to bring together diverse areas of research in retina and vitreous with three novel approaches. Firstly, IJRV will be entirely web based with paper based copies only by request, although PDF of articles will be available through the website. Secondly, IJRV will be an open access journal, which means access to its content with no subscription barriers. Third, initially we will be fortunate to be supported by the Brazilian Retina and Vitreous Society, which is covering the costs of publication so that authors do not need to pay an article processing chargeWith these online, open access characteristics, IJRV intends to allow timely publication and broad dissemination of research to a global audience of ophthalmologists, retinal specialists, retina-interested physicians, and trainee physicians. As electronic and digital communication allows rapid exchange of ideas and information, while discoveries are made continuously and following experimentation and analysis, research should be disseminated immediately . With thWhile this journal expects to be one of the pre-eminent international publications, it also serves as the representative journal for the Brazilian Retina and Vitreous Society. When the Brazilian ophthalmologists Joviano Rezende Filho, Luiz Assumpção Osório, Francisco Mais, Sérgio Cunha, and Christiano Barsante met in September 7th 1977, they knew the field of retina deserved a new society to enable discussion and scientific progress in retina. At that time, they organized the first Brazilian retinal meeting - a course with Prof. Charles Schepens that involved around 250 ophthalmologists in Rio de Janeiro. From there the BRVS was founded in 1977 with the mission to stimulate discussion and scientific progress in retina in Brazil. BRVS is now composed of around 900 dedicated active members fascinated by the field of retina and vitreous.Since its inception, the BRVS and its members have actively participated in international symposia and published scientific articles in important medical journals thereby assisting in the progress of the area of research. For the past few years many BRVS members have worked very hard to enable development of a new Journal and to insert the society in the global network of retinal research. This effort resulted in the partnership with BioMed Central to launch IJRV. The BRVS and its partners are also proud to join the open access era by publishing a journal for the great field of retina.In summary, we hope that IJRV will serve as a vehicle for bringing together multidisciplinary perspectives, research and initiatives from around the globe who are interested in advancing the field of retina. We would welcome your comments on the articles and other work published in the journal. As Co-Editors-in-Chief, together with our international Editorial Board, we are committed to making this journal a success, and your support is welcome and appreciated.International Journal of Retina and Vitreous.IJRV realizes the importance of indexing databases  and will have the Journal submitted to those services as soon as possible. We intend to have the journal registered with the Directory of Open Access Journals, and cited by PubMed and other search engines in the very near future. On behalf of the Editors and Editorial Board members, welcome to the


Since the last major theoretical integration in evolutionary biology—the modern synthesis (MS) of the 1940s—the biosciences have made significant advances. The rise of molecular biology and evolutionary developmental biology, the recognition of ecological development, niche construction and multiple inheritance systems, the ‘-omics’ revolution and the science of systems biology, among other developments, have provided a wealth of new knowledge about the factors responsible for evolutionary change. Some of these results are in agreement with the standard theory and others reveal different properties of the evolutionary process. A renewed and extended theoretical synthesis, advocated by several authors in this issue, aims to unite pertinent concepts that emerge from the novel fields with elements of the standard theory. The resulting theoretical framework differs from the latter in its core logic and predictive capacities. Whereas the MS theory and its various amendments concentrate on genetic and adaptive variation in populations, the extended framework emphasizes the role of constructive processes, ecological interactions and systems dynamics in the evolution of organismal complexity as well as its social and cultural conditions. Single-level and unilinear causation is replaced by multilevel and reciprocal causation. Among other consequences, the extended framework overcomes many of the limitations of traditional gene-centric explanation and entails a revised understanding of the role of natural selection in the evolutionary process. All these features stimulate research into new areas of evolutionary biology. The path of scientific advance is often made impassable for a long time through such errors.’ [A century ago, it was noted in the domain of physics that ‘concepts that have proven useful in ordering things easily achieve such an authority over us that we forget their earthly origins and accept them as unalterable givens. Thus, they come to be stamped as “necessities of thought”, “errors.’ . Evolutiet al. [In fact, our theoretical understanding of biological evolution has not remained unaltered. Slight modifications and adjustments to the received theory are recognized even in the most traditional quarters. But in the past decade, without much notice by general audiences, a more wide-ranging debate has arisen from different areas of biology as well as from history and philosophy of science, about whether and in which ways evolutionary theory is affected, challenged or changed by the advances in biology and other fields. As usual in such cases, more conservative perspectives and more progressive ones are in conflict with each other, with differences ranging from minor to intense. A rising number of publications argue for a major revision or even a replacement of the standard theory of evolution –14, indiet al. , has cauThe theory of evolution is the fundamental conceptual framework of biology all scientific explanations of living phenomena must be consistent with. As it does not describe a universal law regarding a single natural phenomenon, such as gravity, but rather the principles of organismal change over time, based on the highly complex inputs and interactions of a multiplicity of different factors, evolutionary theory cannot be expected to remain static but is subject to change in the light of new empirical evidence. This is a normal process of scientific advancement and not a heretical undertaking as it is sometimes perceived to be. Explanations of organismal diversity have changed significantly during pre- and post-Darwinian periods, and it should not come as a surprise that fresh stimuli arise from the new methodologies and the expanded scope of modern biological research. Indeed, a growing number of challenges to the classical model of evolution have emerged over the past few years, such as from evolutionary developmental biology , epigeneSometimes these challenges are met with dogmatic hostility, decrying any criticism of the traditional theoretical edifice as fatuous , but mor2.When attempting to define the issues at stake in the current debate, it is necessary to keep in sight what it is that should be explained by a theory of evolution. Evolutionary biology, as practised today, does not represent a single coherent approach but includes sets of different topics and research programmes. For instance, one may be interested in the patterns of phylogenetic relatedness and the processes of species formation. Here, the emphasis is on reconstructing relationships among organisms and unravelling the principles of the separation and diversification of higher taxonomical clades, as pursued by the field of phylogenetics. Another approach examines genetic and phenotypic variation in populations in order to derive rules of variational change over time, a perspective most elaborately pursued by population genetics and quantitative genetics. Still another approach is the study of the origin of complex organismal features, such as morphological, physiological or behavioural traits, in order to explain the evolution of the processes that generate these features and how—in turn—these processes influence the course of evolution, as investigated by evolutionary developmental biology (evo-devo), systems biology, or the behavioural sciences. Finally, one may study evolution with a view to the origins of mind, language, society and culture, as well as their feedback on biological evolution, as conducted by the fields of cognitive biology, linguistics, anthropology and certain domains of the social sciences.The vastly different explananda and the progress made in each of these fields must be kept in mind when we examine the tenets of the present theory of evolution. While documenting numerous empirical and theoretical advances, at the level of core assumption most current textbooks on evolution, whether explicitly or implicitly, still offer a theoretical framework that is largely based on the MS of the 1930s and 1940s. Even though it never constituted an encompassing formal synthesis , this moEven though claims have been made that classical evolutionary biology has continuously incorporated aspects from new conceptual domains ,36, the all evolutionary phenomena, thereby negating the fact that, on the one hand, not all of its predictions can be confirmed under all circumstances, and, on the other hand, a wealth of evolutionary phenomena remains excluded. For instance, the theory largely avoids the question of how the complex organizations of organismal structure, physiology, development or behaviour—whose variation it describes—actually arise in evolution, and it also provides no adequate means for including factors that are not part of the population genetic framework, such as developmental, systems theoretical, ecological or cultural influences.As can be noted from the listed principles, current evolutionary theory is predominantly oriented towards a genetic explanation of variation, and, except for some minor semantic modifications, this has not changed over the past seven or eight decades. Whatever lip service is paid to taking into account other factors than those traditionally accepted, we find that the theory, as presented in extant writings, concentrates on a limited set of evolutionary explananda, excluding the majority of those mentioned among the explanatory goals above. The theory performs well with regard to the issues it concentrates on, providing testable and abundantly confirmed predictions on the dynamics of genetic variation in evolving populations, on the gradual variation and adaptation of phenotypic traits, and on certain genetic features of speciation. If the explanation would stop here, no controversy would exist. But it has become habitual in evolutionary biology to take population genetics as the privileged type of explanation of the essential prerequisite without which ‘my theory would absolutely break down.’ [Criticisms of the shortcomings of the MS framework have a long history. One of them concerns the profoundly gradualist conception the MS has inherited from the Darwinian account of evolution. Darwin saw slight, incremental and accumulating variation as k down.’  a positik down.’  as an ‘uk down.’ . In addiConnected with the gradualist requirement of the MS theory is the deeply entrenched notion of adaptation. Again, we are confronted with a feature of the classical theory that has been criticized repeatedly in the past, both on empirical and theoretical grounds ,41 but aNatural selection, the cornerstone of the MS theory so intimately linked to both gradualism and adaptationism, has itself been the subject of a fair share of critical debate. In this case, it is not so much the principle itself that is contested, but the uniqueness of the causal agency that has been ascribed to it. Are all features of biological organisms necessarily the result of natural selection, and is it the only factor in the evolutionary process that provides directionality to organismal change? Numerous authors have challenged the pervasiveness of natural selection as a unique ‘force’ of evolution, whereas others have questioned whether the individual is the sole and appropriate ‘target’ of selection or whether other levels of selection at supra- and infra-individual levels also need to be included in selectionist scenarios –44. AgaiFinally, it is apparent that nearly all of the relevant predictions that derive from the MS theory are based on genetic principles and gene determinist convictions. Although the long-held belief that genes are the unique determinants of biological form in development and evolution has been challenged by an extensive number of commentators ,23,45–48The limitations of the MS theory are not only highlighted by the criticisms directed against several of its traditional tenets but also by the failure to address some of the most important phenomena of organismal evolution. The question, for instance, of how complex phenotypic organizations arise in evolution is sidestepped by the population theoretical account, as is the reciprocal influence of these features of higher levels of organization on the evolutionary process. Indeed, the MS theory lacks a theory of organization that can account for the characteristic features of phenotypic evolution, such as novelty, modularity, homology, homoplasy or the origin of lineage-defining body plans. As will be shown below, evo-devo, niche construction, systems biology and other areas harbour the capacity to address at least certain aspects of these topics where the classical theory fails.structure of evolutionary theory as its title suggests. All the extensive discussions, led over decades, seem not to have altered the preponderant stance to hold on to the classical prerequisites of gradualism, adaptationism, selectionism and gene-centrism. The predictions that follow from the MS framework continue to be based on these prerequisites and ignore all predictions derived from alternative models. Hence, the claim of continuous incorporation of new conceptual components by the MS theory is misleading.Even though only the most prominent issues were mentioned here, this brief overview indicates that the problem agenda associated with the MS theory is extensive. The fact, often mentioned by defenders of the orthodoxy, that these issues have been raised before, does not alleviate the problems. Rather, the current evolutionary paradigm is still dominated by the very same basic assumptions that marked the origin of the synthesis approach. Despite the fact that substantial challenges to these positions have arisen in the past decades from a host of different areas of biology, they have rarely resulted in alternative proposals. Gould's 2002 comprehensive treatment of the history of evolutionary debate , for ins3.et al. [Today, evolutionary biology exhibits a very different landscape. An abundance of new theoretical concepts has arisen since the time of the formulation of the population theoretical synthesis, some of which offer challenges to the received theory or have not been included into a common theoretical framework. Only a brief overview of the most relevant conceptual innovations is possible in the present context. For more elaborate treatments see Pigliucci & Müller  or Lalanet al. .3.1.A suite of new concepts emerges from evo-devo, a field of research that arose in the early 1980s from a discontent with the exclusion of developmental biology from evolutionary theory –53. The First, the kind of selectable phenotypic variation that can be produced by a developmental system of a given type is neither infinite nor random. Rather, selectable variation is both constrained  and faciIn addition, the research approach of evo-devo permits addressing the processes responsible for the evolution of phenotypic organization, a topic thoroughly avoided by the synthesis theory. The issue cannot be reduced to the evolution of gene regulation, because, on the one hand, highly conserved developmental control genes, e.g. homeotic genes, can exhibit non-homologous expression domains in embryos of closely related phylogenetic lineages, and on the other hand, homologous structures can be specified by non-homologous genes, a characteristic of the genotype–phenotype relation described by developmental systems drift . Evo-devOverall, the evo-devo results indicate that phenotypic variation is neither necessarily gradual nor random. Irrespective of whether they are perturbed by selectional, mutational or experimental intervention, developmental systems exhibit emergent behaviours and generate nonlinear effects, i.e. the phenotypic outcome is only indirectly related to genetic variation and yet still follows predictable pathways. In other words, the variational range of a population is not defined merely by genetic variation but by the developmental system as a whole, providing sources of phenotypic bias and novelty ,74. It i3.2.The population context of development is mostly provided by the study of developmental plasticity, a component of phenotypic plasticity. Developmental plasticity is the capacity of organisms to develop altered phenotypes in reaction to different environmental conditions. Among its evolutionary effects, the influence on a population's variational response to selection and the acceleration of the colonization of novel environments are well documented ,75,76, aAccording to the developmental plasticity concept, fixation of environmentally induced variants may happen through phenotypic and genetic accommodation ,80. Phen3.3.The science most central to the MS, genetics, likewise has substantially changed since the time of the synthesis and especially over the past two decades. Now that whole genomes can be studied, we have learned that in the course of evolution significant portions of the genome have been duplicated, deleted or co-opted into new functions . In addi3.4.Conceptual change is also underway with regard to the understanding of natural selection. Whereas the classical view posited the individual as the unit of selection, it is now held more often that natural selection can also act at levels above and below the individual. Hierarchical selection theory  and mult3.5.The concepts of inheritance equally have undergone revision in recent decades. In addition to genetic inheritance, the only means of transgenerational transmission of information acknowledged by the MS, several forms of non-genetic inheritance are recognized today. These include epigenetic, behavioural, ecological and cultural forms of inheritance ,9.In the domain of epigenetic inheritance it is not merely the well-known patterns of post-translational modifications of histone proteins or methylation of cytosines that can be transmitted across generations . Especia3.6.Advances at the interface of ecology, behaviour and culture have shown that populations of organisms are not merely passively exposed to natural selection but are actively involved in the formation of those environments that constitute the selective conditions for later populations. This mode of evolution, in which organisms co-direct their own evolution and that of other species, has been characterized by niche construction theory, which includes concepts of migration, dispersal and habitat selection, but also of gene–culture co-evolution. Niche construction processes can lead to the fixation of alleles that may otherwise be deleterious, it can facilitate the endurance of organisms in adverse environments and it can be beneficial despite being costly due to advantages that accrue for later generations .. Clearly, the interconnections between biological and cultural evolution cannot be sidelined [Niche construction captures important links between biological and cultural evolution, such as the modification of selection on a plethora of human genes in response to culturally transmitted activities, the effects of which can be shown in mathematical models ,96. Equaidelined , and nic3.7.From a different domain, systems biology, arise theoretical conceptions that have the capacity to integrate several of the previously mentioned evolutionary components. The kind of systems biology capable of doing this is not the ubiquitous ‘-omics’ blossoming today, but the theoretical framework that deals with the study of systems properties of organisms and their interactions across levels of organization, from molecules to populations of organisms, including physiological, behavioural and cultural factors. Although today's organismal systems biology is mostly rooted in biophysics and biological function , with piThese examples of conceptual change in various domains of evolutionary biology represent only a condensed segment of the advances made since the inception of the MS theory some 80 years ago. Relatively minor attention has been paid to the fact that many of these concepts, which are in full use today, sometimes contradict or expand central tenets of the MS theory. Given proper attention, these conceptual expansions force us to consider what they mean for our present understanding of evolution. Obviously, several of the cornerstones of the traditional evolutionary framework need to be revised and new components incorporated into a common theoretical structure. Below, I will sketch out an expanded framework to which several of the authors in this issue have contributed.4.a) and the extended framework (figure 2b). Several significant distinctions are noticeable. Foremost among them is the abandonment of the notion that the range of phenotypic variation in a population is sufficiently explained by the statistical correlation with concomitant variation in a population's ‘gene pool’. Instead, as the results from evo-devo and systems biology suggest, the capacity for variation in populations is determined by the developmental systems properties of a population that, in addition to genetic variation, include a host of dynamically interacting components, many of which are not genetically specified as discussed above. This may be called the ‘developmental systems pool’ of a population (figure 2b). Its dynamics plays out before the background of developmental plasticity and evolving gene regulation, but it also includes the self-organizing, physics-dependent and environmentally mediated properties of development. In this perspective, developmental bias and plasticity assume central roles as generators of novel and coordinated phenotypic variation by conferring directionality on the selective processes.The EES was proposed as a theoretical framework that takes account of the plurality of factors and causal relations in evolutionary processes ,49. It cfigure 2Inheritance is another component of the standard framework that is strongly modified in the extended picture: multiple systems of inheritance are recognized. In addition to the transmission of DNA sequences from one generation to the next, the EES includes epigenetic inheritance, in a sense that is not limited to epigenetic markings but also includes small RNAs and other maternal or paternal components as well as components of the cell that are inherited independently of the DNA. In addition, the EES accepts behavioural, ecological and cultural transmission as well as the interactions between the different modes of transgenerational inheritance. Even though the precise evolutionary contribution of each of these modes requires further study, their existence is indisputable, and distinguishing their various contributions to inclusive inheritance is essential for understanding evolutionary dynamics .Natural selection remains a key factor of the EES, but its roles are reinterpreted. In the MS, at least in its bare bones interpretations, organismal shape and structure were regarded entirely as products of external selection, and the directionality of evolutionary change was supposed to result from natural selection alone. In the EES, besides the expanded range of selection to multiple levels of organization, the generative properties of developmental systems are viewed as responsible for producing phenotypic specificity, whereas natural selection serves to release that developmental potential. Particular forms of phenotypic change are taken as the result of internal generative conditions rather than external pruning. Thus, a significant amount of explanatory weight is shifted from external conditions to the internal properties of evolving populations. In addition, natural selection may be ‘bypassed’ by environmental induction, causing potentially adaptive developmental variation in many individuals of a population at once and long before natural selection may become effective.programmed to a constructive role of developmental processes in evolution. Furthermore, the constructive aspect also concerns the interactions between all other levels of organization such as the behavioural, social and cultural. Together, they constitute the kernel of an organizational theory component that sets the EES apart from the MS.As a consequence, unlike the MS, the EES includes a constructive component. Instead of chance variation in DNA composition, evolving developmental interactions account for the specificities of phenotypic construction. This interpretation is also based on a fundamentally different account of the role of genes in development and evolution. In the EES, genes are not causally privileged as programs or blueprints that control and dictate phenotypic outcomes, but are rather parts of the systemic dynamics of interactions that mobilize self-organizing processes in the evolution of development and entire life cycles. This represents a shift from a Another distinctive feature of the EES is causal reciprocity. This is true for two domains. One is the construction of phenotypic complexity, in which causation not only flows from the lower levels of biological organization, such as DNA, ‘upwards’ to cells, tissues and organisms, but also from the higher level ‘downwards’, such as through environmental- or tissue-induced gene regulation. The second aspect of causal reciprocity lies in the fact that populations of organisms are not relegated to being passive recipients of external selection pressures but, through various forms of niche construction, actively modify the environments that become the selective conditions for later generations. Thus, a major feature of the EES is that causation not only runs one way but assumes dialectical relations between its participating components, both in the relationship of populations with the environment and in the generation of heritable phenotypic architectures.The novelty of the EES and the differences with the MS theory become most apparent in the predictions that derive from the EES framework, both with regard to short-term and long-term effects of organismal evolution. The most important predictions concern the following: (i) the generation of heritable phenotypic variation ; (ii) the origin of phenotypic novelty ; (iii) the sequence of genetic and phenotypic change (emergent phenotypic structures can be captured and stabilized by evolving gene regulatory circuitry and assume fitness subsequently); (iv) inheritance ; (v) tempo of evolution ; (vi) environmental induction ; (vii) organismal activity  natural selection .et al. [Overall, the EES proposes that variation is more predictable and selection effects are less directional than hitherto argued. The EES addresses organizing principles instead of statistical correlations or evolving instruction programs. It represents a pluralistic, process-based framework of dynamical interactions between a multitude of evolutionarily effective factors and generates its own set of evolutionary predictions that make it clearly distinct from the MS account. These genuine predictions of the EES give rise to new research programmes, which have already generated validating empirical results. It is beyond the scope of this article to discuss the range of predictions and their consequences in greater detail, but more extensive treatments can be found in Laland et al. .5.The EES is not a simple, unfounded call for a new theory but has become an ongoing project for integrating the theoretically relevant concepts that have arisen from multiple fields of evolutionary biology. Although the EES recognizes the fundaments of the classical MS theory, it differs in its interpretation of the role of some of its elements and integrates new components, such as constructive processes of development, multiple inheritance mechanisms, niche reciprocity, as well as behavioural and cultural elements . It is unavoidable to notice that an integration of these concepts means not a simple add-on of a few peripheral notions to the MS model without any effects on its core logic. Rather, the EES establishes a new structure of the theoretical evolutionary framework that goes beyond the reductionist and gene-centred perspective of the past. It represents a different way of thinking about evolution, historically rooted in the organicist tradition . Its preProposals of an EES generally elicit rather positive reactions from the representatives of different fields of science, many of whom are convinced that an expanded theoretical framework has become necessary for evolutionary biology. Opposition comes in three different versions. One is the ‘absorption argument’, i.e. the standard framework is said to no longer be the MS but to have continually absorbed various conceptual advances . The defThe second response  runs: ‘this has been said before’, implying either that the arguments are outdated or deemed irrelevant. It remains unclear why empirical findings or conceptual proposals that have been stated previously are thereby rendered irrelevant. When this objection fails, the argument usually becomes that the processes central to the EES are merely add-ons to the basic processes required by the MS, such as natural selection, mutation, recombination, drift and gene flow, but are ‘not essential’ for evolution . Given tA subtler version of the this-has-been-said-before argument used to deflect any challenges to the received view is to pull the issue into the never ending micro-versus-macroevolution debate. Whereas ‘microevolution’ is regarded as the continuous change of allele frequencies within a species or population , the illof the MS, as sometimes wrongly implied, but to indicate a comprehensive new synthesis. Whether eventually that new framework will be called EES or a different name is not important. What is important is that a different theory structure is necessary to accommodate the new concepts that are in everyday use and have become part of the current toolkit of evolutionary biology. Therefore, a theory change is not a future goal, but we are in the midst of it, with the EES attempting to provide a structure for the present state of evolutionary thought.Interestingly, a third class of responses to the EES is this: the proposed modifications are not radical enough, a much more fundamental change is required . Also, hThis is an exciting period in evolutionary biology. The principal Darwinian research tradition is upheld, but the specifics of evolutionary theory structure are undergoing ferment, including the revision of some of its traditional elements and the incorporation of new elements. Instead of privileging selected mechanisms such as random variation, genetic control and natural selection, the multitude of factors that dynamically interact in the evolutionary process will be better expounded by a pluralistic theory framework. Current evolutionary research already reflects this pluralism, and as many of its underlying concepts have drifted from the standard theoretical paradigm, an adjusted evolutionary framework that adequately synthesizes the multitude of new theoretical elements has become a necessity. The EES represents one possibility for such integration.