The existing evidence is limited and contradicting on the co-occurrence of anemia and stunting (CAS) at individual level, despite a great overlap in their risk factors. We aimed to determine the prevalence of CAS, and the dietary and non-dietary factors associated with it, among infants and young children in Ethiopia.We used a nationally representative sample of 2902 children aged 6–23 months from the Ethiopian demographic and health survey, conducted in 2016. The study was cross-sectional in design. Samples were selected by two-stage clustering sampling method. CAS prevalence was estimated by various sociodemographic factors. To identify the dietary and non-dietary factors associated with CAS, we conducted hierarchical logistic regression analyses.P = 0.003], consumption of vitamin A rich fruit and vegetables , meat , legumes , and meal frequency > 3 . The non-dietary household and child factors found significantly linked to higher odds of CAS were rural residence , low household wealth , low caregivers’ education level , male sex , age 12–23 months , history of infection , and small birth size .The overall prevalence of CAS was 23.9%. The dietary factors found significantly linked to lower odds of CAS were use of vitamin A supplement [adjusted odds ratio (AOR) = 1.19, 95%CI = 1.06–1.33, Among infants and young children in Ethiopia, there was a concerning high level of CAS, which was associated with various dietary and non-dietary factors. Enhanced public health/nutrition interventions, with due emphasis on the multifactorial nature of CAS, might stand an important consideration to reduce the burden of CAS in Ethiopia and beyond. Malnutrition remains a major public health challenge in Ethiopia, with anemia and stunting being the top two prevalent nutritional problems among infants and young children , 2. The Clustering of nutrition problems could occur at country, household, or individual levels. For most of the under-nutrition problems, there is a considerable risk factor overlap, particularly in the basic and underlying determinants –6. Poor As each of anemia and stunting poses a significant challenge to the health system as well as the survival of children , 13, theTo the best of our knowledge, there is no previous study on CAS in Ethiopia as the existing studies were focused on either of anemia or stunting, i.e. did not report on CAS. In Ethiopia, both anemia and stunting are high. Child care and complementary feeding practices also remain poorly practiced . Thus, wThe data used for this work were extracted from the Ethiopian Demographic and Health Survey (EDHS). The survey was conducted in 2016 by the United States Agency for International Development (USAID) in collaboration with the Ministry of Health of Ethiopia and other partner organizations [The study was cross-sectional in design and representative at both national and regional levels, and urban and rural divisions . The surData were taken on various demographic, health and nutrition variables of public health importance using the standardized DHS questionnaire, that has been used in Ethiopia as well as other countries included in the International DHS Project. The data collectors received a four weeks training on the survey questionnaire administration, anthropometric measurement, and biological sample collection procedures. Pilot testing and field practice were also done in clusters not included in the actual survey. The closest caregiver of the child, mostly the biological mother, was the primary source of information on the child-related variables of interest. When the biological mother could not be accessed, a member of the family responsible for the caring of the child was interviewed. The household head, mostly the father or the mother, was the primary informant on household-related variables of interest. All data were collected through house-to-house visits .The main variable of interest was CAS, defined when a child was both anemic and stunted. Anemia status was defined by hemoglobin < 11 g/dL . HemogloAll analyses were done taking into account the complex design of the survey, such that all the estimates were done after weighting the sample by the sample weighting factor and taking into account the cluster design of the study. While it ensures data representativeness at both national and subnational levels, the DHS sampling procedure over-represents small regions. Thus, sample weighting was applied to compensate for the unequal probability of sample selection and ensure the sample resembles the true population distribution. The procedure resulted in a final weighted sample size of 2902 children. Besides, as the study participants were selected by two-stage cluster sampling strategy, adjustment for effect of the cluster design was done by applying the STATA command ‘svyset:’. More information about the DHS sample weighting and adjustment for cluster design is found in the guide to DHS statistics .P < 0.20 during the bivariate analyses. The reasons for our use of a relaxed P-value (P < 0.20), instead of the usual P = 0.05, were: a) the purpose of the bivariate analyses was to identify potential predictor variables for the multivariate analyses rather than testing hypothesis, and b) it would minimize the risk of excluding variables with a biological  plausibility from the multivariate analyses due to reasons, including confounding [P ≤ 0.05, because of its common usage in medical research.CAS prevalence by various characteristics was estimated. Adjusted odds ratios (AOR) were estimated by running multiple hierarchical logistic regression analyses, which took into account the hierarchical interrelationship among the potential predictors of CAS. The selection of the variables was done taking into account both biological  plausibility and statistical assumptions for multivariate analyses. Thus, bivariate analyses were done for all variables with the potential to influence CAS. Then, multivariate models were run using variables which demonstrated founding . HoweverP < 0.20 value during the bivariate analyses were included in the multiple hierarchical logistic regression analyses. Thus, Model-1 included the distal factors which demonstrated P < 0.20 during the bivariate analyses. Model-2 included the underlying factors which demonstrated P < 0.20 during the bivariate analyses and factors from model-1 which demonstrated P < 0.20. Model-3 included the proximal factors and factors from Model-2 which demonstrated P < 0.20. Statistical significance (P ≤ 0.05) of a specific variable during the hierarchical regression analyses was determined at the corresponding model in which the variable was first entered, irrespective its performance in the next model(s). The approach was aimed to rule out the possibility that the intermediate factors weaken the relationship between the distal factors and the dependent variable of interest [After the bivariate analyses, three-level hierarchical regression models were run following the recommendation of Victoria et al. . The firinterest . All staThe main characteristics of the study participants are shown in Table Overall, 72 and 32.6% of children were anemic and stunted, respectively. The overall prevalence of CAS was 23.9%. CAS prevalence among urban and rural children was 16.1 and 25.0%, respectively. Among boys and girls, the prevalence was 21.2 and 20.1%, respectively. The age-specific estimates were 12.1 and 25.4% in those aged under 12 months and above 12 months, respectively. The prevalence of CAS by other maternal and child characteristics is shown in Table P < 0.001), compared to urban residence. The odds of CAS was significantly higher in children of low household wealth category, compared to children of high household wealth category . Compared to children of caregivers with secondary+ education level, the odds of CAS was 2.14 times higher in children of caregivers with no education  and 2.38 times higher in children of caregivers with only primary education . In boys, the likelihood of CAS was 1.25 times that of girls . Above 12 months of age was significantly associated with a higher odds of CAS, compared to below 12 months of age . Small birth size was significantly associated with a higher odds of CAS, compared to large birth size . Infection was linked to a marginally higher odds of CAS .Results of the bivariate analyses of the basic, underlying, and proximal variables with CAS are shown in Table P = 0.003). The odds of CAS was also significantly higher in children who did not receive VARFV, compared to those who received . The odds of CAS related to no meat consumption was 1.55 times higher compared to its consumption . The odds of CAS related with no legumes consumption was 1.38 times, higher compared to its consumption . Meal frequency was also significantly associated with CAS, such that the odds of CAS was 1.22 times higher in those who didn’t meet MMF, compared to those who meet it .Children who did not take vitamin A supplement within the previous six months had a higher odds of CAS, compared to those who took (AOR = 1.19, 95%CI = 1.06–1.1.33, This was the first study aimed to determine the prevalence of CAS, and its multilevel associated factors, among infants and young children in Ethiopia. The work provided evidence that there was a high level of anemia and stunting co-occurrence in Ethiopia, with almost a quarter of the children affected. We found CAS linked to various multiple-level influences. The distal factors associated with higher odds of CAS were living in rural areas, low household wealth, and low caregivers’ educational level. The proximal factors found associated with higher odds of CAS were male sex, age above 12 months, small birth size, no vitamin A supplement use, no consumption of vitamin A rich food items, meat and legumes, and low meal frequency.We found a concerning high level of anemia, with only less than a third of the children being not anemic. The finding was, however, consistent with the recent national DHS report which showed 72 and 56% anemia prevalence among under-2 and under-5 children, respectively . StuntinWe found various factors linked to CAS. Children of low household wealth or caregivers of low education level were more likely to be concurrently anemic and stunted. These findings could be easily acknowledged because child health-enhancing behaviors, like proper feeding, hygiene, and utilization of health services, are often sub-optimally practiced among communities of low wealth and educational status , 11, 24.Vitamin A intake, in dietary as well as supplement form, was associated with a significantly lower CAS prevalence. This would be most likely due to the role of vitamin A in promoting optimal hematologic and linear growth status , 27–29. Among the dietary factors, milk consumption was not significantly linked to CAS. This could be, in part, because most of the study participants were of less educated caregivers and from rural areas, where animal milk is consumed mainly raw. Previous reports showed opposing effects of raw animal milk on height and hemoglobin statuses , 34. It The findings of this study have important policy and research implications. The high level of CAS was concerning given each of the two conditions are of significant consequences and their co-occurrence would be more threating to the health of children. It is also important to note the criticality of the first 1000 days of life, during which the body is more vulnerable to both nutritional and non-nutritional threats , 11. ThuThe main strengths of this study were it was based on a nationally representative data and took into account the multi-factorial nature of CAS, by incorporating not only the immediate dietary factors but also the non-dietary factors with the potential to influence CAS. Our analysis approach, hierarchical regression, took into account the interrelationships among the various explanatory variables and enabled building models according to the level of the variable influence. One of the main limitations of the study was that a cause-effect relationship could not be inferred as it was based on cross-sectional data. The collection of data on some variables, like birth size, infection history, dietary frequency, and diversity, based on the subjective memory of the caregiver might have introduced recall bias and miss-classification.In conclusion, we provided evidence that there was a concerning high level of anemia and stunting clustering among infants and young children in Ethiopia. CAS was associated with various dietary and non-dietary factors, originating from community, maternal and child levels. Strengthening the existing comprehensive public health/nutrition interventions, with due emphasis on the multifactorial nature of CAS, might stand an important consideration to reduce the burden of CAS in Ethiopia and beyond.


BackgroundApproximately 90% of Americans have access to the internet with the majority of people searching online for medical information pertaining to their health, or the health of loved ones. The public relies immensely on online health information to make decisions related to their healthcare. The American Medical Association (AMA) and the National Institute of Health (NIH) recommend that publicly available health-related information be written at the level of the sixth-seventh grade.Materials and methodsAnnals.org, a website sponsored by the American College of Physicians, were collected. All 89 patient education articles were downloaded from the website and analyzed for their ease of readability. The articles were analyzed utilizing a readability software generating five quantitative readability scores: Flesch Reading Ease (FRE), Flesch-Kincaid Grade Level (FKGL), Gunning Fog Index (GFI), Coleman-Liau Index (CLI), Simple Measure of Gobbledygook (SMOG). All scores, with the exception of FRE, generate a grade level that correlates with the required school-grade level to ensure adequate readability of the information.Patient education materials available to the public on the ResultsEighty-nine articles were analyzed generating an average score as follows: FRE 62.8, FKGL 7.0, GFI 8.6, CLI 9.6 and SMOG 9.8. Overall, 87.6% of the articles were written at a level higher than the 7th-grade level, which is recommended by the AMA and NIH.ConclusionIn an era of increased reliance on the internet for medical information pertaining to patients’ health, materials written at a higher grade than recommended has the potential to negatively impact patients’ well-being, in addition to tremendous ramifications on the healthcare system. Potentially redrafting, these articles can prove beneficial to patients who rely on these resources for making healthcare-related decisions. In an era of widespread internet availability, it is estimated that approximately 90% of Americans have access to the internet, with more than 80% of internet users searching online for medical information. This translates to more than eight million Americans searching the internet for health-related information, on any given day -2. Only Unfortunately, the 2003 National Assessment of Adult Literacy (NAAL) showed that 14% of Americans could not read, or understand text written in English and were only able to comprehend very basic, simple text . AccordiTherefore, it is of utmost importance to define health literacy and eHealth literacy in this era. The Institute of Medicine defines health literacy as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decision” . MultiplIn an effort to address the extent of inadequacies related to health literacy, the US Department of Health and Human Services (USDHHS), the American Medical Association, and the National Institute of Health have all published guidelines related to the readability of patient-related information . These organizations recommend that health information directed towards patient be written at the level of sixth- to seventh-grade reading level, corresponding to a reading level associated with ages 11-13 years ,10,14. Phttp://annals.org/aim/pages/patient-information [Online patient education materials available to the public from “Annals of Internal Medicine: Patient Information” website, ormation , were reA total of 93 hyperlinks were found on the website, with one duplicate hyperlink for information related to colon cancer screening and three hyperlinks yielded unavailable pages. Duplicate and unavailable links were excluded from analysis. Articles that were targeting physicians or practitioners were excluded. The hyperlinks were all patient-related information. The text from the 89 remaining articles was copied and pasted as plain text into individual documents using Microsoft® Word® . The text was reviewed by the authors independently. During the review, all medical terms followed by explanation were removed from the text prior to analysis, for example when mentioned “sputum; mucus brought up with coughing”, the word sputum would be removed from the text. Likewise, when a medical procedure is explained, for example, when “endoscopic retrograde cholangiopancreatography, which examines the pancreas through a tube inserted down the throat into the stomach and pancreas”, the words endoscopic retrograde cholangiopancreatography were removed. Medical terms or procedures not explained in the text were not removed. In addition, all hyperlinks, tables, advertisements, figures, images, and tables were removed. Further editing was done on the remaining text with expunction of any headings, bullet points, and decimals. References were also expunged, as well as author names and websites. Names of medications, whether brand or generic, were similarly removed from the text.https://readable.com. Five validated scales were then used to quantitatively analyze the articles  [Comparing the readability of online education materials found on 1.8 (SD) ,10-13. UAnnals.org website provide patients with an excellent source of information to enable them to care for themselves and loved ones. Nevertheless, the majority of the materials are written at a readability level higher than recommended by the AMA and NIH. Given the integral role that online patient education materials play in the decision-making process of patients and follow-up care with physicians, greater emphasis should be placed on the readability and comprehensibility of online educational materials. The online patient education materials found on the


The prevalence of polysubstance use is well described, but less is known about correlates and patterns of polysubstance use. Previous research characterized latent subgroups of substance users by the type substance used. Racial disparities in the prevalence of polysubstance use exist, particularly for American Indian/Alaska Native (AI/AN) populations. The objective of our study was to describe differences in patterns of polysubstance use between non-Hispanic white and AI/AN adolescents.We obtained data from the 2013 Youth Risk Behavior Survey (YRBS). We analyzed substance use patterns  separately among 375 AI/AN and 15,633 non-Hispanic white adolescents. We calculated pairwise correlations. Exploratory factor analysis identified latent factors of polysubstance use patterns.The use of all substances by AI/AN adolescents was the same or higher than use by non-Hispanic white adolescents, particularly for cocaine, heroin, and steroids. We found strong correlations between use of heroin and injected drugs and between use of cocaine and ecstasy among both populations. We found a latent factor for cigarettes, alcohol, and marijuana and another factor for broad polysubstance use among both populations. We found a factor for steroids and injected drugs among AI/AN adolescents, a factor for cocaine and ecstasy among non-Hispanic white adolescents, and a unique factor for methamphetamines.Differences in substance use patterns exist between AI/AN and non-Hispanic white adolescents, particularly for illegal drug use. If validated in future research, information on these differences could be used to inform tailored intervention programs aimed at preventing substance use. Polysubstance use among adolescents in the United States is rising, and rates of substance use differ by race/ethnicity. Typically, substance use among non-Hispanic white adolescents is less prevalent than among American Indian/Alaska Native adolescents.American Indian/Alaska Native adolescents tended to use steroids and injected drugs together, whereas non-Hispanic white adolescents used cocaine and ecstasy together. Both groups used tobacco, marijuana, and alcohol together and a cluster of other illicit substances together.These findings can be used in the clinical setting to screen for and prevent substance and polysubstance use among adolescents.Substance use is well understood to have negative, life-long consequences. Particularly concerning is the use of substances among adolescents, because initiation often occurs during these formative years, thus increasing the likelihood of addiction and continued use . In 2013Prevalence of substance use is well known for individual substances at the general population level; however, substance use differs widely across subgroups of the population. For example, with the exception of alcohol, substance use is more prevalent among American Indian/Alaska Native (AI/AN) populations than among white populations . In addiEven after accounting for demographic characteristics, adolescent populations have distinct heterogeneous subgroups  that differ in their patterns of polysubstance use –9. CommoConsidering that racial differences exist among these social and environmental risk factors for substance use, it is plausible that common patterns of substance use could fundamentally differ by racial or ethnic group. Little is known about whether such differences in patterns of substance use exist between AI/AN and non-Hispanic white adolescents. If differences do exist, then that information could be used to identify adolescents at higher risk for polysubstance use. Effective treatment plans and education could then be designed and implemented to prevent additional substance use. Our study used data from the 2013 Youth Risk Behavior Survey (YRBS) to examine potential differences in correlations and patterns of substance use between AI/AN and non-Hispanic white adolescents.We used publicly available data from the 2013 YRBS . The YRBS is an observational, cross-sectional survey designed in 1990 by the Centers for Disease Control and Prevention to monitor the leading risk behaviors of US adolescents and young adults that contribute to death, disability, and social problems .We limited our analysis to 2 self-reported race/ethnicities: AI/AN  and non-Hispanic white . We found a substantial amount of missing data on substance use variables, which was handled with listwise deletion, resulting in a final sample size of 375 AI/AN adolescents and 15,633 non-Hispanic white adolescents. We used listwise deletion because research shows that it is preferable to other methods  in pattern-based analyses such as ours .The University of North Dakota Institutional Review Board approved this study. All analyses were conducted at the University of North Dakota, Grand Forks, North Dakota, from March 2015 through February 2018.We analyzed survey data on the following substances: tobacco (cigarettes), alcohol, marijuana, cocaine, inhalants, heroin, methamphetamines, ecstasy, steroids, and injected drugs.Cigarette and alcohol use were each assessed by the self-reported number of days of the past 30 days that each substance was used. Original responses were given as 0 days, 1 or 2 days, 3 to 5 days, 6 to 9 days, 10 to 19 days, 20 to 29 days, or all 30 days. We used the midpoint value of each category for the analyses of the responses.Marijuana was assessed by the self-reported number of lifetime uses of marijuana. Original responses were given as 0 times, 1 or 2 times, 3 to 9 times, 10 to 19 times, 20 to 39 times, 40 to 99 times, or 100 or more times. We used the midpoint value of each category for the analyses of the responses, and values were top coded at 100.Cocaine , inhalants , heroin , methamphetamines , ecstasy (including “MDMA”), and steroids (“steroid pills or shots without a doctor’s prescription”) were assessed by the self-reported number of days in the participant’s lifetime that each substance was used. Original responses were given as 0 times, 1 or 2 times, 3 to 9 times, 10 to 19 times, 20 to 39 times, or 40 or more times. We used the midpoint value of each category for the analyses of the responses, and values were top coded at 40.The use of injected drugs  was assessed by the self-reported number of days in the participant’s lifetime that the substance was used. Original responses were given as 0 times, 1 time, or 2 or more times. These values were analyzed numerically and were top coded at 2.patterns of polysubstance use across AI/AN and non-Hispanic white samples rather than to produce population-level parameter estimates.The YRBS has a complex, multistage sampling process, and survey weights are available to account for this sampling design in standard analyses . However, we intentionally did not account for survey weights because 1) our study was exploratory and 2) standard and automatic procedures for incorporating survey weights are lacking for the type of analysis we conducted. In other words, our focus was to examine broad, qualitative differences in To quantify the pairwise association between each possible pair of substances, we calculated Spearman ρ, a nonparametric correlation statistic; we used a nonparametric test because the data were not normally distributed. We adjusted for multiple comparisons of the Spearman ρ test by using the Bonferroni correction. We then visualized all pairwise correlations simultaneously by creating a heatmap.Next, we performed an exploratory factor analysis on each group to identify latent factors based on substance use patterns among each group. Exploratory factor analysis tests the hypothesis that each group (non-Hispanic white and AI/AN) contains subgroups with fundamentally different substance use patterns. Preliminary analyses based on scree plots (not shown) suggested that the optimal number of factors was 2 to 5 factors for the AI/AN group and 4 or 5 factors for the non-Hispanic white group. We selected the final number of factors on the basis of interpretability, model fit, and simplicity of structure . We used oblique rotation to allow correlation between the latent factors and ordinary least squares factoring to find the minimum residual solution while accounting for nonnormality among variables. We used the Tucker-Lewis Index and the root-mean-square error of approximation to evaluate the goodness-of-fit for the exploratory factor analysis. A Tucker-Lewis Index of 0.9 or greater is considered a good fit  as is a We conducted all analyses and plots by using R version 3.1.3  run separately for AI/AN and non-Hispanic white samples.AI/AN adolescents had a higher rate than non-Hispanic white adolescents of past 30-day use of tobacco and alcohol and lifetime use of marijuana, cocaine, inhalants, heroin, methamphetamines, ecstasy, steroids, and injected drugs . Among uP < .001), cocaine with methamphetamines , and steroids with injected drugs . The top 3 pairwise correlations for non-Hispanic white adolescents were cocaine with methamphetamines , heroin with injected drugs , and cigarettes with marijuana . Cocaine with methamphetamine and heroin with injected drugs were in the top 3 most strongly correlated pairs among both AI/AN and non-Hispanic white adolescents.Pairwise correlations showed strong similarities across groups in which pairs of substances were correlated with each other and, in general, the correlations were slightly stronger among AI/AN adolescents than among non-Hispanic white adolescents . The topIn the exploratory factor analyses, a 3-factor solution was chosen for the AI/AN group, and a 4-factor solution was chosen for the non-Hispanic white group . Both moThese results identified both similarities and differences among AI/AN and non-Hispanic white adolescents. Both groups had a distinct latent factor for cigarettes, alcohol, and marijuana. Other commonalities included a link between 1) heroin and inhalants, 2) steroids and injected drugs, and 3) cocaine and ecstasy. One prominent difference was that methamphetamine was its own independent variable among non-Hispanic white adolescents, but it was linked with other substances among AI/AN adolescents. Additionally, steroids and injected drugs comprised their own latent factor among AI/AN adolescents, whereas cocaine and ecstasy comprised their own latent factor among non-Hispanic white adolescents.We conducted an exploratory analysis of differences in substance use patterns among AI/AN and non-Hispanic white adolescents in the United States. Pairwise correlations overall showed similar patterns of substance use, particularly for heroin with injected drugs and cocaine with methamphetamines, although the strength of correlations was generally higher among AI/AN adolescents. Exploratory factor analysis identified a common factor for cigarettes, alcohol, and marijuana across both groups, but distinct factors also emerged in each group. Among AI/AN adolescents, injected drugs and steroids comprised a latent factor, whereas among non-Hispanic white adolescents, cocaine and ecstasy comprised a separate latent factor, and methamphetamine alone loaded onto its own factor.Our study parallels well-known findings about substance use disparities across racial/ethnic groups in adults –22. It aOne pattern of substance use common among both AI/AN and non-Hispanic white adolescents was the combination of cocaine and ecstasy; these were strongly associated according to both the correlation analysis and the exploratory factor analysis. Other remarkable correlations in both populations were cigarettes with marijuana and alcohol. Both the heatmap and the factor analysis indicated that if an adolescent used cocaine, he or she would be more likely than not to have also used ecstasy, heroin, methamphetamines, or inhalants. Likewise, if an adolescent used cigarettes, he or she would be more likely than not to have used marijuana and alcohol. Our findings are broadly consistent with previous research on latent classes of substance use  in that We found notable differences between AI/AN and non-Hispanic white adolescents in illegal substance use. In particular, nonmedical steroid use and injected drugs were associated with both AI/AN and non-Hispanic white adolescents, but this pairing comprised its own unique factor among AI/AN adolescents. This pairing indicates that AI/AN adolescents who illicitly use steroids and injected drugs are a distinct subpopulation of AI/AN adolescents. A link between steroid use and injected drugs was reported previously , but to Future research should focus on replicating these patterns in other independent samples, examining temporality and possible causality and further refining the exact nature  and timing  of these patterns. Validation of racial/ethnic differences in polysubstance use patterns would motivate the development of tailored interventions for subgroups to prevent or reduce the prevalence of polysubstance use.Strengths of our study include the novel use of exploratory methods to assess polysubstance abuse among AI/AN and non-Hispanic white adolescents. Additionally, our study extends previous research on racial/ethnic disparities in the prevalence of use to examine patterns of polysubstance use. Finally, our study used a large, national data set, which increases the generalizability of the findings to the larger population of high school–aged students in the United States.Our study had several limitations. First, it used cross-sectional data, which cannot be used to assess causality or rule out residual confounding. Second, because YRBS data are self-reported, they are subject to social desirability and recall biases. Third, the use of cigarettes and alcohol were measured in “use within the past 30 days,” while all other substances were measured in “lifetime use.” This difference results in imperfect direct comparisons between substances. Fourth, the YRBSS has a large degree of missing data on substance use, and these data may not be missing at random. For example, because the sample is limited to students who were at school on the day of the survey, truancy could have affected the findings, especially since truancy is known to be associated with substance use. The patterns of missing data may have affected our findings in unknown ways, and thus the findings should be considered exploratory only. Fifth, it was not possible to examine national YRBS public use data by state or region, and because AI/AN subpopulations can differ by state or region in important ways, further research is needed to explore these differences. Sixth, factor analysis should be considered an exploratory method, and the results may be sensitive to the particular sample or to the specific method of measuring the latent factors . Additionally, factor analysis is somewhat subjective, particularly in the way factors are interpreted and the role of interpretability in selecting the number of factors. Finally, several of the substance use items, such as steroids, inhalants, and injected drugs, were broadly defined, and detailed information on the exact substance was not available.The practicality of our study is noteworthy. The data show strong pairwise correlations between common substances of abuse and classify AI/AN and non-Hispanic white adolescents into well-structured latent factors, indicating that distinct patterns of polysubstance use exist in each subpopulation. A health care professional could use this information to inquire about substance use if a substance is known to be used and subsequently educate susceptible adolescents about substance use habits with the goal of preventing polysubstance abuse. Public health interventions and policy makers can also use these data to formulate strategies for reaching certain racial/ethnic groups to decrease the prevalence of substance abuse with more efficiency and effectiveness.


Psychiatric diagnoses, static risk factors, and criminogenic needs at time of admission and release were examined in a mentally ill sample of psychiatrically detained sexual offenders. Although clinically found to be at low or even very low risk at discharge, 12% reoffended sexually over an average follow-up of 7 years. Psychotic disorders were present in only 5% of offenders, whereas 93% had a personality disorder diagnosis and 76% a paraphilic disorder diagnosis. Only exhibitionism and alcohol misuse were associated with relapse. Static risk factors captured by the Static-99 also did not significantly predict recidivism; however, the VRS-SO—a structured risk assessment tool that assesses criminogenic needs and changes in risk from treatment or other change agents, rated retrospectively on the present sample—predicted sexual recidivism as well as any new imprisonment or psychiatric placement. In particular, the sexual deviance factor of the VRS-SO had large in magnitude predictive associations with sexual reoffending, while treatment related changes assessed on this factor were significantly related to non-reoffending. Findings corroborate the advantages of structured risk assessment and structured change monitoring, particularly for complex clientele such as mentally ill sexual offenders. The rate of admission of sexual offenders to forensic psychiatric institutions is usually low. In Germany and Austria, for instance, less than 10% of all convicted sexual offenders are found legally to be dangerous owing to a “severe mental illness” and therefore subsequently detained in forensic psychiatric facilities , the extUltimately, in constitutional states, decisions about a psychiatric detainment are court decisions. They heavily rely on expert witnesses, who have to certify whether: 1) the offender has a psychiatric diagnosis, 2) the diagnosis is causally linked to the offense for which s/he is accused, 3) if the diagnosis meets the criteria of a severe disorder , and 4) whether the disorder renders the individual to be a high risk for reoffending, absent effective treatment . Since dRisk relevant change cannot be communicated by means of categorial diagnoses, particularly if the diagnoses connote some form of long-term impairment or vulnerability for a distinct pattern of behavior, such is the case with substance use disorders, paraphilias, or personality disorders. There has yet to be an empirically supported model to translate clinical change into decreased sexual recidivism among psychiatrically detained sexual offenders. This is a significant limitation of psycholegal practice in several respects. First, offenders and treatment service providers face uncertainty as to which specific interventions contribute to the ultimate goal of risk reduction. Second, even if treatment occurs, offender clientele may have benefited minimally  or they may even deteriorate owing to unwanted adverse effects of psychotherapy and institutionalization , and continue to pose a substantial recidivism risk upon release. Third, even when these individuals make meaningful strides in treatment, they may still nonetheless be assessed as sexually dangerous or acutely mentally ill, resulting in unnecessary detention in high secure facilities .The Violence Risk Scale–Sexual Offense version VRS-SO;  is a risIn the current study, we investigated the predictive properties of DSM-IV-TR diagnoses  in a samN = 91) in Austria previously placed into a psychiatric facility as a result of a criminal court decision and released between 2008 and 2012. All offenders had been declared to no longer meet the legal criteria for dangerousness by a criminal court as a prerequisite for release. In their index offenses, n = 38 (41.8%) men had sexually assaulted adults and n = 53 (58.2%) had sexually offended against minors .The present study sample comprised all adult male sexual offenders . High mortality rates in repeated violent offenders have been reported elsewhere (SD = 14.04) and the sample was followed up an average 7.17 years (SD = 2.47) in the community. Reoffense data were available for n = 85 offenders, of whom n = 11 (12.1%) reoffended sexually  while n = 19 (20.9%) were returned to prison or psychiatrically rehospitalized for a new criminal offense. Reliable diagnostic data from assessment at the time of intake and release was available for n = 74 offenders. Sufficient information from file was available to complete VRS-SO pretreatment ratings for n = 70 cases and posttreatment ratings for n = 57 men.Two of the men died during their hospitalization and 14 died during the follow-up period; however, for those who died postrelease, there was sufficient follow-up time to be included in the study sample  to continuously evaluate the accuracy of its risk assessment approaches. The FECVSO is a subdivision of the Austrian Ministry of Justice. This evaluation study, therefore, was performed in line with the legal and ethical standards of the Austrian Ministry of Justice and the National and European Data Protection Act. It also relates to the Recommendations of the Committee of Ministers to Member States (Counsel of Europe) Concerning Dangerous Offenders  and the VRS-SO. The VRS-SO comprises seven static items  and 17 dynamic  items reflecting domains of psychological, social, emotional and interpersonal functioning. All items are empirically, theoretically, or conceptually linked to risk for sexual reoffending. Items are rated on a 4-point  ordinal scale; items receiving a 2 or 3 rating are considered criminogenic and prioritized for treatment. Change is captured by a modified version of the transtheoretical model of change which outlines the cognitive, behavioral, and experiential dynamics as the individual attempts to change identified areas of concern  statistics. Values of .56, .64, and .71 represent small, medium, and large effects, respectively  were diagnosed with a DSM-IV-TR Axis I mental disorder, n = 69 (93.3%) received an Axis II disorder diagnosis, and n = 56 (75.7%) had a paraphilic disorder. None of the psychiatric diagnoses significantly predicted sexual recidivism or reimprisonment, except for exhibitionistic disorder (both outcomes) and a history of substance abuse (any new conviction leading to imprisonment).Diagnoses of ysis see Table 1.M = 4.66 (SD = 2.43) representing the risk category referenced as Level IVa or above average (M = 46.93 (SD = 9.34), which was also Level IVa, above average (M = 37.33 (SD = 6.71). Pretreatment sexual deviance, criminality, and treatment responsivity factor scores were M = 11.71 (SD = 4.19), M = 11.40 (SD = 6.71), and M = 9.54 (SD = 2.22), respectively.The Static-99 total score for the released sample was  average . The tot average . The VRSAUC = .70, p = .005), and improved in predictive accuracy after treatment at time of release , with moderate to high AUC magnitudes. The criminality and treatment responsivity factors were not significantly predictive of sexual recidivism but were predictive of any reimprisonment or new psychiatric placement ; that is, positive changes in this domain in terms of risk reduction were associated with decreased sexual recidivism on release. Specifically, the finding would be interpreted as a 76% probability that a randomly selected sexual nonrecidivist to have made greater risk changes in the domain of sexual deviance, than a randomly selected sexual recidivist, controlling for pretreatment score. Positive changes on the remaining two factors were not significantly associated with changes either recidivism outcome. The change findings broadly bode favorably for the efficacy of treatment and are discussed further.Finally, residualized change scores for the sexual deviance factor had significant large in magnitude associations with decreased sexual reoffense  of the VRS-SO could be shown to be predictive for sexual reoffense and for a further imprisonment or psychiatric placement. The sexual deviance factor of the VRS-SO was found to be of particular interest: not only that it was By contrast, the criminality and treatment responsivity factors were found to be significant predictors of general recidivism only, although change was not significantly related to outcome. In all, these findings corroborate those found by Beggs and Grace , who demThe most apparent limitations of this study are the relatively small sample size and the retrospective design. These limitations, however, are offset by virtue of the fact that our analyses comprise a sample of psychiatrically placed and released sexual offenders assessed for risk with the VRS-SO at admission and release, and subsequently followed up for 7 years postrelease. In addition, this is the first study empirically contrasting treatment outcome with reoffense data of psychiatrically detained and released sexual offenders. Finally, our data support the utility of the VRS-SO at least for psychiatrically detained sexual offenders in Austria and Germany, when risk relevant change must be captured and communicated. Studies with larger samples and in a prospective research design are needed to empirically strengthen the utility of the VRS-SO for this offender population.The datasets generated for this study will not be made publicly available. Data requests have to be individually authorized by the Federal Ministry of Justice, Austria.The study “The predictive properties of psychiatric diagnoses, dynamic risk and dynamic risk change assessed by the VRS-SO in forensically admitted and released sexual offenders” is a study conducted solely through retrospective data analysis. It was ordered and approved by the Permanent Control Board for Psychiatrically Detained Patients (Ständiger Controllingbeirat Maßnahmenvollzug) of the Austrian Ministry of Justice. All high ethical and legal standards concerning research on a vulnerable population are guaranteed.Materials and Methods and Results, and approved the submitted version.RE designed the research study and supervised SH, AB, and SD. He did all statistical analyses and wrote up the paper. SH and AB completed the VRS-SO ratings and translated diagnoses of the files into DSM-IV-TR diagnoses. SD analyzed and computed reoffense data. DT reviewed and revised an earlier draft of the manuscript. He also contributed to the analyses of the psychiatric diagnoses. MO provided consultation on data analysis and interpretation, reviewed and revised an earlier draft of the manuscript, including contributing new content to the 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.


In order to obtain a well understanding of the toxicity and ecological effects of trace elements in the environment, it is necessary to determine not only the total amount, but also their existing species. Speciation analysis has become increasingly important in making risk assessments of toxic elements since the toxicity and bioavailability strongly depend on their chemical forms. Effective separation of different species in combination with highly sensitive detectors to quantify these particular species is indispensable to meet this requirement. In this paper, we present the recent progresses on the speciation analysis of trace arsenic, mercury, selenium and antimony in environmental and biological samples with an emphasis on the separation and detection techniques, especially the recent applications of high performance liquid chromatography (HPLC) hyphenated to atomic spectrometry or mass spectrometry. Trace elements, as important components of the environment, play crucial roles in the functioning of life. Some elements such as arsenic (As), mercury (Hg) and antimony (Sb) can be highly toxic to various life forms, while some others are probably considered to be essential, but they can become toxic at higher doses. For example, selenium (Se) is widely recognized as an essential dietary component with numerous beneficial effects on health, but at levels higher than 5 µg/L will cause toxic effects ,2. It is“Chemical species” refers to the specific form of an element defined as to isotopic composition, electronic or oxidation state, and/or complex or molecular structure . UsuallyN-acetyl-4-hydroxyphenylarsonic acid (N-AHPAA) were found in chicken liver [However, the main species existing in aquatic environments are inorganic forms, i.e., As(III), As(V); Hg(II); Sb(III), Sb(V); and Se(IV), Se(VI) ,12,13, ben liver .The lack of accurate speciation information is the major limitation for us to understand the environmental biogeochemical cycles of trace elements in the aquatic environments. In view of this, speciation analysis has become one of the fastest developed areas of analytical chemistry over the last two decades. “Speciation analysis” is defined by the IUPAC as analytical activities of identifying and/or measuring the quantities of one or more individual chemical species in a sample. It plays a unique role in the studies of biogeochemical cycles of compounds, determination of toxicity and eco-toxicity of selected elements, quality control of food products, control of medicines and pharmaceutical products, examination of occupational exposure and clinical analysis, etc. . GeneralThe chemical form and quantitative information of a given element can be acquired by the application of basic chemistry methods. In other word, non-chromatographic procedures can provide simple methods to obtain sufficient information on the elemental species. Many review papers are available for the non-chromatographic speciation analysis methods ,34,35, aExtraction is usually used to separate one or a group of species from complex matrices, especially for environmental and biological samples ,37. LiquN-benzoyl-N-phenylhydroxylamine-chloroform single drop; Single-drop gold nanoparticles for headspace microextraction and colorimetric assay of Hg(II) in environmental waters was developed by Tolessa et al. [LPME is introduced to reduce the consumption of solvent, in which a drop of organic solvent is suspended at the tip of a microsyringe and exposed to the analytical sample. Subsequently, the drop is retracted and transferred to a particular analytical instrument after extraction. For example, speciation analysis of As(III) and As(V) based on Triton X-100 hollow fiber LPME coupled with flame atomic absorption spectrometry (FAAS) was developed by Zeng et al. , during a et al. , and the3O4 (C8-Fe3O4@SiO2) nanoparticles was proposed by Li et al. [8-Fe3O4@SiO2 nanoparticles, whereas Sb(V) remains as free species in aqueous solution. A method for multi-element inorganic speciation analysis of As, Se and Sb in natural water using SPE technology was developed by Zhang et al. [2 was used to adsorb total inorganic As, Se and Sb, while As(III), Se(IV) and Sb(III) were coprecipitated with Pb-PDC. The concentration of As(V), Se(VI) and Sb(V) was subsequently calculated by the differences. Recently, Peng et al. [SPE is popular for sample preparation in organic analysis, but it is also found to be used for speciation analysis of inorganic elements. The analytes are extracted by selective sorption and subsequently derivatized or directly detected after eluted with a small amount of organic solvent ,52. Sorbi et al.  for the g et al. , during g et al.  synthesiSPME offers a fast way for species separation by collecting target analytes from the sample headspace or liquid phase directly or after derivatization. It offers the possibility to eliminate the interferences from matrices without the use of organic solvents ,56,57. FSome assistant extracting techniques such as microwave-assisted extraction (MWAE) and ultrasound-assisted extraction (USAE) ,62,63,64Selective reduction is used based on the differences of reduction potential between different species. The reduction potential can be controlled by the concentration of reductants, pH, as well as by the presence of catalysts or chelating agents. Selective reduction is generally related to the chemical vapor generation (CVG) methods, by which the volatile derivatives are produced during reduction ,69. 4−, which is the most frequently used reductant during CVG. In view of this, photochemical reduction by exposure to ultraviolet (UV) irradiation or ultrasound (US) is often used. For example, when Hg(II) and MeHg were determined by Hu et al. [m/v) KBH4, while the MeHg needs to be transformed into elemental mercury vapor under the ultraviolet atomization. when total Hg and MeHg in biological samples were detected by Vieira et al. [v/v acetic acid into TMAH solution. Mendez et al. [3 at concentration larger than 1×10−3 M. Subsequently, the same authors [It is noted that some organic Se and Hg species are not easily reduced by BHu et al.  using hya et al. , total Hz et al.  assessedz et al.  systemat authors  developeDue to the different volatility of Hg and its compounds, thermal desorption is also used to distinguish their different species. For example, thermal release analysis in combination with AAS was developed and applied by Shuvaeva et al.  to deterIt is noted that any pretreatment processes during speciation analysis even the routine processes such as the changes of pH, temperature and pressure can bring about irreversible transformation of the analyzed species. Non-chromatographic speciation analysis methods often employ multi-step procedures resulting in a high risk for the loss of analytes or species conversion. In this sense, these characteristics make such methods very difficult to automate and integrate into modern systems. Therefore, high selective and sensitive analytical methods without or with few pretreatment steps are more competent for speciation analysis. The most detailed information in relation to speciation analysis is no doubt derived from hyphenated techniques, in particular those involving separation by HPLC, GC or CE with ICP-MS or atomic spectrometry detectors. The main advantages of those techniques include extremely low detection limit, insignificant interference, high precision and repeatability, etc. The selection of a proper separation technique depends on the physico-chemical properties such as volatility, charge or polarity of the different species, and sometimes combination of two or more separation methods is also adopted.GC is mainly used for Hg species separation when compared with that used for As, Se and Sb, during which volatile Hg species are stripped from the sample solution after derivatization, and subsequently pre-concentrated mainly through sorptive, extraction, etc ,80,81. TBecause the packed columns will lead to poor reproducibility, thus capillary or multi-capillary GC is usually used to provide superior separation power and better detection limits . UsuallyOf course, there are also some applications of GC on the speciation analysis of As, Se and Sb ,87,88,89Among the most popular hyphenated techniques used for the determination of As, Hg, Se and Sb species, the coupling of various liquid chromatographies (LC) including ion-exchange chromatography (IEC) and reverse-phase chromatography (RPC) with particular detectors has obtained the fastest development . Table 28 or C18 linear hydrocarbon, and a relatively polar mobile phase. RPC is usually superior to IEC for the separation of organometallic species. The separation of species in IEC is based on the interactions between the positively or negatively charged species and the stationary phase that contains a cationic functional group (anion exchange) or an anionic functional group (cation exchange). IEC is an ideal technique for the separation of inorganic As, Sb, Se and many charged organometallic ions such as organoselenium and organoarsenic. Buffer solutions are commonly used as eluents for IEC with concentration usually not exceeding 25 mM. RPC is used based on the partition of the analytes between a non-polar stationary phase, in which it usually contains a covalently bound C4As+ for such compounds at cationic or neutral states cannot be retained by an anion-exchange mechanism. Of course, both anion and cation exchange columns are sometimes used in a complementary fashion [4NO3 as mobile phase was shown to produce good signal stability on the ICP-MS with minimal salt deposit on the sample and skimmer cones [IEC is the most extensively used method for As, Sb and Se speciation separation, followed closely by the use of ion-pair reversed-phase chromatography (IP-RPC). Many factors, such as the pH, ionic strength, concentration and flow rate of mobile phase, the concentration and species of organic modifiers, will all influence the separation and retention of analytes in IEC and IP-RPC. For example, arsenic species are neutral, anionic or cationic depending on the pH. As a result, their retention will strongly depend on the pH of mobile phase. Therefore, anion-exchange chromatography is often used to separate As(III), As(V), MMA and DMA, while cation-exchange chromatography is used to separate AsB, AsC, TMAO, Me fashion . Based o fashion , carbona fashion , nitrate fashion , acetate fashion  or misce fashion ,135 are er cones .a value of 9.2. Chromatographic column also plays an important role in the separation of species. Usually, different chromatographic columns of the same separation mechanism have different separation effects. For example, Ammann [− were more retained on AG7. Gao et al. [When IP-RPC is used for species separation, a counterion is added to the mobile phase, and a secondary chemical equilibrium of the ion-pair is used to control the retention and selectivity ,119,137., Ammann  investigWhen LC is employed for Hg species separation, a RP column is commonly used. However, the organic solvent concentration in the mobile phase must be as low as possible in order to reduce carbon deposit on the ICP-MS instrument interface. In order to overcome the drawback caused by organic solvent, vapor generation (VG) technique can be employed after the LC separation, by which only the volatile Hg species are introduced into the plasma. Of course, Hg(II), MeHg, EtHg and PhHg can be separated in a cation-exchange chromatographic column due to they present in positively charged ions. For example, the four species were separated and determined by Chen et al.  by the c4)2CO3 buffer. Of course, it is noted that the mobile phase used in multidimensional chromatography should be compatible with both chromatographic mechanisms.Both isocratic and gradient ion-exchange chromatographic systems are used for species separation. Gradient separation generally has better resolution among different species, and is often used to reduce analytical time of strong retention species. However, gradient IP-RPC is not commonly adopted when ICP-MS is used as detector due to the signal drift is likely when substantially changing the organic content of the mobile phase. In addition, as the differences in structure and charge of different species, a single chromatographic mechanism is probably not sufficient for simultaneous study of organic and inorganic species. Combination of different chromatographic modes has therefore been applied by using columns in series or column-switching systems. For example, Milstein et al.  successfo-arsanilic acid, p-ureidophenylarsonic acid, and 4-nitrophenylarsonic acid were simultaneously determined by Liu et al. [Capillary electrophoresis (CE) is discussed as a complementary technique to GC and HPLC, and is a powerful tool in element speciation with high separation capability and environmentally friendly nature due to the use of aqueous buffer solutions with moderate pH and its extremely low reagent and sample consumption . For exau et al.  by CE cou et al. ,145,146.® based nebulizer as aerosol generation unit was presented by Kovachev et al. [Separation by CE is usually faster than that by LC, and therefore is potentially a rapid and highly efficient separation technique. However, some problems are presented when CE is coupled to ICP-OES or ICP-MS due to liquid flow incompatibility, i.e., the liquid flow is one order of magnitude lower in CE than in ICP sample introduction system. The detection limit is often insufficient resulting from the very small sample volumes used in CE, and therefore some interface techniques were developed. For example, a novel system for CE and ICP sample introduction that incorporates a dedicated Flow Focusingv et al. , and on-v et al.  using a v et al.  to proviv et al. .It is noted that although there has been significant progress in speciation analysis based on the hyphenated chromatographic separation with atomic spectrometry or mass spectrometry detectors, and these hyphenated methods can provide the most complete information on the species distributions and even structures, they also have themselves disadvantages. A limitation related to the hyphenated techniques is the low sample volume introduced into the system which leads to the necessity of a very sensitive detector. It sometimes seems that non-chromatographic techniques are more suitable if sample volume is not a limitation, and thus less sensitive and less expensive detectors can be used due to the possibility of separation and pre-concentration the desired species. In addition, investment and operational costs associated with hyphenated techniques sometimes also play important roles to restrict the spread of speciation analysis as a usual task.The selection of detection techniques depends on the concentration level of the species presented in the sample and also the type of matrix and its composition. In terms of the detection approaches for speciation analysis, they must be selective and extremely sensitive since the species of interest usually accounts for only a small fraction of the total amount. The frequently used detection methods with high selectivity and sensitivity for As, Hg, Se and Sb species can be classified into atomic spectrometry and mass spectrometry methods.4− with the acidized sample prior to detector is proved to be an effective measure to reduce interferences and background signal from the sample matrices. The detection limits lower than µg/L will be obtained using HPLC-HG-AFS for As speciation analysis [Atomic spectrometry are subdivided into AFS, AAS, and AES (or OES), among which AFS is the most often used method, and represents a suitable alternative to the other atomic spectrometric and mass spectrometric techniques . The diranalysis . Howeveranalysis ,78. 3O4 magnetic nanoparticles [2-catalyzed photo-oxidation of As species. Illuminating for 3 min can quantitatively converted As(III), As(V), MMA and DMA into As(V) at 1% K2S2O8 (w/v).Although there are some reports about the applications of AFS for the speciation analysis of As, Hg, Se, and Sb in recent years ,157,158,articles  were alsarticles  developeIt is noted that the higher chemical valence of analytes would be dominant after the eluted organic compounds are oxidized either via a UV or microwave digestion process. Therefore, a pretreatment to transfer into lower valence compounds is required, that is As(V)→As(III), Sb(V)→Sb(III) and Se(VI)→Se(IV). For example, As(V) has low HG efficiency, and thus in order to improve the analytical sensitive, an acidic thiourea solution was used on-line by Yu et al.  and thioAlthough there are some reports on the analysis of As, Hg, Se and Sb species by AAS ,166,167 The unquestionable advantages of ICP-MS over other species detectors are its high sensitivity and multi-element on-line detection capacity. In addition, the application of MS allows not only to obtain the information on the qualitative and quantitative contents of the sample, but also to determine the structure and molar masses of the analytes. The coupling of different separation techniques with ICP-MS has become common practice for the speciation analysis of trace As, Hg, Se and Sb ,172. UnlEven though the interface of ICP-MS detector with HPLC is relatively simple, the main problem is that the mobile phase used must be compatible with detection system. Sodium or potassium phosphate buffer mobile phases often utilized in IEC are not appropriate for a MS detector. As discussed above, non-volatile buffer salts can be collected on the lenses and skimmer cones resulting in signal drift and a high maintenance level for cleaning the inner surfaces of the MS detector, and thus the use of volatile buffer systems or ones that have low residue is required . Organic38Ar37Cl+, 40Ar35Cl+ (the m/z 75 is the same as 75As) are generated if samples contain high amount of chloride [m/z [m/z are allowed to enter the CRC, by which it contributes to a better control over the reactions taking place in the cell. For example, arsenic species in seafood were determined by Schmidt et al. [2 as reaction gas for the conversion of 75As to 75As16O. ICP-MS/MS was used by Gao et al. [2, O2) and a collision mode (He) were investigated and found that H2 mode was the best choice for eliminating interferences and obtaining a higher signal-to-noise ratio.Although ICP-MS exhibits very good analytical performances for ultra-trace determination, one of its disadvantages is vulnerable to interferences with the molecular ion signals by atomic argon (Ar) and chlorine which can hinder the measurement of Se and As species. For example, when ICP-MS is used as a detector for As determination, it frequently suffers from chloride interference as chloride ,176. Howide [m/z ,177,178.ide [m/z ,180. ICPt et al.  by LC-ICo et al.  for the m/z [4− to generation hydride/vapor are limited. For example, it is thought that Se(VI) is not reducible into hydride according to the studies on the reduction kinetics of inorganic Se species with NaBH4. Consequently, inorganic Se(VI) and Se(IV) analysis by HG technique must be carried out by first determining Se(IV) and then transforming Se(VI) to Se(IV) prior to the determination. Meanwhile, the stability of plasma may worsen when determined by HG-ICP-MS because online HG system delivers not only hydride vapor but also large amounts of hydrogen into the ICP. Therefore, the other alternative vapor generation techniques are developed. For example, an on-line sequential photocatalyst-assisted digestion and vaporization device was coupled between LC and ICP-MS by Tsai et al. [MS detection allows the use of isotope dilution analysis (IDA) for speciation analysis due to its specific detection based on the ratio m/z . ID-MS im/z  for quanm/z  to overcm/z ,185. As i et al.  for Se sIt is noted that although modern techniques using MS detection can help to obtain a better understanding of the experimental data and species identification, many analytical laboratories cannot support such instruments due to their high price and expensive maintenance. Therefore, the hyphenation of chromatography with atomic spectrometry seems to be a well substitute of mass spectrometry. As far as the separation and detection of element speciation in environmental and biological samples are concerned, different approaches can be used based on on-line or off-line procedures. The hyphenated techniques, in which effective separation methods are coupled on-line with diverse selective and sensitive detectors, are attractive tools in the speciation analysis of As, Hg, Se and Se. Their main advantages include extremely low limits of detection and quantification, insignificant influence of interferences on the determination process, as well as very high precision and repeatability. Although powerful techniques based on MS are nowadays extensively used for the speciation analysis of trace elements, it is considered as an expensive instrument to purchase and maintain, and only few laboratories can support the high cost of such techniques. The hyphenation of chromatography to atomic spectrometry detectors especially the AFS is still liable and low-cost alternative for routine laboratories. Meanwhile, HG in conjunction with AFS detection deserves more research because it can be hyphenated easily to LC, and provides detection limits of the same order of those obtained with MS techniques. Therefore, it is predictable that HPLC coupled with HG-AFS will be promising for speciation analysis of As, Hg, Se and Sb in environmental and biological samples, and has vast potential for further development.


Background: Human breast milk provides a child with complete nutrition but is also a popular therapeutic remedy that has been used in traditional, natural pharmacopeia, and ethnomedicine for many years. The aim of this current review is to summarize studies of non-nutritional uses of mothers’ milk. Methods: Two databases (PubMed and Google Scholar) were searched with a combination of twelve search terms. We selected articles that were published between 1 January 2010, and 1 January 2019. The language of publication was limited to English. Results: Fifteen studies were included in the systematic review. Ten of these were randomized controlled trials, one was a quasi-experimental study, two were in vitro studies, and four employed an animal research model. Conclusions: Many human milk components have shown promise in preclinical studies and are undergoing active clinical evaluation. The protective and treatment role of fresh breast milk is particularly important in areas where mothers and infants do not have ready access to medicine. Human breast milk (HBM) is perhaps the most important functional food known. It is a dynamic food with both nutritional and health benefits for neonates and infants. Human milk has powerful immunological properties, protecting infants from respiratory diseases, middle ear infections, and gastro-intestinal diseases. It is now appreciated that human breast milk has health impacts that are lifelong, with breastfeeding showing protective effects against diabetes mellitus, obesity, hyperlipidemia, hypertension, cardiovascular diseases, autoimmunity, and asthma . HoweverThere is no doubt that incorporating traditional and modern evidence-based medicine (EBM) as integral parts of the formal health-care system is important and likely to be achieved in many countries. The aim of the current review is to summarize studies of non-nutritional usage of mothers’ milk. Due to its low cost, wide availability, and lack of undesirable effects, mothers’ milk has the potential to play a role in human health and in evidence-based therapy.The literature review was performed by conducting an electronic search of PubMed and Google Scholar. No filter or limitation was used during the search. Reference lists from selected studies were manually scanned to identify any other relevant studies. The electronic search used the following keywords and medical subject headings (MeSH) terms: Human milk; breast milk, mother milk, colostrum, atopic eczema, diaper dermatitis, nipple pain, breast inflammation, umbilical cord separation, neonatal conjunctivitis, HAMLET, topical treatment. The two authors independently searched databases and reviewed articles. Bibliographic references to retrieved reviews and studies were searched for additional articles. We included articles that were published between 1 January 2010, and 1 January 2019. The language of publication was limited to English.From total of 1503 initially screened articles, only 15 fulfilled all the inclusion criteria. The following criteria needed to be fulfilled for a study to be included in this review: (1) Topical application of human milk or human milk active factors versus control; (2) in the case of human studies, participants had to be newborns; (3) in the case of animal models, HBM in vitro assessment had to be included. Articles that did not provide sufficient information from the title and abstract were included for further evaluation, and reading was done in full. Records were first selected after which 1469 were excluded based on excluded criteria: Did not report the data of interest, the language of publication, no access to the full text, conference proceeding, reviews. There was no restriction of study designs included. In order to limit bias in the inclusion–exclusion process, the selection was made on the basis of the consensus of two authors. The Cohen’s kappa index was calculated to assess the agreement between the two reviewers and any discrepancy was resolved by consensus or by a third reviewer. The reviewers were not blind to author, institutions, or manuscript journals. Data extraction and analysis were performed by the same two reviewers. We present a narrative summary of studies, rather than a meta-analysis, because of the heterogeneity in measurement tools, populations, interventions, and design . The reporting in this review follows the Preferred Reporting Items for Systematic Reviews and MetaAnalysis (PRISMA) guidelines, where warranted.p = 0.02). Seven studies were conducted in Iran, two in the USA, two in each of Turkey and Sweden, and one in each of Norway and Germany , and one was a quasi-experimental study. We also considered two in vitro studies and four with animal research models. We decided to include these because they have practical implication for clinical trials and, in our opinion, are examples of translational science.Below we briefly describe the studies by medical problem.Recently, a few studies have been published on the topical anti-inflammatory effects of human breast milk in the treatment of skin problems, such as atopic eczema and diaper dermatitis ,20,21. OBerents and colleagues, in a small pilot study, did not find any effect on eczema spots treated with topical application of fresh human milk. However, this clinical trial has some limitations. First, it had a very small study population of six children; second, two of them were treated with their mother’s milk produced for a younger sibling. The mean age of the children was 18.5 months (ranging from 4 to 32) .p = 0.002) [Gozen et al. tested the effectiveness of human milk and barrier cream (40% zinc oxide with cod liver oil formulation) on the healing of diaper dermatitis. The population of the trial included 63 term and preterm newborns with developed diaper dermatitis in neonatal intensive care units, divided into two groups. There were no statistically significant differences between the groups in terms of the mean number of clinical improvement days, but the postlesion score in the barrier cream group was lower than in human milk group (= 0.002) . As the p = 0.043). According to many studies, the women who applied expressed breast milk had significantly lower perceptions of nipple pain following four to five days of treatment than the women who applied lanolin. However, this beneficial effect was not maintained after six to seven days of treatment. At no assessment were there any group differences in nipple pain perceptions between the women who applied expressed breast milk and the women who had applied lanolin, warm compresses, or nothing [A common breastfeeding difficulty for mothers is painful nipples. One traditional non-pharmacological intervention to reduce nipple pain in breastfeeding women is topical treatment with expressed breast milk. Abou-Dakn et al. carried out clinical trials to evaluate the efficacy of lanolin versus breast milk on painful and damaged nipples during lactation . They ev nothing .n = 89) received two drops of colostrum in each eye, the second (n = 82) was treated with topical erythromycin ointment (0.5%), and the control group (97) received no treatment. The frequency of conjunctivitis was higher in the control group, followed by the group receiving topical application of colostrum and antibiotic (p = 0.003) [p < 0.001) [Treatment of ocular surface disease with human milk is documented in ancient Egyptian, Roman, Greek, and Byzantine texts and was traditionally used by mothers to treat infectious conjunctivitis. Ghaemi et al. have shown the beneficial preventive effects of colostrum against neonatal conjunctivitis on 89 breastfeeding neonates. The 269 preterm neonates were randomly divided into three groups: The first (= 0.003) . However= 0.003) . Accordi< 0.001) . They coBreast milk is widely reported to be used for umbilical cord care in developing countries, as evidenced by numerous publications. Since 1998, the World Health Organization (WHO) has advocated the use of dry umbilical cord care in high-resource settings but has also recommended research into the use of breast milk and colostrum in umbilical cord care . There ap = 0.001). The median number of bleeding days after cord separation was 1.2 ± 2.33 and 3.1 ± 3.77, respectively [Aghamohammadi et al. randomized 130 singletons, all mature and healthy newborns born in hospital, and compared the effect of topical application of human milk and dry cord care on umbilical cord separation time. Newborns were breastfed. Mothers were asked not to cover the cord with diapers and not to bath the child until the cord had separated. All mothers received instructions, a form for recording symptoms of infection and cord bleeding, and a form for observation on the progress of care. The human milk group dropped milk on the remaining part of the cord and the cut edge, letting it dry, three times a day for two days after separation of the cord. Two days after cord separation, a physician checked the cord. The median time of the cord separation was 150.95 ± 28.68 hours in the human milk topical application group and 180.93 ± 37.42 hours in the dry cord care group (ectively .p < 0.0001) and drying groups (p < 0.003) [In the study of Golshan et al., 300 healthy neonates, delivered normally or by Cesarean section, were divided into three random groups, in which ethanol, their mother’s milk, or dry cord care was applied. In the milk group, mothers washed the umbilical cord stump with their milk two times a day. Umbilical separation time in neonates of the human milk group was 6.5 ± 1.93 days, whereas in the ethanol and dry care group this was 8.94 ± 2.39 and 7.54 ± 2.37 days, respectively. The frequency of omphalitis was not significantly different between the three groups. Umbilical separation time in the human milk group was significantly shorter than in the ethanol (< 0.003) .p < 0.001) [In a clinical trial by Abbaszadeh et al., 162 healthy, hospital-borne neonates were assigned to two groups, where cord care was performed using human milk or chlorhexidine. Human milk was applied to the umbilical cord every twelve hours for days after separation. The shortest cord separation time was 3 days in the topical human milk group (7.14 ± 2.15), while the longest was 53 days in chlorhexidine group (13.28 ± 6.79)  was discovered by the Svanborg group when they were studying antiadhesive molecules in human milk .HAMLET is formed during low-pH precipitation of the casein fraction, which allows for partial unfolding of the α-lactalbumin structure and binding with the fatty acid. HAMLET triggers rapid carcinoma cell detachment in vitro and in cancer patients after topical administration of the lyophilized complex. To form HAMLET, α-lactalbumin is obtained from human milk by chromatography. The partially unfold protein is subsequently bound to oleic acid on an ion-exchange matrix, and the complex is eluted with salt, purified, lyophilized, and frozen in aliquots for instillation .p < 0.02) and the tumors were significantly reduced  [p < 0.0001 for total tumor count), reduced polyps by about 58% (p = 0.0001), and improved survival (p = 0.0103) over the control group mice.The therapeutic efficacy of HAMLET has been demonstrated through in vitro research in animal models of glioblastoma, bladder cancer, and intestinal cancer; and in clinical studies targeting bladder cancers and skin papillomas ,28. Loca < 0.02) . Puthia Through gene set enrichment analysis, the researchers concluded that the prophylactic and therapeutic effects of HAMLET are accompanied by well-defined series of stable changes in gene expression, affecting Wnt signaling and β-catenin, glycolysis, oxidative phosphorylation, and lipid metabolism in tumor tissue .Streptococcus pneumoniae by cell shrinkage, DNA condensation, and DNA degradation [The same complex showed strong bactericidal activity against specific pathogens of the oral cavity and respiratory track, with the highest activity against the gram-positive organism radation .The transfer of traditional medical knowledge is an ongoing process. It is important both for the preservation of traditional natural medicine, but also in the search for novel agents in treatment. Home remedies are generally believed to be natural ways to cure minor illnesses or conditions. They are usually cultural practices, traditions, customs, or folk remedies that have been passed down from generation to generation or from person to person. However, it should be kept in mind that there is not necessarily any medical proof that any of these treatments work, or whether they can cause more harm than good. Human milk is considered to be the gold standard in infant nutrition, providing optimal nutrients for normal growth and development. Apart from its nutritional benefits, human milk contains multiple bioactive and immunomodulatory components. The latter of these include growth and immunological factors, as well as micro-RNAs, cellular components such as leukocytes, epithelial cells, progenitor cells, and stem cells . FurtherCommon skin problems may appear during lactation and breastfeeding, particularly affecting the nipple, areola, and breast. Some medications used in the treatment of skin conditions are unsuitable during lactation. It has been shown that expressing a few drops of milk and rubbing them gently into the sore nipples, then allowing it to dry naturally, takes advantage of the healing properties of human milk. Many studies have indicated that bioactive components of human milk and microbiota have promise as adjuvants for wound healing ,34. FromBreast milk is used in many cultures for skin irritations. Breast milk involves no risk of allergy, contains antibodies, epidermal growth factor (EGF), and erythropoietin, which may promote the growth and repair of skin cells. Human milk is a source of commensal bacteria that can play an anti-infectious, immunomodulatory role. Their possible function in the acceleration of conditions for skin biofilm formation can open new perspectives for the prevention and treatment of skin and wound healing diseases. Interestingly, the analysis of Simpson et al. showed that miRNAs are possible mediators of the observed preventative effects of atopic dermatitis .The concentration, regulation, and individual variation between bioactive element, immune factors, various progenitor and mature cell types, and stage of lactation are not well established. Complexity and variability in human milk composition, and infants’ responses to many human milk constituents may also explain some of the conflicting results of studies evaluating the effects of non-nutritional uses of human milk.The studies considered here vary in methodology and in definition of outcomes, which leads to considerable heterogeneity. Human milk composition varies both within and between individuals, and this may partially explain the conflicting data.However, the use of breast milk in the treatment of inflamed or injured eyes is not applicable in all cases. It should rather serve as complementary therapy, and not the only mode of treatment. At our present level of knowledge, non-nutritional uses of breast milk are certainly better suited to prevention than to a medicated process. However, in areas where mothers and infants do not have ready access to medicine, such as in developing countries, the application of breast milk is often a determining factor in infant recovery and survival.Fresh whole human milk and its components have potential as a novel therapeutic tool in the treatment of many diseases. In our opinion, the future implications of non-nutritional application are associated with particular components of breast milk, rather than with the whole milk.In Hakansson’s study of the antimicrobial activity of human milk, a complex of α-lactalbumin and oleic acid induced apoptosis in tumor cells without affecting healthy differentiated cells. HAMLET is a tumoricidal protein–lipid complex from human milk with broad effects against cancer cells of different origins. The mechanism of its action is unusual, as the complex interacts with a number of molecular targets and cellular components. Importantly, HAMLET does not have any toxic effects on healthy tissues in the treated patients and animals. HAMLET has been shown to be safe and effective in humans in two proof-of-concept human clinical trials: Convincing therapeutic efficacy was demonstrated in a topical skin papilloma study and in patients with bladder cancer  . PublicaMany studies highlight progenitor and breast milk stem cells. The presence of stem cells in human milk poses numerous questions and implications for breastfeeding, newborn, and maternal health, but also opens a new perspective of future potential applications of these cells in personal and regenerative medicine. The goals of future research should be to assess the function, potency, and therapeutic value of breast milk cells—including cell therapy for future applications—and should determine the direct or indirect effects of breast milk cell components on promoting immunological tolerance and newborn development, and also on providing effective and complementary treatment of diaper rash, atopic eczema, diaper dermatitis, umbilical cord separation, and eye problems. Without any doubt, future research on these topics will need to involve evidence-based medicine and clinical trials.Due to the limited and heterogeneous body of evidence that included animal studies, human intervention studies, and observational human studies, the risk of bias assessment for individual studies was not performed. The overall body of evidence was narratively discussed.This article is limited by its emphasis on papers published in English in journal databases, so many useful local ethnomedical studies may have been missed. Evidence-based medicine focuses more on new approaches than on developing traditional folk and ethnobiological data, so many promising intervention studies are not published in papers indexed in PubMed with high impact factor. It is unclear whether a lack of institutional support and funding for clinical trials of natural products might be critical in the low number of studies.The findings of this review provide information about possible non-nutritional uses of breast milk in postnatal care. Breast milk is a natural agent and is biologically suitable for the body, having no side effects; it is always available and can be used in all social and economic groups of society. The health implications of milk components—such as macronutrients, biologically active factors, and somatic cells—remain unknown or not well understood. The positive effects of HBM found by in vitro and animal studies must be substantiated by findings from clinical studies. The most reliable clinical studies for assessing the benefits of HBM are randomized, double-blinded, multicenter controlled trials but to date, they are very scarce.Non-nutritional uses of human breast milk can be considered examples of personalized medicine. Further research including developed countries is recommended to find or confirm the results and to evaluate the effects of traditional therapies. This knowledge may also have the effect of convincing mothers to continue to breastfeed with their own milk, as a substance that possesses extraordinary properties, not only for nutrition.


Oxytocin (OT) and vasopressin (AVP) are neuropeptides that govern the social-emotional functioning of humans. We contend that to fully understand their function, research should consider how they are flexibly fitted to maximize survival and reproduction given the variety of human experience. In a series of two studies, we show that early life stress is associated with change in the core function of OT and AVP in evolutionary predictable ways: Under high early life stress, AVP promotes threat-detection capabilities, whereas OT motivates non-selective proximity seeking to others. Conversely, under low early life stress these neuropeptides have an opposite, yet adaptive response: AVP promotes low vigilance and preservation of energy, whereas OT increases detection of interpersonal flaws. Our results demonstrate the plasticity of neuropeptide functioning that mirrors the variance in human social-emotional functioning. Since the discovery of neuropeptides e.g., , there hThe plasticity of human behavior at times of threat was suggested by Research in attachment theory  also lenResearch has indicated that OT governs social bonding and social cognition such as increased romantic connectedness , provisiAmong people with a history of stressful and insecure interactions and a relatively unsafe environment, the need to maintain interpersonal proximity, and thus security, may override considerations that otherwise promote selectivity. Thus, OT is expected to increase affiliation tendencies among people with early life adversity to the point of overlooking other people’s flaws, because in stressful environments being with others, even imperfect others , enhances survival more than being alone.Vasopressin regulates social-related threat by increasing vigilance and the motivation to act . MaintaiTo examine these predictions, we conducted two studies. In Study 1, we examined the links between people’s basal levels of OT and AVP and hypervigilant responses as a function of early life stress. In Study 2, we examined the effects of OT administration on hypervigilant responses as a function of early life stress.M = 23.71, SD = 3.27), who were individually invited to a lab. We did not include in the study women who were pregnant or breastfeeding, individuals who suffer from psychiatric disorders, head injuries, heart disorders, and addiction to alcohol or drugs, and those who take medication with endocrine-related effects  500 KIU, per 1 ml blood. Blood samples were then centrifuged at 1,600 × 8VP-EIA kit ADI 900-017 , consistent with previous research (N = 673 plasma samples) OT values from extracted and un-extracted samples and found that the two showed very similar results for the current kit. We found that when using the Oxytocin ELISA kit 900-153, the extracted and non-extracted samples gave very similar values. For instance, in the current study, the mean of eight direct un-extracted blood samples was 383.75 and that of 8 extracted blood sample was 374.5 pg/ml. Samples were diluted (1:5) in the suitable assay buffer for OT or AVP and further treated according to kit’s instructions. Dilution has already shown to give results within the linear portion of the standard curve. Measurements performed in duplicates.Determination of hormones was performed by using a 96-plate commercial kits, OT-ELISA kit ADI-900-153 and Argresearch . The immresearch . The kitSample Concentration of OT or AVP, were calculated by MatLab-7  according to the relevant standard curve. The intra-assay coefficients of variation of OT or AVP were less than 10.3 and 6.09%, respectively.never true (1) to very often true (2). For each participant, we calculate the level of childhood emotional (α = 0.62), physical (α = 0.84), and sexual (α = 0.89) abuse and emotional (α = 0.88) and physical (α = 0.61) neglect by averaging the answers in the relevant items. Next, we conducted a parallel analysis to determine the ideal number of factors for the variables of negative life events and childhood trauma, which recommended one-factor solution. A factor analysis with maximum likelihood as the extraction method and oblimin rotation has revealed that all six factors were significantly loaded on one factor , which we named “early life stress” and that had excellent goodness of fit, χ2(9) = 9.41, p = 0.40. For each participant, we calculated his or her level of early life stress by employing Anderson-Rubin method.Following the collection of blood samples, we obtained a self-report of positive and negative events experienced during childhood, and the perceived stress associated with those events, by employing an edited version of the Life Experiences Survey  i.e., L, which cFollowing these questionnaires, we assessed participants’ ability to detect social-related  and non-social-related threats  by employing To assess participants’ ability to detect poisonous animals as a threat, we employed a second task with similar parameters in which they were asked to detect as quickly as possible a target picture portraying a threat from a poisonous animal  out of a matrix of control pictures  between males and females. Because of the documented sexual dimorphism in OT and AVP systems, we adjusted the main analyses for the contribution of biological sex nevertheless. Pattern of associations between main study measures as well as means and standard deviations are presented in As a preliminary analysis, we examine biological sex differences in basal levels of OT and AVP and in early life stress. Research has indicated that males and females differ in OT and AVP basal levels and in the prevalence of OT and AVP receptors in the brain e.g., , as welltest see , we haveb = 3.49, p = 0.022), but with higher accuracy among people with low early life stress and safer environments (one standard deviation below the mean of early life stress) .Using hierarchical regression analyses, we examined the number of mistakes in detecting infidelity and poisonous animals as a function of participants’ basal levels of OT and AVP, early life stress, and their interactions. We also included gender as a covariate to adjust the analyses for its effect. Regression coefficients are presented in b = -5.26, p = 0.034) and poisonous animals  among people with high early life stress (one standard deviation above the mean of early life stress)  but with lower accuracy  among people with low early life stress and, thus, safer environments (one standard deviation below the mean of early life stress) . Overall, the models explained 34.1% of the variance in accuracy in detecting infidelity, and 14.8% of the variance in accuracy in detecting poisonous animals.The analyses also revealed the expected interaction between AVP and early life stress in detecting infidelity . Conversely, under conditions of low early life stress and safer environments, AVP promoted the maintenance of lower vigilance to social and non-social threats, and, thus, the preservation of metabolic energy, while OT promoted the accurate appraisal of people’s social network by increasing the perception and detection of social cues. Although Study 1 supported our main predictions it is correlational in nature. In Study 2, we wished to replicate part of the results of Study 1 by examining the causal link between OT and hypervigilant responses as a function of early life stress.In Study 2, we examined whether early life stress moderated the effects of OT administration on hypervigilant responses. To do so, we examined people’s ability to detect social  and non-social  threats before and after an OT administration (OT vs. Placebo). We predicted that for people with a history of secure interactions and a relatively safe environment, OT administration will improve the ability to detect a social threat but not a non-social threat. Conversely, for people with a history of insecure interactions and a relatively unsafe environment, OT administration will decrease the ability to detect a social threat but not a non-social threat. We did not use AVP administration because it was not available in Israel during the time of the study (2016).M = 24.23, SD = 3.51) from the Interdisciplinary Center (IDC) Herzliya, participated in the study for a monetary compensation of 150 NIS (approximately 35$). The criteria for exclusion and inclusion were similar to those of Study 1. The study was approved by the Bar-Ilan’s and Interdisciplinary Center (IDC) Herzliya’s IRBs. The sample size was predetermined by a power analysis . The packet included a measure of stressful life events LES;  and chil1).After completing these tasks, participants were randomly assigned to experimental conditions. Participants were self-administered 16 IU of synthetic oxytocin  delivered intranasally in two puffs per nostril (with 4 IU per puff), or a matching placebo nasal spray containing non-active ingredients. This dosage was found to have similar affects as 24 IU  which isApproximately 45 min after the administration, participants completed the computerized infidelity detection task and the poisonous animals detection task for a second time . Finally, participants completed a socio-demographic questionnaire, debriefed and thanked.t-tests, we found that before the OT administration, the number of mistakes in detecting infidelity  and/or poisonous animals  did not differ significantly between the OT and the placebo groups. This finding establishes the random selection of participants to experimental conditions.Pattern of associations between main study measures as well as means and standard deviations are presented in 2(1) = 253.32, p < 0.0001, we used ranked score for the number of mistakes in detection. The analyses revealed the expected interaction between OT and early life stress in detecting infidelity . Conversely and unlike Study 1, for people with high early life stress (one standard deviation above the mean of early life stress), OT administration had no effect on the change in accuracy in detecting a social threat . Thus, unlike high basal levels of OT that were linked with lower sensitivity among people with high early life stress in Study 1, OT administration, which temporarily increases OT levels, did not have similar effect on sensitivity to social cues.Using hierarchical regression analyses, we examined change in the number of mistakes in detecting infidelity and poisonous animals as a function of OT administration, early life stress, and their interactions. As in Study 1, we included gender as a covariate to adjust the analyses for its effect. Specifically, in the first step of the analyses, we introduced the number of mistakes before the administration, and gender as a covariate. This step allowed us to estimate whether OT administration as a function of early life stress predict the increase and/or decrease in the accuracy in detection. In the second step of the analyses, we added early life stress and OT group  as predictors. In the third step of the analyses, we added the interaction between OT group and early life stress. Regression coefficients are presented in lity see  but not In the current research, we set out to explore whether early life stress qualified the function of OT and AVP in an evolutionary predictable way in keeping with various differential susceptibility models . In StudThese findings highlight the possibility that via epigenetic processes, neuropeptides such as OT and AVP adapt their function to maximize organisms’ likelihood to survive and reproduce. Other research has already shown that proxies of early life stress (such as attachment styles) are linked with different epigenetic profiles e.g.,  and specThe current research also highlights possible differences between OT levels (as was captured in Study 1) and responsiveness (as tested in Study 2). Specifically, in Study 1, basal levels of OT were linked with higher sensitivity in detecting social threats among people with low early life stress, but with lower sensitivity in detecting such threats among people with high early life stress. In Study 2, OT administration was only linked with increased sensitivity in detecting social threats among people with low early life stress , and not with decreased sensitivity in detecting such threats among people with high early life stress . Therefore, it might be that early life stress not only influences the function of various neuropeptides but also their plasticity and system responsiveness. High early life stress might decrease the responsiveness of such systems, as previous research indicates e.g., .per se. Despite the limitations, our findings provide a glimpse in to the way the environment tailors our bodily functions to optimize survival.The results of this research notwithstanding, there are some limitations that need to be considered. First, AP-P was a Ph.D. student under the supervision of TE-D and RF. AP-P conducted the study and written the method sections. TE-D supervised the work, conducted the analyses, and wrote the first draft. GH and SBB edited the manuscript and wrote the final version of the manuscript. RF supervised the work and with the assistance of OZ-S analyzed the basal levels of OT and AVP.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.