Social cognition is the way in which people process, remember, and use information in social contexts to explain and predict their own behavior and that of others. Children’s social cognition may be influenced by multiple factors, both external and internal to the child. In the current study, two aspects of social cognition were examined: Theory of Mind and Emotion Understanding. The aim of this study was to analyze the effects of type of early care (0–3 years of age), maternal education, parents’ country of birth, and child’s language on the social cognition of 118 Italian preschoolers. To our knowledge, the joint effect of these variables on social cognition has not previously been investigated in the literature. The measures used to collect social cognition and linguistic data were not parent- or teacher-reports, but based on direct assessment of the children through two standardized tests, the Test of Emotion Comprehension and the ToM Storybooks. Relationships among the variables showed a complex pattern. Overall, maternal education and linguistic competence showed a systematic effect on social cognition; the linguistic competence mediated the effect of maternal education. In children who had experienced centre-base care in the first 3 years of life, the effect of maternal education disappeared, supporting the protective role of centre-base care for children with less educated mothers. The children with native and foreign parents did not significantly differ on the social cognition tasks. Limits of the study, possible educational outcomes and future research lines were discussed. Social cognition is the way in which individuals process, remember, and use information in social contexts to explain and predict how people behave . In the From a theoretical point of view, ToM and EU are partly correlated. In The current study focused on some factors, both external and internal to the child that can influence social cognition abilities in a group of Italian pre-schoolers: the role of early type of care on ToM and EU has been examined together with the effects of other intervening variables as maternal education, parents’ country of birth, and linguistic competence. In what follows, the literature showed that the effect of type of care on social cognition has not been studied yet; that a complex interplay among these factors could be expected and that a study to take into concern simultaneously these several variables is necessary. This study focused firstly on early type of care and other variables that are strictly related to it; some other factors that could influence children’s social cognition development as socio-economic status , cognitiIn early childhood, toddlers receive two main types of care: centre-based and home-based. In centre-based care, children experience daily life in a group setting with adults and peers, and routines, spaces and toys are organized for a group of children and adults; in addition, the adults providing the care are trained professionals. In home-based arrangements, children are more likely to be alone with adults or to share routines and toys with a very small number of other children, usually younger or older siblings. In these informal settings, caretakers are usually mothers, grandparents or non-professional baby-sitters , all of them attending kindergartens in Turin : see Table 1. Data were collected between 2009 and 2012; most of the children in the current study also took part in earlier reported research by The sample comprised 118 typically developing children , IQ (p = 0.174), type of early childcare received (p = 0.530), maternal education (p = 0.187), parents’ country of birth (p = 0.650) and verbal quotient .Sixty-four children were girls (54.2%). A t-test analysis confirmed that the two final subsamples of children, with less educated and more highly educated mothers, respectively, were similar in terms of age (p = 0.644), gender (p = 0.784), type of care (p = 0.116) and parents’ country of origin (p = 0.163). The IQ and VQ scores of the children with more highly educated mothers were significantly higher than those of the children whose mothers had completed a lower level of education .With regard to education, 53 mothers had completed lower secondary school (44.9%), 52 held an upper secondary school diploma (44.1%) and 13 were university graduates (11.0%). Overall, the sample displayed a lower level of educational achievement than the Italian population between 25 and 64 years of age in 2011, in which 44% had completed lower secondary education, 41% upper secondary education, and 15% third level education . For thet-test analysis confirmed that the two final subsamples, composed of children with at least one native-born parent and first-generation children with two foreign-born parents, respectively, were similar with respect to age (p = 0.433), IQ (p = 0.104), VQ (p = 0.319), gender (p = 0.627), type of early childcare (p = 0.402) and maternal education (p = 0.166).With regard to parent’s country of birth, 92 of the children had two native-born parents (77.9%); 14 had one foreign-born parent (11.9%) and 12 two foreign-born parents (10.2%). In our sample, the percentage of children with two foreign-born parents was slightly lower than in the Italian population (14.5%) and the percentage of children from mixed couples was higher , IQ (p = 0.276), VQ (p = 0.136), gender (p = 0.530) and parents’ country of birth (p = 0.215), but differed significantly in relation to maternal education: highly educated mothers were more likely to choose centre-based care (p = 0.021).In relation to type of care, in the first 3 years of life 54 children had received centre-based care (45.8%) and 64 children had been in exclusively home-based care. Home-based care had consisted of either exclusive maternal care or being looked after by other family members or babysitters. In 2010/11, 14.0% of Italian children between 0 and 2 years of age were enrolled in centre-based care, with marked differences among the different geographical regions: for instance, in the North, 29.4% of children attended day care in Emilia Romagna and 15.4% in Piemonte, while in the South, percentages varied from 9.6% in Abruzzo to 2.4% in Calabria . A t-tesAt three separate sessions conducted within a month of each other, the children were individually assessed at kindergarten using four standardized tests: the ToM Storybooks  were useThe ToM Storybooks is a comprehensive 93-item instrument tapping the five components in z-score was used. Each TEC components are proposed in the frame of a short pictured story; the child answers to the task questions by indicating the facial expression of the correct emotion, accordingly to what happened. For example, in the displayed emotion task, in which the difference between apparent and real emotion is tapped, the experimenter reads this story: “This is Sarah and this is Dorothy. Dorothy is teasing Sarah because Dorothy has lots of marbles and Sarah doesn’t have any. Sarah is smiling because she doesn’t want to show Dorothy how she is feeling inside. How is Sarah feeling inside? Is she happy, alright, angry or scared?”The TEC evaluates nine hierarchically organized components of EU that emerge between 3 and 11 years. The simplest ones are recognition of emotional expressions and external causes of emotion, followed by the role of desire, beliefs and external reminder on emotions, emotion regulation, displayed emotions, role of moral dimension and mixed emotions. The TEC raw score varied from 0 to 9 and in this study the Italian standardized Parents were asked to complete a questionnaire on their socio-demographic background, which assessed both parent-related characteristics  and child-related characteristics . Thus, the data concerning the type of early care received in the first 3 years of life was collected retrospectively.Mothers’ level of education was coded in terms of the Italian school system: (0) lower level of education ; (1) more highly educated .For each child, parents’ country of birth was coded as follows: (0) native children ; (1) first-generation children .T-tests for small sample sizes were performed to check for significant differences in the children’s ToM and EU scores as an effect of type of early childcare, parents’ country of birth and maternal education. The direct effect of language on social cognition was assessed by analyzing the correlations between linguistic competence scores and ToM and EU scores, respectively.t-tests for the effect of maternal education on ToM and EU were performed on the type of care and parental country of origin subsamples. An ANOVA analysis has not been run: the sample size was too small to test the interaction effects through an ANOVA; for this reason, a regression analysis was not run as well.To test for interactions between maternal education and type of early childcare or parents’ country of birth, separate The mediating effect of linguistic competence was investigated by conducting two regression analyses, with ToM and EU scores as dependent variables and maternal education and parents’ country of birth as independent variables.Table 2). Maternal education was found to have a significant direct effect on ToM and EU scores. First-generation children obtained the lowest mean scores on the social cognition measures: although these scores did not significantly differ from those of the other children, the effect size was relevant (Table 2). Finally, linguistic competence was found to be correlated with both ToM and EU scores .Type of early childcare did not lead to significant differences in ToM and EU and the effect size was not relevant as well (Table 3).Type of care and maternal education were found to interact, in that maternal education had an effect on the social cognition abilities of children who had received home-based care only, but not on those of children who had been in centre-based care. More specifically, children whose mothers had completed a lower level of education only obtained significantly lower ToM scores than children with more highly educated mothers when they had received exclusively home-based care in the first 3 years of life (Table 4). Nevertheless, considering the effect size, the differences due to parents’ country of birth were lower than the differences observed in respect to the maternal education.Parental country of birth and maternal education were found to interact: namely, maternal education had an effect on the social cognition abilities of children with native-born parents, but not on those of first-generation children. More specifically, children whose mothers had completed a lower level of education only obtained significantly lower ToM and EU scores than children with more highly educated mothers when both parents were native-born , the correlation between maternal education and language ability scores was 0.283 (p < 0.01), the partial correlation between linguistic competence and ToM scores  was 0.465 (p < 0.01), while the direct correlation between maternal education and ToM scores was 0.269 (p < 0.01), and this correlation was reduced if the language effect was considered .With respect to ToM : the partial correlation between linguistic competence and EU scores  was 0.380 (p < 0.01), the direct correlation between maternal education and EU scores was 0.235 (p < 0.05), and this correlation was reduced if the linguistic competence effect was considered .Turning to EU, the same pattern of results was found . With respect to children in home-based care, two significant direct correlations were found: between maternal education and linguistic competence  and between maternal education and ToM scores ; furthermore, linguistic competence and ToM scores were correlated, partializing for maternal education . Moreover, linguistic competence mediated the relationship between maternal education and ToM: in fact, the direct correlation between maternal education and ToM was reduced if the linguistic competence effect was considered . With respect to children in centre-based care, the correlation between linguistic competence and ToM was the only significant relationship identified , with no correlations found between maternal education and ToM or between maternal education and language.When these correlations were analyzed separately in the two groups of children who had received home-based only versus centre-based care, the pattern of results differed : in the subsample of children who had received home-based care only, there were direct correlation between maternal education and linguistic competence , and between maternal education and EU scores ; linguistic competence correlated with EU , and mediated the relationship between maternal education and EU: more specifically, the direct correlation between maternal education and ToM was reduced if the linguistic competence effect was taken into account . On the contrary, in children in centre-based care the only significant relationship identified was the correlation between linguistic competence and EU .A similar pattern of results was found for EU (Table 5). However, no mediation effect was found: parents’ country of birth was not correlated with language , nor with ToM , nor with EU .When parents’ country of birth was included in the analysis, only linguistic competence was strongly correlated with ToM and EU, in both migrant parent and native-born parent subgroups  approved the current research run on human voluntary participants. The Committee approved: 1) the design of the research and the assessment tools; 2) the sample recruitment criteria; 3) the procedure for the collection of the informed consent form. The study involved preschool-aged children: their parents’ consent for participating in the study was collected. The children were observed at school, after an agreement with the school Director and the teachers. Each child gave her or his personal vocal consent to participate in the study assessment.DB and PM substantially contributed to the conception of the work and to the acquisition, analysis, and interpretation of data of the current study. DB and PM wrote the manuscript and revised it critically, adding important intellectual content. DB and PM approved the final version of the manuscript to be published. DB and PM agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.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 reviewer AS and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Background:Familismo or familism is a cultural value frequently seen in Hispanic cultures, in which a higher emphasis is placed on the family unit in terms of respect, support, obligation, and reference. Familism has been implicated as a protective factor against mental health problems and may foster the growth and development of children. This study aims at measuring the size of the relationship between familism and mental health outcomes of depression, suicide, substance abuse, internalizing, and externalizing behaviors.Methods: Thirty-nine studies were systematically reviewed to assess the relationship between familism and mental health outcomes. Data from the studies were comprised and organized into five categories: depression, suicide, internalizing symptoms, externalizing symptoms, and substance use. The Cohen's d of each value (dependent variable in comparison to familism) was calculated. Results were weighted based on sample sizes (n) and total effect sizes were then calculated. It was hypothesized that there would be a large effect size in the relationship between familism and depression, suicide, internalizing, and externalizing symptoms and substance use in Hispanics.Results: The meta-analysis showed small effect sizes in the relationship between familism and depression, suicide and internalizing behaviors. And no significant effects for substance abuse and externalizing behaviors.Discussion: The small effects found in this study may be explained by the presence of moderator variables between familism and mental health outcomes . In addition, variability in the Latino samples and in the measurements used might explain the small and non-significant effects found. According to the U.S. Census Bureau , the Latfamilismo or familism in which a higher emphasis is placed on the family unit in terms of respect, support, obligation, and reference  and outcome , while others show contradicting evidence  population, (b) sample size, (c) sample characteristics, (d) measure of familism used, (e) mental health outcome analyzed, (f) measure of mental health outcome used, and (g) type of statistical analysis used. This information is presented in Table All studies contained a sample of Latinos or Hispanics living in the United States. The studies required participants to self-identify as Hispanic or Latino. Participants were either foreign born or U.S. born. Those participants who were born in the U.S. had a Latin American background . As presented in Table A variety of scales were used to determine familism scores for the participants in each study. The most widely used was the Attitudinal Familism Scale (AFS) generated by Lugo Steidel and Contreras , which wThe most used measure was the Center for Epidemiologic Studies Depression Scale, CES-D Radloff, , utilizeSuicidal attempts in each study were defined as any act of self-harm or intention of hurting or killing oneself. There was no scale to measure suicide; in each of the four suicidal studies, the participants were chosen for each condition based on medical records and/or reports by the school or family. Suicidal attempts, regardless of the level of lethality, were considered under the “suicide” condition while suicidal ideation was considered under internalizing.Substance use was self-reported by the participants. A variety of substances were encompassed in the studies including marijuana, alcohol, illicit drugs, and cigarettes. The most used instrument for self-reporting substance was the Youth Risk Behavior Survey (Centers for Disease Control and Prevention (CDC), The most frequently used scale to measure internalizing and externalizing symptoms in participants was the Youth Self Report Scale YSRS Baham, , in six r correlation coefficient, odds ratios, hierarchical, standardized and unstandardized regression coefficients, or means and standard deviations for group comparisons . In order to calculate a summarized effect of these studies, the data extracted from the articles were converted to standardized effect size measures. For each study, an effect size was calculated with Cohen's d :Total effect sizes were calculated for each mental health outcome variable . Results were weighted based on sample sizes , suicide (d = 0.20), and depression (d = 0.21) showed a small effect with familism. The remaining two variables did not display a significant relationship.Effect sizes for Cohen's d = 0.02 to d = 0.75. Out of 24 studies on depression, 13 showed no significant effect (54.2%), 8 showed a small effect (33.3%), and 3 had moderate effect sizes (12.5%).As Table d = 0.00 to d = 1.29. Fourteen studies showed no significant effect sizes (66.7%); 4 studies had a small effect (19.0%) and 3 showed moderate effect sizes (14.3%).Substance use analysis included 21 studies, with effect sizes ranging from d ). Out of 5 studies on suicide, 3 had small effect sizes and the rest no significant effects.The range of effect sizes for suicide was narrower, suggesting less variability within the relationship of familism and suicide . With a very different distribution of effect sizes, the externalizing behaviors analysis showed a range of d = 0.02 to d = 1.03. Half of the studies showed no significant effects (7 out of 14 studies), 5 had small effect sizes, and only 2 reached moderate sizes for the effect.For the internalizing behaviors analysis, the effect sizes were distributed similarly. With a range of The results of this meta-analysis showed a small effect of familism on depression, suicide, and internalizing behaviors, and no effect for substance use and externalizing symptoms.The small effects on depression, suicide and internalizing behaviors are coherent since depression and suicidal behavior are frequently associated with internalizing symptoms  and time in the U.S. The concerns about sample variability have been exposed above.The interest of familism in Hispanic or Latino cultures is a relatively new but quickly growing field of interest. Further research and evidence proving the effects of familism on mental health could give a greater grasp on etiology and treatment options for psychopathologies. The aspects discussed in this section in terms of sample characteristics and measurement should be taken into consideration for future studies.EV and CP conducted the literature research and conducted the statistical analysis. CP wrote most of the Introduction and EV wrote most of the Methods, Results and Discussion sections. MG helped with data analysis and interpretation. MS and DJ supervised the study and gave feedback, made corrections and contributed with important ideas for the introduction and discussion.Support from NIA Developmental Grant R21TW009665 and the University of Kansas Open Access Author Fund.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.


Meniere disease (MD) is a heterogeneous clinical condition characterized by sensorineural hearing loss, episodic vestibular symptoms, and tinnitus associated with several comorbidities, such as migraine or autoimmune disorders (AD). The frequency of bilateral involvement may range from 5 to 50%, and it depends on the duration of the disease. We have performed a two-step cluster analysis in 398 patients with bilateral MD (BMD) to identify the best predictors to define clinical subgroups with a potential different etiology to improve the phenotyping of BMD and to develop new treatments. We have defined five clinical variants in BMD. Group 1 is the most frequently found, includes 46% of patients, and is defined by metachronic hearing loss without migraine and without AD. Group 2 is found in 17% of patients, and it is defined by synchronic hearing loss without migraine or AD. Group 3, with 13% of patients, is characterized by familial MD, while group 4, that includes 12% of patients, is associated by the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by AD. This approach can be helpful in selecting patients for genetic and clinical research. However, further studies will be required to improve the phenotyping in these clinical variants for a better understanding of the diverse etiological factors contributing to BMD. Meniere’s disease (MD) is a long-lasting disorder of the inner ear characterized by episodes of vertigo lasting from 20 min to hours, low-to-middle frequencies sensorineural hearing loss  was defined as the combination of clinical symptoms and audiometric tests, the frequency would be 2–47% , 10–13, MICA and TLR10 genes, involved in the innate immune response, may influence the susceptibility and time course of hearing loss of MD in European population  . FamiliaEvery patient underwent a complete neuro-otological evaluation, including a pure-tone audiometry, an otoscopy, nystagmus examination, and a caloric testing. A brain MRI was performed to exclude any other possible cause of neurological symptoms. Patients with simultaneous SNHL in both ears were considered to have synchronic SNHL, while metachronic SNHL was considered if an interval longer than 1 month between the first and the second ear was observed.Clinical variables studied were as follows: gender, duration of disease, age of onset, family history of MD, hearing loss at diagnosis, hearing stage defined as four-tone average of 0.5, 1, 2, and 3 kHz according to the AAO-HNS criteria , type of headache , history of autoimmune disease (AD), cardiovascular risk factors , Tumarkin crisis, and the Functional Scale of the AAO-HNS.T-test. Qualitative variables were compared using crosstabs and Fisher’s exact test. Nominal p-values <0.05 were considered statistically significant.A descriptive statistical analysis was carried out using SPSS software v.22 . Data are shown as means with their SDs. Quantitative variables were compared using Student’s unpaired We carried out a two-step cluster analysis using log-likelihood distance measures, which can detect relationships within a complex dataset between patients with multiple distinct characteristics. It tries to identify homogenous groups of cases based on the distribution of some variables (input variables). The method identifies the groups by running pre-clustering first and then by using hierarchical methods to classify and to find the optimal number of clusters.Initially, we selected variables showing differences between the clinical groups during the descriptive analysis to test its relevance as predictors of clusters. The procedure was iterated several times until we found the minimum number of homogenous clusters. The final cluster analysis was applied using the four following categorical variables: history of autoimmune disease, onset of hearing loss (synchronic/metachronic), FMD or sporadic cases, and migraine. The four variables included produced a silhouette of cohesion and division of 0.8, indicative of good data partitioning. Two additional variables were added to the model: age of onset <40 years old and gender, although their contribution to refine the clustering was limited.p = 0.003) and a higher prevalence of autoimmune comorbidities . Although apparently there were no clinical differences in the phenotype between sporadic and familial cases, FMD had an earlier age of onset  compared with patients without autoimmune comorbidities (33 and 16%), suggesting a potential association between migraine and autoimmunity in patients with sporadic BMD Table .p = 0.0004), and the worst hearing stage was observed in patients with metachronic hearing loss (p = 0.004).We also compared patients according to the onset of hearing loss Table . One hunWe performed cluster analysis to identify groups of patients with common clinical features in BMD. Figure We have defined five clusters for BMD and ranked them according to its relative frequency Figure . Clusterp = 0.0003). The type of hearing loss, FMD, migraine, and autoimmune comorbidities strongly differ among groups, and these variables are the basis to assign a given patient to each cluster.Table The diagnostic criteria for MD formulated by the Classification Committee of the Bárány Society state that bilateral involvement is determined by hearing loss defined in the audiogram . So, if Our study demonstrates that BMD is a heterogeneous disorder, and two-step cluster analysis is a very useful tool to define groups of patients with BMD according to four clinical predictors: FMD, autoimmune history, migraine, and the type of onset for hearing loss. We selected this method since it allows the inclusion of quantitative and categorical variables to define clusters .We present a new classification for BMD in five groups of patients with potential etiological implications, which probably will improve the diagnostic workflow and the management of patients with BMD. Previous studies in patients with BMD were focused in the diagnosis by electrocochleography or MRI –56, but The most remarkable finding in our study is that the five groups of patients identified do not overlap themselves, and each of them has a set of features able to define the group.Bilateral MD type 1 is the most common clinical variant, and it includes patients with MD in one ear , and they develop the hearing loss in the contralateral ear . The mean age of onset was 46 years old, comparable to BMD type 2, but it is significantly higher than it was observed in the rest of the groups . BMD type 1 has no familial or autoimmune history, and patients do not have migraine, so further studies are required to investigate other concurrent comorbidities to determine contributing factors.p = 0.078), but further studies should assess the role of vascular risk factors in labyrinthine microcirculation in MD.Bilateral MD type 2 is the second most frequently observed clinical variant, and fluctuating bilateral SNHL loss may resemble AIED, since simultaneous SNHL with vestibular symptoms can occur in 50% patients with AIED . HoweverComparing the hearing stage for the worst ear, it seems to be worse in BMD type 1 (metachronic SNHL) than in type 2 (synchronic SNLH). Since both groups do not differ for the age of onset, duration of disease, or gender distribution, we cannot determine the reason for the severe SNHL in the first ear in BMD type 1.Bilateral MD type 3 includes all patients with familiar history of MD, and we could subtype them in two subgroups . These findings confirm the early description of families with MD co-segregating migraine and MD  and the Bilateral MD type 4 is associated with migraine in all cases, but they do not have familial history of MD. This group may overlap with VM, and it may share common pathophysiological mechanisms . PatientBilateral MD type 5 could be considered as autoimmune MD, since all patients have another concurrent AD. However, this group is heterogeneous and includes patients with sporadic (71%), FMD (29%), migraine (38%), and both synchronic (38%) and metachronic SNHL (62%). Patients with BMD type 5 and migraine may have either synchronic or metachronic SNHL.Our study has several limitations. Despite our efforts to improve phenotyping in patients with BMD, we could not classify 95 patients with BMD in any cluster, and they were excluded of the model. In fact, the largest group (BMD type 1) remains poorly characterized, since it is not associated with any particular clinical feature or etiological factor. The role of allergy in MD deserves more research efforts, since a high prevalence of sensitization to inhalant or food allergies have been reported in MD –67.However, the recognizing of different subgroups of patients and the definition of clinical variants in BMD is not only the first step to improve the selection of patients for genetic and immunological studies but also for randomized clinical trials (RCT). Most of the RCT performed in MD, were not able to demonstrate any effects of diuretics  or betahLF and JL-E conceived and designed the study. AS-V, SS-P, AB-C, VP-G, HP-G, JF, EM-S, MT, GT, AG-A, RG-A, JE-S, PM, PP, JB, and JL-E collected clinical information. LF and JL-E analyzed the data and drafted the manuscript. LF, AS-V, SS-P, AB-C, VP-G, HP-G, JF, EM-S, MT, GT, AG-A, RG-A, JE-S, PM, PP, JB, and JL-E revised and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Bos taurus breed that have adapted to the wet tropical conditions of the Amazon. This breed has integrated into the culture of the indigenous Shuar-Asuar nations probably since its origins, being one of the few European zoogenetic resources assimilated by the deep-jungle Amazon communities. Despite its potential for local endogenous sustainable development, this breed is currently endangered. The present study used molecular genetics tools to investigate the within- and between-breeds diversity, in order to characterize the breed population, define its associations with other breeds, and infer its origin and evolution. The within-breed genetic diversity showed high values, as indicated by all genetic parameters, such as the mean number of alleles (MNA = 7.25±2.03), the observed heterozygosity (Ho = 0.72±0.02) and the expected heterozygosity (He = 0.72±0.02). The between-breeds diversity analysis, which included factorial correspondence analysis, Reynolds genetic distance, neighbor-joining analysis, and genetic structure analysis, showed that the Macabea breed belongs to the group of the American Creoles, with a Southern-Spain origin. Our outcomes demonstrated that the Macabea breed has a high level of purity and null influences of exotic cosmopolitan breeds with European or Asiatic origin. This breed is an important zoogenetic resource of Ecuador, with relevant and unique attributes; therefore, there is an urgent need to develop conservation strategies for the Macabea breed.Macabea cattle are the only  The group of the American Creole cattle breeds, which were formed in the American continent after the European colonization , represeCapitanies [Bos indicus breeds from the Asian colonies of the British Empire. Already at the beginning of the 20th century, Asiatic breeds such as Guzerat, Nelore, and Gyr had an extended distribution across the United States, Mexico, and Brazil [The first arrival of cattle to America occurred in the second voyage of Columbus in 1493, which set sail from the south of the Iberian Peninsula . After tBos taurus and B. indicus have a common ancestor in the Aurochsen wild B. primigenius, which marked the start of domestication approximately 11000 years ago [ears ago , even thears ago .Bos indicus animals became massive and indiscriminate, producing extensive deforestation especially in river basins. Today only few local breeds from Bos Taurus type exist one of this is the Ecuadorian Macabea breed. The animals from this breed present excellent meat attributes.The Amazonian region was almost free of cattle until the 20th century, when farming practices became more aggressive and sprawled into natural environments. At the same time, the introduction of The origin of the Macabea breed is unknown. Presumably, they reached the Ecuadorian Amazon along with the Spanish incursions developed between 1540 and 1548 from Quito and Guayaquil . HoweverMacabea cattle  are currThere are several enigmatic controversies around the genetics origins of Macabea breed, and in particular, if it should be admitted as a resource for the sustainable development of the Amazonian region. There is a persistent pressure from conservationist groups against the presence of farm animals in the natural environment. The aim of this study was to genetically characterize the Macabea cattle breed based on microsatellites markers, in order to generate scientific data about this rare genetic resource and its genetic relation with other Creole or exotic breeds, searching for a geo-evolutionary explanation of its origin and dissemination. These findings would support the conservation of this important breed, and propose the Macabea breed as a resource for the endogenous sustainable development of the region, in terms of its excellent meat quality and its ability to adapt to the wet tropic. Microsatellite markers have been widely used for population genetic analyses of livestock species –11, as tEthical approval was not needed for this study. All hair samples collections were non-invasive (hair roots) and carried out during routine veterinary visits in the farms on live animals. The fieldwork did not involve any endangered or protected species. Hair root were manually collected without any injury in the back of the animals No other kind of tissues  were used in this study.2 area of the Amazonian Provinces of Pastaza and Morona Santiago, in Ecuador; in particular the following location were visited: Palora ; Jimbitono ; Macas ; Puyo ; Morona-Santiago ; All the farms were isolated, distributed in the deep-jungle, accessed only by river routes, and with a considerable distance between them (~50–100 km). Cattle owners belonged to the native nationality Shuar-Achuar, which still maintain strong traditional culture practices. After collection, hair samples were stored in labeled envelopes, and brought from the collecting point to the Universidad Estatal Amazónica . DNA was extracted using three hair roots cut and incubated at 95°C during 15 minutes and at 99°C during 3 minutes in a 100 μl solution of Chelex100 resin . After incubation, extracted DNA was conserved at –20°C until use.Hair samples of 25 Macabea individuals were randA panel of 28 microsatellite markers , selectewww.datadryad.org): doi:10.5061/dryad.1dh4cData used in this paper have been archived at Dryad (http://www.biobovis.jimdo.com); these breeds represented evolutionary branches to be tested to determine the genetic origin and the evolutionary associations of Macabea. Data are deposited and available at Laboratory of Applied Molecular Genetics. As outgroup-breeds, we chose the Rubia Gallega (RGA), which represents Celtic animals from northern Spain, and the Berrenda en Colorado (BC) and the Marismeña (MA), both representing southern Spanish resources. In theory, Macabea cattle reached the Amazon with colonizers from the Pacific coast; therefore, we included the Ecuadorian Creole Ecuadorian of Southern (EC) and the Colombian Creoles Hartón del Valle (HV), and Blanco Orejinegro (BON). In order to test recent influences of cosmopolitan European breeds specialized in milk and beef production, we included the most influential breeds of these groups in the region: Hereford (HER), Brown Swiss (BWS), Holstein (HOL), Jersey (JER), Simmental (SIM), and Charolaise (CHAR). Finally, to test the possible influence of the zebuine expansion in the Amazon on the Macabea breed, the Brahman (BRH), Gyr (GYR), Nellore (NEL), and Cuban Zebu (ZEBU) were also used in this study. To explore the between-breeds diversity, we used 621 genotypes belonging to outgroup-animals. This information, and the individual breeds sample sizes are shown in We obtained data on different bovine breeds from the BIOBOVIS project , unbiased expected heterozygosity (He), the average number of alleles (Na) and the content of polymorphic information (PIC) for the breed and for each marker by means of using the Microsatellite Toolkit software . The Fisa posteriori distribution of each individual admixture coefficient (q). The mean in this distribution represents an estimation of the proportion of the parental population genome present in the individuals. This program develops a clustering of the individuals in different number of clusters (K), representing the number of populations admitted in an admixture model, in which each individual genome could content different percentages of the ancestral population genomes where they come from. Alternatively, two structure runs were carried out: in the first one, all breeds were included, and the results were displayed using Distruct v1.1 software [k colored segments, which represents the genotypic fractions of each inferred cluster. Secondly, we calculated a structure run only including MAC, EC, BON and HV breeds, where we used the kriging interpolation method [To infer the genetic relation between the Macabea breed and all the determined outgroups, we performed a factorial correspondence analysis (FCA) using the Genetix v. 4.05.2 software . In addisoftware  and the software . In the n method  to assesn method  was usedThe microsatellites panel used in this study has been previously applied and proved in several cattle studies, conducted by our own research team , 2, 29. FIS = 0.03(0.02–0.05), FIT = 0.16(0.14–0.18), and FST = 0.13(0.12–0.15). Macabea cattle showed a high mean of alleles, with a value 7.79±2.02; the other Ecuadorian breed EC presented the highest value (9.47±2.44), and the lower value was detected in JER (4.79±1.03). This trend was confirmed by the allelic richness and the heterozygosity data  and significant (P<0.05). When observed by breed, the FIS index from EC, BC, HER, GYR, and NEL breeds showed slightly significant values, and with Macabea presented no significant deviation.Most of the markers in the studied breeds were in HW equilibrium ; seven bity data . The oveFIS and Reynolds distances). In both cases, Macabea showed extreme distances in respect to the zebuine breeds, and a close position in respect to the EC and the Colombian breeds (HV and BON). These results are supported by FST pairwise-distances are graphically represented by using a color gradient matrix. Two clusters belonging to the Bos indicus and Bos taurus cattle types are visible. In this scenario, Macabea cattle breed showed very large distances with respect to all the Bos indicus breeds, with FST values ranging between 0.18 and 0.23, and between 0.18 and 0.21 for Reynolds distances. In general, Macabea breed also showed important distances in respect the other international Bos taurus breeds, with FST values ranging between 0.07 and 0.15, and between 0.06 and 0.14 for Reynolds distances. The shorter distance of Macabea with international breeds was detected in respect to the BWS breed. The Spanish outgroups RGA (representing the Celtic breeds from the northern Spain), and the MA and BC (Southern-Spain breeds) showed diverse patterns of distances with MAC, being the southern breeds closer than the northern breeds, with FST values of 0.06, 0.08, and 0.11, respectively, and Reynolds distances of 0.06, 0.08 and 0.10, respectively. Finally, the group that was detected to be the most related to Macabea was formed by the other Creoles, in particular, the Colombian HV and the EC .Bos taurus vs. Bos indicus); and the second level considered each geographical origin . P<0.01). Variation between-groups were 11.67% (P <0.05) and 7.86% (P<0.01) for the phylogenetic and geographical groups comparisons, respectively. The results of the factorial correspondence analysis conducted with all the studied breeds, and then avoiding the zebuines, both supported the results obtained in the AMOVA: breeds were grouped in the space according to their phylogenetic origin , using as reference the clusters k2 and k3, results very illustrative. We described a unique cattle breed adapted in a tropical environment of Ecuador. The importance of this genetic resource goes further in the field of biodiversity conservation; in fact, these animals reared in extremely marginal areas, with low technological inputs, demonstrate a unique capacity of adaptation to produce high quality beef in the wet tropics, intended as a money reservoir for native nationalities. In general, the daily protein consumption of families is sustained through hunting, fishing, and pigs and chicken. The cattle, however, are often converted into money when needed by the family. The official recognition supported by the molecular findings could add value to this particular economy and improve the quality of life of the disadvantaged population.Within-breed diversity results supplied robust and important arguments to support Macabea conservation status. We must first highlight that only four of our 28 markers were not in HW equilibrium; this outcome denotes a genetic stability in the population that corresponds to a consolidated breed with no recent bottleneck or migration events. Other general parameters also support this hypothesis, such as the mean number of alleles, all of which reflect a high level of within-breed variability. These general parameters were higher than those previously reported for European breeds , 32, 33,Cattle reached Ecuador from Panama during the beginning of the regional Spanish conquest arriving directly to the Caribbean Islands, which was the first point of cattle colonization in the Americas . ProbablThe panel of microsatellites markers used in the present study resulted highly informative and with sufficient statistical power for biodiversity studies as just described in different works on bovine species  suitableFIS values, which were undistinguishable from cero, demonstrated a general HW equilibrium. These results indicated that Macabea presents a level of genetic differentiation that is sufficient to be considered as an independent breed, according to international conventions [The general ventions . Thus, MFST distances were robust: we demonstrated the no existence of zebuines breeds introgression on Macabea, which remark its resistance despite a challenging context with massive introductions of zebuines in the region. In addition, we demonstrated the isolation of Macabea breed with respect of previous introductions of international Bos taurus breeds, highly specialized in meat or dairy productions.Once covered the objective of breed-genetic characterization by means of the within-breed diversity study, the second purpose of this study was to explore Macabea phylogenetic evolution. This second objective was tackled by means of the between-breeds diversity study, taking into account representatives of all branches used as outgroups, representing different hypothesis of the origin, genetic relationships, and evolution of the Macabea breed. The results of the Reynolds and Our results on the genetic association of the Macabea with the Spanish breeds, both the southern and northern representatives, are very interesting and support the hypothesis of the traditional integration of the breed in the Shuar-Asuar culture (old “head reducers”). The relationship between the Macabea cattle and the Shuar-Asuar communities, as pointed out by us earlier, probably started in 1599 when the city of Sevilla de Oro; the first European Amazonian settling founded in 1577, was destroyed by these native nationalities [There was a strong association of Macabea with southern Spanish breeds, supporting the hypothesis extracted from the chronicles, which described that the commercial trade between Spain and the American colonies was monopolized by the southern-Spanish ports for a long period , 38. FinBos taurus members, in particular, when the zebuines were included Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Background: Allergic diseases are thought to be inherited. Prevalence of allergic diseases has, however, increased dramatically in last decades, suggesting environmental causes for the development of allergic diseases.Objective: We studied risk factors associated with the development of atopic dermatitis (AD), allergic rhinitis (AR) and asthma (AS) in children of non-atopic parents in a subtropical country.Methods: In a birth cohort of 1,497 newborns, parents were prenatally enrolled and validated for allergic diseases by questionnaire, physician-verified and total or specific Immunoglobulin E (IgE) levels; 1,236 and 756 children, respectively, completed their 3-year and 6-year follow-up. Clinical examination, questionnaire, and blood samples for total and specific IgE of the children were collected at each follow-up visit.p<.001) and AS (p=.018) was significantly higher in children of parents who were both atopic. A combination of Cesarean section (C/S) and breastfeeding for more than 1 month showed the highest risk for AD . Infants living in homes with curtains and no air filters had the highest risk for AR , and male infants of non-atopic parents living in homes without air filters had the highest risk for AS .Results: Prevalence of AD, AR and AS was, respectively, 8.2%, 30.8% and 12.4% in children of non-atopic parents. Prevalence of AR (Conclusions: Breastfeeding and C/S affect development of AD. Gender, use of curtains and/or air filters affect AR and AS, suggesting that control of the perinatal environment is necessary for the prevention of atopic diseases in children of non-atopic parents. Prevalence of allergic diseases, including atopic dermatitis (AD), allergic rhinitis (AR), and asthma (AS) has increased dramatically in the last decades and has raised concern over the influence of lifestyle and environmental factors on the development of allergic diseases . AllergiIn a birth cohort study, we found that the interactions between genes and environmental factors on blood IgE levels began during the prenatal stage , and theIn the birth cohort follow-up, we attempted to examine the environmental risk factors for the development of allergic disorders in children of non-atopic parents in Taiwan. We compared the prevalence of allergic disorders and analyzed the distribution of the risk factors among 3 groups of children according to different parental atopy . We then focused on analyses of potential risk factors for the development of AD, AR, and AS in children of non-atopic parents.In total, 1,848 newborns were recruited, 1,629 infants were followed at least once. Of these newborns born in the hospital, 1497 received CBIgE measurement, 1,236 and 756 children completed 3-year-old and 6-year-old follow-ups, and 737 children had all charts and blood tests for analysis. Of the 737 children, 380 children were neither parents atopic, 293 children were one parent atopic, and 64 were both parents atopic. The demographic data and baseline parental characteristics between children with and without completion of 6-year-old follow-up revealed no significant differences . The prevalence of AR was significantly higher in children of parents who were both atopic . The prevalence of AS was also significantly higher in children whose parents were atopic  . This bias might be related to recognition of the value of breastfeeding in the prevention of allergic diseases by atopic parents. Umbilical cord blood IgE (CBIgE) level cut-off 0.35 kU/L was significantly higher in newborns from atopic parents than those from non-atopic parents ; however, the elevated CBIgE level could not predict childhood AD (p=.184), AS (p=.425) or AR (p=.090).More than three-fifths of the mothers breastfed their infants in the first month, and then stop or supplemented with infant formula. We analyzed the influence of breastfeeding by using a cut-off at equal to or more than one month of breastfeeding. Among the three study groups, children from the non-atopic parents had a significantly lower rate of breastfeeding over one month with 63.6%, in comparison with children from atopic parents (72.6%) or one atopic parent (70.1%)  in the cohort. In univariate analysis (UVA) for all subjects in the cohort, we found that breastfeeding for more than 1 month  was borderline significant associated with AD. In the multivariate logistic regression analysis (MVA) for all subjects in the cohort, no risk factor was significantly associated with AD. Breastfeeding for more than 1 month approached borderline significance  in predicting AD and air filter use reached borderline significance in predicting protection from AD . In contrast, we found that breastfeeding for more than 1 month  and dehumidifier use  were significantly associated with development of AD in children of parents without atopy in UVA. While controlling other risk factors in MVA, breastfeeding for more than 1 month remained a significant predictor for AD , and C/S was also a significant risk factor for AD  in children from non-atopic parents.In AR, we found that male gender was a significant risk factor for AR , while preterm birth and living in a townhouse were significant protective factors for AR  in UVA. In MVA for AR, male gender remained a significant predictor  and preterm birth and living in a townhouse were significantly protective factors for AR . In children of parents without atopy, male gender  and use of curtains  were significant risk factors for AR; and preterm birth  and air filter use  were significantly protective factors in UVA. While controlling other risk factors in MVA, male gender , family member smoking , use of curtains  and tile floor  were significant risk factors for AR of children from both non-atopic parents.In prediction of AS, UVA analyses found that male gender was a borderline significant predictor for AS  in all children studied. In MVA, none of the risk factors reached a statistically significant relationship with AS. Results of children from both non-atopic parents also showed no risk factor significantly associated with development of AS Table . This suWe performed several analyses to investigate co-existing risk factors for the development of AD, AR or AS. We selected the risk factors individually associated with AD, AR or AS, and calculated the odds ratios (OR) for two or three coexisting risk factors for the development of allergic diseases based on the ratio of affected children in the risk group versus those in the non-risk group. Coexistence of breastfeeding and C/S revealed the highest risk for AD , and the coexistence of breastfeeding, family member smoking and tile flooring also revealed a significant predictor for AD . The coexistence of family member smoking, use of curtains, and tile flooring was a significant predictor for AR , and combinations of either two of the three factors all presented statistical significance Table . Living In the group with a comorbidity of “AD and/or AR”, significant risk factors were male gender  and tile floor use . Air filter use showed a significant protective factor  for the comorbidity of “AD and/or AR”. Analysis of the comorbidity of “AR and/or AS” showed that male gender , use of curtains OR=2.56, p=.030), and tile floor use  were significant risk factors. In the patients with a comorbidity of “AD and/or AR and/or AS”, male gender  and tile floor  raised a significant risk. Use of air filter lowered the risk with a borderline significance  for the comorbid allergic diseases. Overall, male gender, use of curtains and/or tile floor are risk factors for comorbidity of allergic diseases, and use of air filters is a protective factor from comorbidity of allergic diseases , however, is only found in children with AR but not AD or AS. This may be attributed to the fact that the prevalence of AR is higher than that of AD or AS. Crump et al.  also conIn addition, male gender was a significant risk factor for AR in children from non-atopic parents. The result was consistent with many studies reporting a higher prevalence of allergic diseases and higher total IgE levels in boys than females . In anotOur study also found that exposure to a family member who smokes was a significant risk factor (OR=1.89) for AR. The combination of exposure to a family member who smokes and tile flooring at home increased the risk for AR in children from non-atopic parents while it is not a significant factor for AS both in univariate and multivariate analyses. This suggests that the impact of perinatal tobacco smoke exposure on the development of allergic diseases did not appear consistent in AS. Ponsonby, et al.  showed tThis large scale study recruited more than one thousand newborns prenatally, and conducted long-term followed-up for more than 6 years. We adopted stringent definitions for parental and childhood allergic diseases, based on clinical features of physician's diagnosis combined with the detection of total and specific IgE levels. Given the detailed information collected, this birth cohort enabled us to include parental and perinatal environmental risk factors for the analyses on the development of allergic diseases from birth to 6 years of age. There are some limitations of the study. Questionnaires were used to collect the participants’ information, which may raise recall bias due to interpersonal reporting bias of parents resulting in over- or under-estimation of the actual risks. Some of the items in the questionnaire were reported dichotomously. Dichotomous responses were unable to be interpreted in dose-response relationships between risk factors and allergic diseases. For example, number of pets kept, hours of daily dehumidifier use and air filter use are not clarified for the analyses. Similarly, severities and dynamics of allergic diseases are also not recorded. The children were followed up to 6 years of age, and some allergic diseases may not have been fully developed in some subjects. The birth cohort was conducted in a medical center in southern Taiwan where is located in a subtropical region. This could limit the generalization of the results to other parts of the country or the world.In conclusion, prevalence of AR (p<.001) and AS (p=.018) was significantly higher in children from atopic parents than those from one atopic or non-atopic parents, suggesting children of parents who are both atopic develop atopic diseases more related to inherited causes. The prevalence of allergic disorders in children of non-atopic parents is similar to those with one atopic parent, indicating children of non-atopic parents develop atopic diseases as a result of environmental influences. Atopic dermatitis is a disease somehow different from airway allergic diseases in term of different inheritance Table  and enviThe study is derived from a birth cohort longitudinally followed for up to 6 years of age. The birth cohort was described in detail in previous works , 34, 35.Umbilical cord blood samples were collected immediately after the infants were born. Birth history, including gestational age, mode of delivery , and gender, was collected by chart review. Total and/or specific IgE levels were measured in umbilical cord blood and during follow up visits. Levels of specific and total IgE levels were determined by Pharmacia CAP system  as described previously , 34. CorData of environmental factors were collected during follow-up in obstetric and pediatric clinics utilizing questionnaires. On recruitment, a questionnaire about parental allergic history, including AD, AR, and AS, and parental smoking were collected in the second or third trimester of pregnancy. At delivery, the information about the mode of delivery, gestational age, parity, and gender of the infant was recorded. Infants at 6 and 18 months of age were followed up to collect their breastfeeding and infection history, housing conditions with and without townhouse, dehumidifier, air filter, curtaining, carpeting, pets, and tile vs. wooden floor, and information on atopic eczema, cough or sneezing without colds, and audible wheezing episodes. Children at 3 and 6 years of age, questionnaires were distributed and performed by a pediatric allergist to collect the information about physician-diagnosed allergy diseases, including AD , AR , and AS .We defined parental atopy by a history of AD, AR, or AS together with either a positive CAP or a total IgE level ≥ 100 kU/L. The CAP test was considered positive for food allergen ≥ 2 tiers (0.7 kU/L) or aeroallergen ≥ 1 (0.35 kU/L) tier. The children completing the 6-year-old follow-up were categorized into 3 groups: neither parent with atopy (n=380), one parent with atopy (n=293), or both parents with atopy (n=64). A childhood allergic disease was defined by a clinical diagnosis of allergic disease of AD, AR, or AS together with aeroallergen sensitization at specific IgE levels ≥ 0.30 kU/L or food allergen sensitization at specific IgE levels ≥ 0.75 kU/L. Clinical diagnosis of AD is defined by physician-diagnosed AD and characteristic distribution of dermatitis for more than 2 weeks in recent 6 months; clinical diagnosis of AR is defined by physician-diagnosed AR and characteristic features with morning and/or night sneezing for more than 2 weeks in recent 6 months; clinical diagnosis of AS is defined by physician-diagnosed AS and characteristic features with exercise-induced cough or morning and/or night cough for more than 2 weeks in recent 6 months.We compared the distribution of demographic data between children with and without completion of the follow-up by Chi-square test. We analyzed the prevalence of allergic disorders among children of parents who are either both atopic, one is atopic or both are non-atopic by Chi-square test. Then we examined the relationships between the risk factors and the development of AD, AR, and/or AS of children from non-atopic parents by univariate logistic regression analysis (UVA) and multivariate logistic regression analysis (MVA). To better understand coexisting risk factors for the development of AD, AR or AS in children from non-atopic parents, we selected the risk factors individually associated with AD, AR or AS, and calculated the odds ratios (OR) for the 2 or 3 coexisting risk factors on the development of allergic diseases based on the ratio of affected children in the risk group (N1) versus the ratio of those in the non-risk group (N2), where N1 is the number of subjects with listed risk factors and N2 is the number of subjects without listed risk factors. A p-value of less than .05 was considered statistically significant. All statistical analyses were carried out by SPSS statistical software package.


With improvement in hospice palliative care services and long-term care, Republic of Korea (hereafter South Korea) has recorded significant changes in places of death , especially among older adults. Over the last few decades, the most common places of death in South Korea were hospitals. However, Koreans, especially older adults, reportedly prefer to receive terminal care and eventually die at home. This study was conducted to investigate trends in places of death among older Korean adults and factors associated therewith.Data were obtained from the Korean Death Registration Database maintained by the National Statistical Office. Decedents who died after the age of 65 years from 2001 to 2014 were included in the analysis. For descriptive analysis, proportions of places of death were analyzed and were used to plot graphs for visualizing trends during 13-year period. Logistic regression model was used to evaluate factors associated with places of death .Two million three hundred fifty eight thousand two hundred eleven older adult decedents were included in final analysis. Hospitals were the most common places of death (57.82%), followed by homes (32.12%). Dying at social welfare facilities was rare (2.61%). A gradual increase in hospital deaths (31.38% in 2001 to 75.30% in 2014) and a subsequent decrease in home deaths (60.44% to 15.95% over the same period) were noted. Hospital deaths were more likely for younger patients , females , and single/divorced or widowed individuals . A higher education level and living in urban areas were strongly associated with a higher likelihood of dying in a hospital.Over the study period, there was a consistent increasing trend in hospital deaths in South Korea. Trends in place of death and factors associated therewith should be more intensely investigated and monitored. Resources and facilities should be increased to fulfill end-of-life care preferences and the needs of an increasingly older population in South Korea. Place of death has been suggested as a key indicator and outcome measure of end-of-life care –4. DistrApproximately half of decedents expressed preference for a home-based end-of-life and eventually die at their usual place of residence –14. HoweIn South Korea, a shift in the distribution of deaths across settings was observed between 1992 and 2001, from deaths at home to deaths in a hospital . While hUsing a death registration database, we conducted this study to provide insight into trends in places of death among older adults in South Korea and associations with independent determinants thereof, including cause of death, socio-demographic factors, and residential area. Since cancer ranks among the most popular causes of death in South Korea , we focuData for this study were obtained from a death registration database maintained by the National Statistical Office (NSO) in South Korea. According to the Korea Family Registration Act, all deaths must be reported to the local administrative government within one month thereafter. The NSO then collects data through National Vital Statistics System. In this study, we included data of all decedents who died at age 65 years or older from 2001 to 2014. Death certificate records include the following information: time of registration , place of residence, sex, time of death , place of death, occupation of decedent, by whom death was diagnosed, marital status, education level, and first and second underlying causes of death according to International Classification of Diseases version 10 (ICD-10) [The NSO classifies places of death as home, medical institution or hospital, residential institution, public administrative area, road, commercial service facilities , industrial area, agricultural area, during hospital transfer, other places, and unknown . We seleExplanatory variables included were sex, age at death, marital status and education level. In accordance with our target population, we analyzed data on eight illnesses common among older adults that are relevant to end-of-life care . We alsoP-values <0.05.Time trends in proportions of death at a hospital, home, or social welfare facility were described. Associations between place of death and explanatory variables were evaluated using Pearson’s Chi-squared test. Dependent variable was defined as “hospital death” (1) versus “home death” (0). Due to our interest in hospital death versus home death, deaths at other places were excluded from the regression model. We conducted univariate and multivariate logistic regressions. Crude odds ratio and adjusted odds ratio (ORs and aORs) were reported together with 95% confidence intervals (95% CI). Statistical significance was set at After excluding 49,829 (2%) subjects with missing data on key variables, the final data set included data on 2,358,211 individuals over the age of 65 years (Table Overall, hospitals were the most common place of death ranging around 60-70% Table . The proTable Figure Figure . Other Asian countries have documented similar shifts from deaths at home to hospital deaths, including Japan and Taiwan. In Japan, a significant reduction in home deaths was observed, from 82% to 13%, as a result of rapid of growth in health care services in the 1960s to 1980s [Utilizing death data for a 14 year-period, we explored trends in places of death in South Korea, primarily focusing on hospital deaths. Deaths in a hospital gradually increased from 2001 to 2014. Together with a previous study on the same topic , we founto 1980s , 21. A sto 1980s . These pto 1980s , Englandto 1980s , US [24,to 1980s , and Canto 1980s . Previouto 1980s , 27: a sto 1980s .Rapid economic transformation has brought about significant changes in South Korea’s demographics, as well as other society-altering phenomena, such as urbanization, changes in living arrangements, and household structure. According to a report from the Korean Ministry of Health and Welfare in 2004, more than half of Korean older adults live alone and/or with only their spouse . FurtherOne study in South Korea concluded that greater hospital bed availability has facilitated a greater odds of dying in a hospital . Their aKnowledge of determinants influencing place of death can be helpful to developing public health strategies targeting end-of-life care. Results from our study indicated that age, sex, education level, marital status, residence area, and causes of death are significantly associated with place of death. In our study, we found that increasing age was consistently a predictor of a reduced likelihood of dying in a hospital. This finding is consistent other studies , 18, 27.Herein, we noted a striking discrepancy in places of death between less and more highly educated individuals. In our study, higher education was consistently a strong predictor of a higher likelihood of dying in a hospital and was consistent with previous investigations in South Korea , 34. In Our analyses highlighted relationships between marital status and where people die similar to those in previous studies , 35–37. In the present study, places of death differed substantially between older adults who died from cancer and those who died from other causes. In particular, compared to non-cancer, hospital deaths were appreciably more common among cancer decedents. This finding is congruent with previous investigations , 21, 35.This study analyzed of a large unique dataset to outline variations in places of death among older adults in South Korea. Analyzing datasets for 14 years, we conducted a comprehensive analysis through which to identify trends and distributions in places of death. Other strengths of this study include the high quality of the datasets with few missing cases and the population-based nature of the datasets. This study does have some limitations that warrant consideration. The use of death certificate data is inherently limited. First, as it is an administrative dataset, we cannot take into account several important factors that may have an impact on where people eventually die; these include medically related factors, such as characteristics of the course of the disease and dying process, and information on the decedent’s income and social support. Death certificate data also lack information on the patients’ preferences on their place of dying. Second, statistical patterns from this quantitative research does not allow us to draw an absolute conclusion about the choices, behaviors, or attitudes underlying those patterns. Another noteworthy point is that, since the South Korean government has implemented long-term care insurance on a nationwide scale, the numbers of both general and long-term care hospitals have increased dramatically recently. However, in the death registration database, long-term care hospitals and palliative care are coded together with general and other kinds of hospitals. Due to this limitation, we could not explore the distribution of deaths in this particular setting.Utilizing Death Registration Database, this study outlined high quality empirical data on where older adults in South Korea died, together with information on factors associated therewith. Our results showed that there was a consistent increasing trend in hospital deaths in South Korea from 2001 to 2014. Therefore, we suggested that more sufficient resources and facilities should be provided to fulfill the end-of-life care preferences and needs of Korea population. Furthermore, forward future planning for palliative care should consider individuals dying from conditions with severely life-limiting symptoms other than cancer, as well as expanding the scope of services and coverage. To avoid unnecessary admissions to hospitals during the last few months of life, enhancing non-hospital based palliative care centers, such as home visits or day-care centers, could be a potential solution.


In the past, increases in childhood cancer incidence were reported in Europe and North America. The aim of this study is to show updated patterns of temporal behavior using data of the Childhood Cancer Registry of Piedmont (CCRP), a region with approximately 4.5 million inhabitants in North-West Italy. CCRP has been recording incident cases in children (0–14 years) since 1967 and in adolescents (15–19) since 2000. Time trends were estimated as annual percent change (APC) over the 1976–2011 period for children, and over 2000–2011 for both children and adolescents. CCRP registered 5020 incident cases from 1967 to 2011. Incidence rates were 157 per million person-years for children (1967–2011) and 282 for adolescents (2000–2011). From 1976–2011, increasing trends were observed in children for all neoplasms  and for both embryonal and non-embryonal tumors: 1.1%,  and 1.2%, , respectively. Increases were observed in several tumor types, including leukemia, lymphoma, central nervous system tumors and neuroblastoma. In 2000–2011, incidence rates showed mostly non statistically significant variations and large variability. The observation of trends over a long period shows that the incidence of most tumors has increased, and this is only partially explained by diagnostic changes. Large rate variability hampers interpretation of trend patterns in short periods. Given that no satisfying explanation for the increases observed in the past was ever found, efforts must be made to understand and interpret this peculiar and still ununderstood pattern of childhood cancer incidence. In the last decades of the previous millennium, strong and unexplained increases in the incidence of childhood tumors were observed in Europe and USA –3. In ItData were obtained from the CCRP, the oldest and largest pediatric population-based cancer Registry active in Italy. The registry has been recording cancer cases in children (0–14 years) since 1965 and in adolescents (15–19 years) since 2000. The first 2 years of registration were used to identify prevalent cases whereas data from 1967 onwards have been used to estimate the incidence. Before avaliability of the hospital admission and discharge files (from mid 90s), cases were searched through manual perusal of hospital registries and clinical records. From then on, cases are identified from the Hospital Admission and Discharge files, including hospital stays of all Piedmont residents in all Italian hospitals. The potentially relevant discharge diagnoses are then selected, and their complete clinical documentation is requested and examined by an experienced pediatrician in order to identify incident cases. Further case ascertainment is obtained from the databases of pathology departments of Piedmont hospitals, records for reimbursements for cancer treatments administered abroad, the Turin Cancer Registry and the database of the Italian Association of Pediatric Hematology and Oncology. Only CCRP authorized personnel can access individual data. Data are anonymised before statistical analysis.CCRP data quality indicators by period of registration are shown in Cases are included in the CCRP only after positive confirmation of age and residence in Piedmont at diagnosis, verified at the residence Town Office Registrar. All diagnoses are coded using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3)  classifiThe list of embryonal tumors includes the following ICD-O-3 morphological codes: 8902, 8910, 8912, 8959, 8960, 8963, 8970, 8972, 8973, 9110, 9270, 9290, 9310, 9330, 9342, 9362, 9370, 9371, 9372, 9392, 9470, 9471, 9472, 9473, 9474, 9480, 9490, 9500, 9501, 9502, 9508, 9510, 9511, 9512, 9513, 9520, 9521 and 9522.From 1970 to 1975 the registration was limited to the Province of Torino.Crude incidence rates were calculated as the number of new cases per million person-years for the 12 main ICCC diagnostic groups as well as for the most important subgroups, by age class. The analysis of incidence trends was restricted to the period 1976–2011 to include data from the whole region of Piedmont (registration was limited to the Province of Torino in the period 1970–1975) and to avoid major diagnostic changes in the diagnosis and classification of leukemia. Time trends were estimated also separately for the last available 12 years of observation (2000–2011), when the analysis is possible in both children and adolescents.With regard to CNS tumors, we started the time trend analysis from 1982 in order to avoid biases due to improvements in diagnostics (such as the use of CT scans at the beginning of the 1980’s). Due to the heterogeneity of behavior, we also estimated time trends for all histologically verified CNS tumors by WHO grading . The ideFor neuroblastomas we conducted a sensitivity analysis starting the time trend analysis from 1990, to account for the introduction of ultrasound techniques for the early detection of newborn hip dysplasia.The trend in incidence rates over time was estimated as the annual percent change (APC) of the incidence rates, using the Joinpoint Regression Program . For theIn 1967–2011, CCRP registered 5020 incident cases. The incidence rate of all tumor types for children (0–14 years) was 156.9 (151.3–161.6) . In 2000Leukemia is the most common cancer type in children. Acute lymphoid leukemia (ALL) accounts for around 73% of all leukemia cases. ALL incidence peaks in the 1–4 year age group, with a rate of 75.9  in the whole observation period (1967–2011) , Fig 2. Lymphomas are the most common cancer type in adolescents. Their incidence rates in children are 18.7 (17.1–20.4) and 89.7 (77.6–103.3) in adolescents . Male prCNS neoplasms are the second most common cancer type in children  and third most common cancer type in adolescents , with high rates in both children 36.7 (34.5–39.0) and adolescents 37.5 (29.8–46.6) , Fig 2. The incidence rate of neuroblastoma is highest in children in their first year of life, 68.0 (56.2–81.6) . The treThe analysis of the period 2000–2011 (with the exception of hepatoblastomas in children) showed no statistically significant variation in incidence rates, neither in children, nor in adolescents. The major ICCC groups  that showed an increase for the 1976-2011period in children, show decreasing rates in 2000–2011 .Analyzing the overall time trends (1976–2011) in children, we found statistically significant increases in incidence rates in all tumors types combined, and in both embryonal and non-embryonal tumors when analysed as separate categories. In the analysis by ICCC diagnostic groups, we found increases in leukemias (mainly due to the increase of ALL), lymphomas, CNS tumors (from 1982) and neuroblastomas.The analysis of the most recent period (2000–2011) did not provide sufficient evidence to claim that the increasing trends that have characterized the whole time series have now started inverting their tendency, since the rarity of cancer in the age groups considered is affected by large variability that hampers interpretation.When we interpret our findings, we must consider that changes in data collection, classification or changes in diagnostic procedures might have influenced our results.The quality and completeness of data collected from CCRP has been high and its data have been included in all major studies on childhood cancer incidence in Italy and Europe ,5,12,23.In our observation window, several relevant diagnostic changes occurred. From mid 1970’s the distinction between ALL and acute myeloid leukemia (AML) became reliable through the introduction of flow cytometry so that the proportion of unspecified leukemias became negligible. For CNS tumors, major diagnostic improvements included the introduction of CT scans and their widespread use in the 1980’s, followed by that of magnetic resonance in the 1990’s, and of cranial ultrasound in newborns from the 1990’s. Relevant diagnostic changes for neuroblastoma  were the antenatal and perinanatal ultrasound imaging in mid 1980’s and the widespread use of hip ultrasound from mid 1990’s.It is unlikely that improved classification explains the observed ALL increasing trends. In our data, from mid 1970’s, the proportion of unspecified leukemias has been constantly low, and that of MV cases for ALL was 100%. Increasing leukemia time trends have been observed in previous CCRP ,24 and IHL behavior is particularly interesting because Italian rates among children and adolescents (0–19 years old) are the highest of the world . In USA The AIRTUM working group  found anThere were previous reports of increasing trends of CNS tumors in Europe and USA –35. The In Europe, the incidence of embryonal tumors like neuroblastoma, nephroblastoma and, to a lesser extent, retinoblastoma and hepatoblastoma, seem to have increased ,11,36–39In conclusion, in Piedmont, the analysis of trends over a long period (1976–2011) shows that the incidence of most tumor types has increased. When we looked more closely at the most recent years of observation (2000–2011), we found that rates seem to have started levelling off. However, large variability hampers interpretation of trends pattern in short periods. In Europe, the upward trends were detected more then 12 years ago, but as yet no satisfying explanation for the past increases has been found. Efforts must be made to understand and interpret this peculiar and still ununderstood pattern of incidence of childhood cancer.