Mothers and children are the most vulnerable members of every society. As a result many deaths occur in these two groups, so caring for these two groups is very important. Today, it is believed that the health of an infant is related to the health of their mother. Maintaining a healthy weight before pregnancy, and optimal weight gain during pregnancy by appropriate and sufficient nutrition, are two effective measures for the prevention of low birth weight.To provide successful health interventions, it is essential to design and implement effective health education programs. Successful education also depends on the proper use of theories and models in health education. The Health Belief Model is a model that illustrates the relationship between beliefs and health, and it is based on the hypothesis that preventive health behavior consists of personal beliefs. The aim of this study was to assess the effects of training on the Health Belief Model on dietary behaviors of a sample of pregnant Iranian women.This study was a randomized controlled clinical trial, involving 130 pregnant women who attended two health care centers of Shahid Beheshti University of Medical Sciences. Data was collected by a structured questionnaire in three parts and seven sub-scales  based on the Health Belief Model.Principles of education were based on the Health Belief Model and performed twice during two-hour sessions in the intervention group. Women in the control group received routine care and did not receive training on the above model. In order to evaluate the intervention, the previously mentioned questionnaire was administered one month after completion of the intervention, and filled by participants in both groups. Data were analyzed by SPSS software and reported with diagrams and tables.The mean score for each variable before the intervention, except for the performance guide variable, was not significantly different between the two groups (p<0.05).A month after the intervention, the mean scores of the knowledge, perceived severity, perceived benefits in each group, were significantly different.These results demonstrated that there were significant differences between the two groups in terms of mean scores of knowledge, perceived severity, perceived barriers, performance guide and individual performance, and the means of these variables in the intervention group were also higher than the control group. On the other hand, after the intervention, there was no statistically significant difference found in the mean scores of perceived benefits and perceived susceptibility between the two groups .Educational interventions based on health promotion patterns can be effective in enhancing awareness, better understanding of risks, reducing barriers to healthy behavior and ultimately, improving women’s health and nutritional performance during pregnancy. Mothers and children are the most vulnerable members in any society, thus in the majority of countries, these two groups have higher mortality numbers.A number of adverse pregnancy outcomes, including; intrauterine growth retardation, low birth weight, anemia, pre-eclampsia, preterm delivery and even fetal or infant death, are due to undernutrition or failure to receive all the necessary micronutrients (micronutrient deficiencies) during pregnancy  has introduced the obesity epidemic as one of the most significant threats to global health, particularly in women of childbearing age . TherefoPrevious studies, particularly in low-income and middle-income countries, have shown that individual education and counseling during the first pregnancy visit helps mothers to improve their food consumption and the use of dietary supplements. This information should focus on the mothers’ needs and their fetus at three months of pregnancy and the need to maintain consistant weight gain in order to avoid long fasting or over-eating and its complications .Poor weight gain, and more importantly, weight gain and obesity in mothers and infants during pregnancy results in subsequent complications and ongoing problems. Like many developing countries, there is a growing trend in these types of issues in Iran .The results of several Iranian studies have suggested that calorie and protein intake is similar in both non-pregnant and pregnant women. As a result pregnant women are not receiving sufficient minerals or vitamins and they require nutritional supplements during pregnancy despite having a normal BMI or weight gain in pregnant women. This condition is often associated with mistakes found in the women’s nutritional habits and deficiencies in their nutritional knowledge, especially among middle and lower socio-economic groups . The HeaThe model includes components of perceived susceptibility, perceived severity, perceived benefits, perceived barriers, and a performance guide .This study assessed the knowledge, beliefs, perceptions and behaviors of expectant mothers with respect to prenatal nutrition. The study aimed to determine the effectiveness of educational interventions based on the HBM to improve the dietary behaviors during pregnancy in a sample of expectant mothers living in Tehran, Iran.This study was a randomized controlled clinical trial, and 130 pregnant women participated from two therapeutic-health centers (Level I) Shahid Beheshti University of Medical Sciences in Tehran. Participants who met the following criteria were selected:Pregnant women with low risk pregnancies, living in Tehran, their first single pregnancy, and pregnancy demands for couples.All of the women first received a phone call and the purposes of research and education methods were explained to them. The women who were willing to participate in the study were included in the final list of subjects. The subjects were then randomized into two groups by a block randomization procedure and performed by Excel software.Written consent was obtained from all participants. The minimum sample size using power = 80 and was obtained in each group and a total of 130 patients were enrolled in the two groups (64 patients in each group).Data was collected by a structured questionnaire based on HBM . The queAll of the education sessions were conducted by the first researcher who had adequate experience in the field of health education and full understanding of this mode of delivery.At the beginning of the classes, a question and answer session was conducted for the initial survey of the women’s knowledge, this was followed by a lecture, presentation of posters, photographs, and training pamphlets, and then continued with group discussions. All participants were followed up by the researcher, and a month later, both groups were re-evaluated by questionnaires. After final evaluation, mothers in the control group were given one day of training and received an educational pamphlet.The correct answers were given a score of 1 and incorrect answers were given a score of 0.In addition, the question components of the model had 6 point Likert score options that ranged from strongly disagree (score 0) to strongly agree (score 5).Scoring of the questions or phrases for dietary behaviors were considered as well as ratings:Level 1 (poor dietary behaviors scores of 0-4), participants who had poor dietary behaviors or did not folliw the healthy, level 2  who met the minimums of standards sometimes, and level 3 , who acted strictly in accordance with the instructions for proper nutrition during pregnancy .Ethical approval for the study was obtained from the ethical review group and the Deputy of Research at the Shahid Beheshti University of Medical Sciences. In addition, Informed consent was obtained from all study participants.Data were analyzed using SPSS software, version 20. Missing data and outliers were checked before data analysis. Data from 130 pregnant women who participated in this study were included in these analyses. Between-group and within-group differences were measured using the two -independent samples t- test and paired samples t- test for the data had a continuous spread, respectively and the chi-square test was used for categorical variables to test the association between the variables. Moreover, correlation between the model’s variables was calculated applying linear correlation and calculation of Pearson’s correlation coefficient. Statistical significance was considered at the 5% level.Overall, all 130 patients completed the study and the response rate was 100%. The mean age of the participants (4.71 ± SD) was 26.22 years, the majority (77%) were in their first pregnancy, 43% were in their second pregnancy, while the others had more than two pregnancies and live births.The mean gestational age of the participants was 21 weeks (SD=0.88), in addition, the majority had attained secondary education (43%) and were housewives (92%). There were no significant differences between the intervention and the control groups in regard to their demographic characteristics, as shown in At first, all model constructs scores was compared applying two independent samples t- test in two experiment and control groups before the intervention. Results showed that there were no significant differences, except for perceived susceptibility, as showed significant differences in the intervention group after the intervention.2).On the other hand, at the begining of the study, no significant differences were observed between the two groups in terms of dietary behaviors, and all participants were in level 1 or 2 as defined before during pregnancy; but after intervention, 86.7% of women in experiment and 13.3% of women in the control group, were in level 3 of dietary behaviors, which indicates that the majority of women who received educations based on the HBM, achieved optimal dietary behaviors and this was a statistically significant difference , but there was not obtained such findings for control. For instance, mean scores of perceived susceptibility, perceived barriers and dietary behaviors in control arm did not significantly differ in the second stage compared with the first stage. However, for constructs knowledge, perceived benefit, perceived severity and cues to action, findings suggested significant differences in the second stage .In the third stage, mean diffences of the model constructs were compared using two independent samples t-test between two arms of study to assess the efficacy of the study intervention. Results manifested thet there were satistically differences for all variables, except for the perceived bebefit. This finding shows that the the majority of the model constructs have significantly progressed in the experiment compared to the control group .The major obstacles for the healthy diet and dietay behaviors noted by the participants were the time and expense needed to be spent for preparing the necessary and nutritive foods, especially proteins; however, this barrier was decreased among women in experiment arm but in the control group the perceived barrier still remained as the most important obstacle .The greatest perceived benefit in the second stage of the control group was related to the beneficial effects of optimal nutrition on infant’s health (78%). Whereas in the intervention group, improvements were shown in maternal and fetal outcomes (67%), maternal awareness in regard to family health (54%), and attempts to eliminate feeding problems (44%).Finally, Pearson’s coefficient was calculated with the correlation between the subscales in the intervention group, and after the educational intervention, the mean score of the subscales had a direct and positive relationship with the mean score of the women’s nutritional performance.Among the subscales, the mean score of knowledge had the highest correlation with the mean dietary behaviors score, which indicates that the more increased awareness, dietary behviors was improved. However, among the model’s subscales, there was only a weak linear relationship found with the mean performance score, and this was not statistically significant .Moreover, a weak linear relationship was shown between knowledge and performance subscales in the control group, but such relationship was not found for the other variables.Participants’ demographic and socioeconomic characteristics in the study, including age, gestational age(less than 20 weeks and more), number of pregnancies,women’s and their spouse’s education level and occupational status were identified as possible confounders in the association between educational intervention and dependent HBM outcomes. Then, multiple linear regressions were appyed to assess the effect of prenatal education based on HBM on the model’s constructs, controlling for above mentioned confounders. Independent variables were excluded from the model if they were insignificant above a two-sided p-value of 0.05 and included if they were statistically significant. However, none of them changed the beta-coefficients of other variables when excluded. Model fit was assessed by adjusted R-squared for linear regressions.This study included 130 pregnant women attending two public health centers in Tehran. The results demonstrated that pregnant women need nutritional prenatal care, and require sufficient and proper knowledge in this area, the second important area is to educate expectant mothers about the risks of complications caused by a failure to comply with correct nutritional recommendations and the severity of potential risks arising from a lack of good nutrition on both the mother’s and their unborn child’s health. Motivation is required to make behavior modifications to produce good nutritional performance, or to replace former bad habits with optimal nutritional behavior instead. The study results indicated that providing group consultations and training to pregnant women, based on known patterns of health promotion, is a better short-term and cost-effective method of increasing the target group’s knowledge and inducing behavior modification than conventional methods.Comparing the mean knowledge scores between the two groups, showed that there were significant differences in both groups at different stages of the study, therefore, we suggest that when giving information by maternal and neonatal health care providers, the needs of the target group must be taken into consideration. Furthermore, answering the women’s questions directly also played a more effective role than conventional methods, such as pamphlets, booklets, or media education. This is because the purpose of education is not only to deliver information, but it also enables the audience to assess their own thoughts, beliefs, and behaviors, regarding the information and then to make their decision on the changes they will need to make. Accordingly, effective training should take into account the audience’s needs; while on the other hand, the groups are influenced by the training, resulting in sharing in a bilateral teaching-learning process.Evaluation of common beliefs is a useful strategy for health care providers in face-to-face situations. If the educator determines that the audience has incorrect beliefs, then the aim should be to be determining the reasons for the fallacy and to help the client to overcome the problem through the provision of correct information . In KazaPromotion of nutritional knowledge in society through nutritional education would go a long way to reduce malnutrition and this could be considered a necessity for developing countries. Selecting a suitable model for health education is the first step toward planning effective health promotion programs .Malnutrition can arise from eating too few or too many calories and result in different adverse effects on pregnancy outcomes. As a result, nutrition is one of the most important factors discussed in various studies emphasizing the importance of health promotion interventions in this era.In the present study, the majority of participants held a number of incorrect beliefs and insufficient information about the mother’s energy needs. This misinformation can lead to excessive intake of calories and create obesity in pregnancy; while on the other hand, reducing the intake of necessary food groups, such as proteins and minerals that are found in fruits and vegetables can lead to malnutrition.Inspite of improvement in Knowledge, perceived benefits and severity, dietary behaviors did not significantly progressed among women in control group in the second investigation compared with the first time. This finding may explain the impact of the model based antenatal education to facilitate decreasing perceived barriers and improve the specific nutrition knowledge into the healthy practice acheivement. de Jersey et al. observed although pregnancy specific nutrition knowledge of a sample of Australian expectant mothers was good, knowledge regarding recommendations for healthy diet during pregnancy such as enough fruit and vegetable consumption was poor and less than one in ten women met important dietary recommendations. These researchers suggest that although knowledge played a key role for behaviour change, nutrition knowledge was independently associated with intake of fruit and vegetables by women and this knowledge inadequacy can not lead to ppropriate behaviour .However, the results indicated an increase in perceived benefits, rather than improvements in eating behavior modification in both groups after the intervention. As a result of improvement in the control group’s performance, no statistically significant difference was found in the second stage response in the control group.Mothers in the control group mostly knew the importance of healthy nutrition for having a healthy baby, in addition they were also aware that healthy families were related to healthy mothers.The findings for the perceived barriers subscale for the control group remained in effect too.These results imply an increase in the mothers’ perception of the benefits of healthy dietary pattern modifications over time, and the women are likely to be more sensitive to the health of their fetus and infant. The importance of correct nutrition notwithstanding, it may also contribute to the prevention of obstetric complications, such as; severe bleeding leading to anemia, impaired wound healing and delayed recovery after childbirth.In this study, the women participating in the intervention group were able to dismantle perceived barriers to a greater extent than the control group, therefore, these findings indicate the effectiveness of the trainings was focused on correcting unhealthy beliefs and insufficient information.For example, in the material given to the mothers in the intervention group, introduced food groups containing proteins were discussed, so if they did not have access to meat protein, inexpensive foods with high protein levels could be used to replace them. Moreover, if they had a milk intolerance or allergy to certain dairy products they could use other foods containing calcium, or if they could not eat fruit, they could introduce a variety of vegetables containing minerals and vitamins using simple and easy to apply explanations.One of the causes of anemia and iron deficiency in Iranian pregnant women may be inappropriate patterns of food intake that can lead to deficient levels and low absorption of iron. Furthermore, a significantly large proportion of pregnant women with iron deficiency anemia lived in low-income areas, and as a result of their lower per capita consumption of protein products, such as meat, eggs, and other essential micronutrients, such disorders were more prevalent in this group of women (Like other studies, this study had some limitations. As the present study was carried out on a small and not very economically advantaged population in urban area and we did not find any differences bwtween education level or occupation status and dietrary behaviors; while findings from two studies showed that higher maternal education level had been associated with greater health knowledge among women  MoreoverThe results of this study showed that improper dietary behavior habits need to be replaced with correct eating behaviors and the application of health promotion models such as the HBM can be combined with usual pregnancy care practices in health care centers. This effective form of health care delivery should be taken into consideration by maternal and neonatal health authorities. This type of education is low cost and can prevent expensive pregnancy complications and adverse obstetric outcomes, and be an effective method of containing the exorbitant costs imposed on families and the health care system.


Coca leaf products are an integral part of the lives of the Andean peoples from both a cultural and traditional medicine perspective. Coca is also the whole plant from which cocaine is derived. Coca products are thought to be a panacea for health troubles in regions of South America. This review will examine the toxicology of whole coca and will also look at medicinal applications of this plant, past, present, and future.  Coca is an indigenous plant of South America with numerous alkaloid components, the most well-known one of which is the psychoactive component, cocaine. Its leaves have been a staple in the Andean lifestyle for thousands of years. Strong interest in coca use has existed in the anthropological world for decades. Areas of study have not only attempted to understand traditional use during the Incan empire and coca's role in folk medicine, but also focused on factors that influence the ability of this native tradition to continue in the face of increasingly strict regulations of coca production. Efforts have been made to understand the long-term Andean use of coca, with subsequent research examining the scientific basis behind local beliefs. This review will examine the history of coca production, its toxicity profile, and its varied uses throughout the centuries. It is important to note that although coca continues to be valuable to native Andean people for religious and cultural reasons, travelers to these regions need to be aware that there is a paucity of medical data supporting the safe use of coca. The astute toxicologist should maintain an understanding of the cultural pressures experienced by contemporary travelers. Erythroxylum (family Erythroxylaceae): Erythroxylum coca Lam. and Erythroxylum novogranatense (Morris) Hieron [ E. coca Lam. var. coca is also known as “Bolivian” or “Huanuco” coca. This is the best-known variety and continues to be widely cultivated throughout the Andean region for both legal uses and the illegal production of cocaine [The Aymara people are an indigenous population of the Andes and Altiplano regions of South America. “Khoka” is an Aymara word that means “the tree.” This is the origin for our modern usage of “coca” . The coc) Hieron . There a cocaine . Other v cocaine . E. coca var. coca, the most widely cultivated variety, has been found to contain approximately 0.6% cocaine in its dried leaves [ Erythroxylum varieties contain eighteen alkaloids, belonging to the tropanes, pyrrolidines, and pyridines [Cocaine is the principal alkaloid found in the cultivated varieties of coca. Cocaine was first isolated in 1860 by Dr. Albert Nieman from leaves of cultivated cocaine . It is ayridines .α- and β-truxilline, hygrine, and cuscohygrine. All compounds were found to be considerably less toxic than cocaine with a lack of the euphoric effects that cocaine is known to have. The reader is referred to the articles by Jenkins et al. and Rivier for identification and quantitation of the alkaloids found in whole coca [An extensive review by Novák et al. details the previously studied biological activity of several of the alkaloids found in coca. Compounds reviewed include cinnamoylcocaine, benzoylecgonine, methylecgonine, pseudotropine, benzoyltropine, tropacocaine, ole coca , 8. HoweThe bulk of toxicology research is based on the pure isolate, cocaine, from coca leaves; therefore the extrapolation to the toxicity of whole coca is somewhat limited. However, of the studied biologically active alkaloids in coca, cocaine is the limiting factor in reaching a toxic dose. The physiologic effects of other alkaloids are considerably less than that of cocaine . A toxicIn comparison to modern usage of cocaine isolates, the amount of the drug used by native peoples was and remains quite low with an estimated 60 grams of coca leaf chewed per day . A coca In contrast, there is a large difference in what an average cocaine user is exposed to in modern times. A “line” of cocaine bought on the street contains an estimated 20–50 mg of cocaine hydrochloride . Modern The estimated minimum lethal dose of cocaine is 1.2 g . HoweverThe pharmacology of cocaine is complex with several organ systems affected simultaneously by the drug. Systems affected by acute and chronic use of cocaine include psychological, neurological, renal, cardiac, pulmonary, gastrointestinal, obstetrical, and otolaryngological ones. As mentioned in the toxicology data, medical and physiologic effects in the literature concentrate on the pure isolate cocaine. As outlined above, coca is quite different from cocaine, including common dosages and safety profiles. Local use patterns of coca are also quite different from that of individuals using the purer isolate, cocaine. Because of this, it is thought that cocaine studies have limited generalizability to coca. It is interesting to note that coca tea ingestion has resulted in a positive urine assay for cocaine metabolite . It is wCocaine serum concentrations are determined by the following: (1) dose; (2) route of administration; (3) binding to plasma proteins; and (4) rate of metabolism . Most phThe antiquity of coca use is well established through archaeological studies in South and Central America. Analysis of mummified human remains from Northern Chile indicates the use of coca as early as 1000 BC . These rUnder Incan rule, coca was used for numerous purposes, including ritual, social, and physiological uses . In 1532Interest in coca was prompted in the nineteenth century in Europe and the United States as discussed in an article by Dr. Weil . MantegaThe Euro-American enthusiasm for coca quickly cooled in the early twentieth century with the increasing concerns of the addictive properties and poor side effect profiles witnessed with the use of cocaine . Coca imThe South American Indians continue to rely on coca as a medicinal remedy in addition to its general usages for stimulant and social purposes . One of One of the usages of coca that continues to intrigue the medical community is as a remedy for dealing with the stresses of life at high altitude . Given tCoca chewing is thought to decrease the feeling of hunger in Andean peoples. Further investigation of this phenomenon has discovered that coca has effects on glucose homeostasis. Chewing coca leaves has been found to elevate blood glucose above the fasting level . This fiAs the drive to understand coca's place in Andean culture increased, there was a flurry of work to pin down the mechanism in which the benefits of taking coca existed. Specific to the realm of high altitude medicine, coca chewers report less head pain and dizziness associated with working at high altitudes , 42. FucAlthough previous work had shown that physiological adaptations to cold may be enhanced by coca use , 38, FucThe belief in coca as an uplifting agent for those individuals working in a high altitude environment is not without its naysayers. Many have argued that it is merely a “spurious correlation” between coca chewing and high altitude . Other tAnthropologists continue to examine patterns of coca use among natives to the Andean regions of South America in order to assist in the preservation of this ancient practice. Possession of coca is illegal in many countries due to one of its products, cocaine. International treatises have called for the destruction of all coca farming. Barring Bolivia and Peru, coca is now banned, even for indigenous use. Despite this ongoing controversy, some practitioners who span the cultural and medical divide have proposed the use of coca for contemporary ailments. Due to consumer demand for more natural forms of treatment, folk medicine may be considered in modern pharmacologic contexts. Possible uses could include gastrointestinal conditions, fast-acting antidepressant, treatment for acute mountain sickness, as an energizer for persons involved in physical labor, and symptomatic treatment of toothache and oral lesions . BecauseAlthough most of the theories produced by these scientists are based on observational and not experimental data, merit is to be given for attempting to understand a custom that has been ongoing for thousands of years. The pursuit of continued research from a physiologic or medical perspective will add to the respect of cultural traditions by trying them to give them a venue in which to thrive in our modern world.


Autism spectrum disorder (ASD) is a common comorbid condition in people with fragile X syndrome (FXS). It has been assumed that ASD symptoms reflect the same underlying psychological and neurobiological impairments in both FXS and non-syndromic ASD, which has led to the claim that targeted pharmaceutical treatments that are efficacious for core symptoms of FXS are likely to be beneficial for non-syndromic ASD as well. In contrast, we present evidence from a variety of sources suggesting that there are important differences in ASD symptoms, behavioral and psychiatric correlates, and developmental trajectories between individuals with comorbid FXS and ASD and those with non-syndromic ASD. We also present evidence suggesting that social impairments may not distinguish individuals with FXS with and without ASD. Finally, we present data that demonstrate that the neurobiological substrates of the behavioral impairments, including those reflecting core ASD symptoms, are different in FXS and non-syndromic ASD. Together, these data suggest that there are clinically important differences between FXS and non-syndromic ASD that are masked by reliance on the categorical diagnosis of ASD. We argue for use of a symptom-based approach in future research, including studies designed to evaluate treatment efficacy. Autism spectrum disorder (ASD) is a common comorbid condition in people with fragile X syndrome (FXS). The prevalence of ASD in FXS has been estimated at 50%, although there is considerable variability across studies . This hiIn trying to understand the FXS–ASD comorbidity, we have turned to five types of data. First, we have explored the individual symptoms leading to the diagnosis of ASD in FXS and the non-syndromic case; in essence, searching for evidence of similarities and differences in the symptom profile “earning” affected individuals the diagnosis. Second, we have examined behaviors and impairments that, although not part of ASD diagnostic criteria, are correlated with the diagnosis or correlated with autism symptom severity, again looking for differences and similarities between FXS and non-syndromic ASD. Third, we have explored the developmental trajectory of autism symptoms in FXS, comparing it to that in non-syndromic ASD, to discern similarities and differences between the two conditions. Fourth, we have sought to understand the symptoms and correlates distinguishing individuals with FXS who receive an ASD diagnosis from those with FXS who do not receive the diagnosis in an attempt to understand the nature of the difference between the two groups of individuals. Fifth, we have begun to consider the neurobiological underpinnings of ASD symptoms in FXS and in relation to the non-syndromic case.In this article, we focus largely on our own research; however, we integrate other published literature to illustrate points of convergence and divergence from our own data. Note, however, that the review is not exhaustive; instead, we are selective, with the aim being to illustrate the pitfalls of assuming the equivalence of a categorical ASD diagnosis in FXS and the non-sndromic case . We concIn any examination of the comorbidity of FXS and ASD, one must address the inherent confound of cognitive ability  with ASD symptomatology in FXS. In FXS, individuals with a comorbid ASD diagnosis have lower IQs, on average, than those without the diagnosis and this characteristic is present over the life course . QuantitThe fact that the relationship between cognitive ability and ASD symptomatology differs for FXS and non-syndromic ASD complicates any comparison between the two disorders because, on average, cognitive abilities are more limited in individuals with FXS than in individuals with non-syndromic ASD; for example, more than 90% of males with FXS have IQs in the range of intellectual disability  comparedFragile X Mental Retardation 1 (FMR1) premutation, who can exhibit autism symptoms while displaying average-range IQs. In the present paper, however, we focus on individuals with the FXS full mutation because there has been substantially more research on the ASD comorbidity in FXS than in the premutation case. Moreover, the prevalence of ASD is higher in individuals with FXS than in the premutation case  to chronological age-matched boys with ASD for whom FXS had been ruled out (n = 39), with the ASD diagnostic classification determined by the combined use of the Autism Diagnostic Observation Schedule  than did the boys with nonsyndromic ASD; however, significant differences emerged only for two items in the RSI domain , one item in the Comm domain , and two items in the RBS domain . Thus, despite earning an ASD diagnosis, young boys with FXS are more socially responsive, less likely to engage in an atypical communicative behavior thought to be a “signature” of ASD , and less apt to display some higher-order repetitive behaviors than boys with non-syndromic ASD. Interestingly, these differences emerged despite the fact that, as would be expected in an age-matched comparison, the participants with FXS had lower IQs, on average, than did the boys with non-syndromic ASD, although, as noted, all had IQs less than 85.n = 21 per group) that not only met diagnostic criteria for ASD but also were matched on the overall severity of their ASD symptoms, using calibrated severity scores from the ADOS  matched on chronological age, IQ (assessed with the Leiter), and ASD symptom severity on the ADOS using the metric introduced by Three findings of interest emerged. First, boys with FXS received higher mean scores, reflective of greater psychiatric problems, on Manic/Hyperactive Behavior and General Anxiety than did the boys with non-syndromic ASD. Interestingly, these same scales were higher for the boys with FXS in the analyses involving other matching strategies, indicating their ubiquity over the full range of the FXS phenotypes. Second, the scales of the ADAMS were, with few exceptions, highly inter-correlated for the age-, IQ-, and ASD symptom severity-matched boys with FXS, with the strongest correlations involving the General Anxiety scale. In contrast, for the matched boys with non-syndromic ASD, the significant inter-correlations were far more sparse, with the only significant correlation being that between Social Avoidance and Obsessive/Compulsive Behavior. Third, the correlation between General Anxiety and Social Avoidance was significantly stronger in the FXS group than in the age-, IQ-, and severity-matched non-syndromic ASD group. Other researchers also have found links between anxiety and behaviors reflective of social avoidance in FXS .It is interesting to note first that there were substantial differences between the FXS and non-syndromic ASD groups as regards psychiatric findings despite their equivalence in ASD symptom severity in the Other studies also have uncovered different patterns of correlations between autism symptoms and other behavioral problems in FXS and non-syndromic ASD. For example, Of course, there also are data suggesting similar patterns of correlation in FXS and non-syndromic ASD for some domains. Additional insight into the nature of the psychological impairments underlying ASD in FXS and non-syndromic ASD can be gleaned by studying the developmental course of ASD symptoms in the two conditions. More generally, In this vein, Considerable change was observed in severity of autism symptoms from the diagnostic reference age to the current age in the Unfortunately, neither It is interesting to note that the autism symptom improvement observed in individuals with FXS by Numerous studies, including several we have conducted, have been designed to understand the symptoms and correlates distinguishing individuals with FXS who receive an ASD diagnosis from those with FXS who do not receive the diagnosis , with ambiguous cases  excluded. After controlling for group differences in non-verbal IQ and chronological age, no statistically significant differences emerged on any of the language measures. The lack of group differences in language is rather surprising in light of the especially serious receptive language impairments often reported for individuals with non-syndromic ASD  to examine patterns of brain activation, we  examinedFragile X mental retardation protein is the protein product that is reduced or absent in FXS. FMRP levels  have generally been found to be correlated with the severity of a wide range of behavioral symptoms in both males and females and throughout the life course. Several studies have examined the relationship between FMRP and autism status or symptom severity.In the In short, the FMRP findings do not generally validate at the biological level the distinction between those with and without comorbid ASD or between those with less and more severe ASD symptoms. Nevertheless, it is important to acknowledge that FMRP has been shown to be a central construct in the control of several important neural pathways implicated in a number of disorders, including schizophrenia , and nonThe picture emerging thus far from our data is one in which there are important differences in the behavioral manifestations, behavioral correlates, and neurobiological substrates of ASD in FXS relative to non-syndromic ASD. Moreover, these differences suggest that the underlying psychological and neurobiological problems may be partly different in the two conditions. In particular, we have found that:1.Individuals with FXS who are diagnosed with ASD have less severe impairments in several of the social and communication symptoms that are diagnostic of ASD than do individuals with non-syndromic ASD, and these differences have emerged in a number of analyses and cohorts and across a variety of matching strategies. Even a hallmark symptom, such as pronoun reversal, distinguishes ASD in FXS and non-syndromic cases and is particularly interesting in light of the language and communication challenges experienced by males with FXS . At the 2.Individuals with FXS who are diagnosed with ASD also present with a number of comorbid problems that further distinguish them from individuals with non-syndromic ASD. In particular, problems with anxiety and hyperactivity are more severe in FXS than in comorbid ASD. Moreover, there is some suggestive evidence that these problems may be driving the emergence of social interaction difficulties that over the course of development create a profile of impairments that lead to the ASD diagnosis in individuals with FXS. Although problems in the domains of anxiety and hyperactivity occur in ASD , they do3.The developmental trajectory of ASD symptoms appears to differ between individuals with FXS and comorbid ASD and those with non-syndromic ASD. Although symptom abatement, at least during the late childhood and early adolescent years, occurs in both conditions, the improvements in communication appear more dramatic in FXS, although more prospective longitudinal data are needed to confirm this conclusion. The ASD symptom improvement during adolescence in FXS is occurring at the same time that cognitive development is actually slowing in FXS, a pattern not seen in non-syndromic ASD.4.Within-syndrome comparisons of individuals with FXS with and without a diagnosis of autism have uncovered differences that are not always consistent with expectations for the “essence” of ASD. On the one hand, individuals with FXS and comorbid autism have more severe receptive language problems than do their FXS peers without an autism diagnosis. On the other hand, these two subgroups do not differ in terms of the social impairments that represent the core deficit of autism, once differences in IQ are controlled, although the data are not consistent across studies in the regard. Replication is thus required.5.In terms of neurobiology, here too we see striking differences between FXS and nonsyndromic ASD in terms of brain structure as well as some more subtle differences in terms of brain function. At the same time, there are differences and similarities in brain structure as regards the distinction between individuals with FXS with and without comorbid ASD. Finally, FMRP does not appear to map strongly onto autism symptomatology in FXS.FMR1 gene and behavior, are needed to tie these differences at the behavioral level to underlying pathology so that we can arrive at a level of explanation that can guide treatment.Although these data strongly suggest that ASD is “not the same disorder” in the FXS and non-syndromic ASD populations, several caveats should be noted. First, in light of the clinical importance of a “mischaracterization” of the problem to be treated, the data we have presented are limited in many ways. Larger, more diverse, samples are needed to ensure that we understand the limits of generalizability of our findings. Examination of these issues across the entire life course is needed, and the samples studied must be enriched in terms of representation of females. Second, although the profile of relative impairments, relationships among impairments, and trajectories of impairment differ between individuals with FXS and comorbid ASD and individuals with non-syndromic ASD, there is considerable overlap, and not absolute difference. It is, however, premature to identify with any certainty the individual symptoms that are reliably common across the two disorders because of variations in sample characteristics and measures across studies and because a lack of differences between participant groups can often reflect limited statistical power. Nevertheless, the available data suggest that many communication impairments may be common across individuals with FXS and comorbid ASD and individuals with non-syndromic ASD , althougWe also note that part of the “confusion” about the comorbidity of FXS and ASD may be traced to reliance on the ADOS and the ADI-R. These measures work very well, and are the gold standards, for diagnosing ASD in non-syndromic individuals, which is the purpose for which they were designed. In the case of FXS (and perhaps other syndromes); however, the range of options for scoring might lead an impairment or unusual behavior to be scored as “autistic” because that is simply a better fit than a score reflecting unimpaired or typical. Perhaps a re-norming of these measures for FXS or the use of a coding scheme that allows finer distinctions to capture the difference between FXS and non-syndromic ASD impairments is needed.The most important implication of the findings considered in this article is that the use of the categorical diagnosis of ASD in FXS masks important differences within the syndrome and between the syndrome and non-syndromic cases of ASD. These differences that are masked by the diagnosis include both individual symptoms that could be the targets of treatments and the underlying mechanisms that can inform the nature of the treatment required.In conclusion, we still believe that the study of FXS can provide insights into non-syndromic ASD. As Leonard Abbeduto has received financial support to develop and implement behavioral outcome measures for fragile X syndrome clinical trials from F. Hoffman-LaRoche, Ltd, Roche TCRC, Inc., and Neuren Pharmaceuticals Limited. No other author has financial disclosures to make.Preparation of this paper was supported by grants R01 HD054764, R01 HD024356, and U54 HD079125, all from the National Institute of Child Health and Human Development.


The existence of an endophenotype of autism spectrum condition (ASC) has been recently suggested by several commentators. It can be estimated by finding differences between controls and people with ASC that are also present when comparing controls and the unaffected siblings of ASC individuals. In this work, we used a multivariate methodology applied on magnetic resonance images to look for such differences. The proposed procedure consists of combining a searchlight approach and a support vector machine classifier to identify the differences between three groups of participants in pairwise comparisons: controls, people with ASC and their unaffected siblings. Then we compared those differences selecting spatially collocated as candidate endophenotypes of ASC. Autism Spectrum Condition (ASC) is a lifelong neurodevelopmental condition affecting approximately 1% of population  is a medical imaging technology that allows detailed visualization of the internal structures of the body. It has been widely used in the neurosciences, including in many studies of ASC. For example, in Sears et al.  from controls and unaffected siblings of ASC individuals. Another univariate approach was used in Salmond et al.   is a recently described methodology based on multivariate pattern analysis (MVPA) that address the small sample size problem by dividing the brain volume into small regions of just a few voxels  had a diagnosis of ASC, either classic autism or Asperger syndrome, 40 participants were unaffected siblings of individuals with ASC. Forty (40) controls with no family history of ASC were also recruited. Demographic details are gathered in Table Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria  operating at 3T. High-resolution T1-weighted three-dimensional magnetization-prepared rapid acquisition gradient-echo (MP-RAGE) structural images were acquired with the following parameters: slice thickness = 1 mm; All MRI datasets were first segmented into their component tissues (gray and white matter) and then normalized to a standard stereotactic space of the Montreal Neurological Institute (MNI) using SPM software  have recently attracted the attention of the pattern recognition community because of the merits derived from statistical learning theory Vapnik, , 1998 def: RN → {±1} using the training data  so that f is able to predict the label y of a new example x. The computation of function f is based on the calculation of a hyperplane, called the maximal margin hyperplane, that has the largest distance to the closest training data point of any class. Then, this hyperplane is used to classify new data points of unknown class. Formally, the decision hyperplane is defined as:w is the weight vector, orthogonal to the decision hyperplane, and w0 is the threshold. When no linear separation of the training data is possible, SVM can work effectively in combination with kernel techniques so that the hyperplane defining the SVM corresponds to a non-linear decision boundary in the input space , but it is performed over small regions and then the result obtained for a region is assigned to all the voxels in that region. We defined as many regions as voxels resulting in a high rate of overlapping and allowing for exhaustive exploration of the image space. Cubic regions with a side of 5 voxels were used, leading to regions containing 125 voxels.k-fold cross-validation (CV) scheme along with a SVM classifier to estimate the accuracy of classifying the images in the two groups. A high accuracy rate indicates that the analyzed region contains large differences between the two groups. On the other hand, a low accuracy rate, about 50%, suggests only small differences. The classification procedure used a linear kernel along with the SVM classifier  and estimated the accuracy rates by means of CV, which is an effective method for estimating the risk of a classifier  were discarded.Subsequently, the significance of the accuracy obtained with each region was assessed with a non-parametric test. This additional test consisted of repeating 1000 times the same classification procedure but using random labels. In this way we were able to estimate the probability that an accuracy rate was obtained by chance Good, . A p-val Miller, , a false Miller,  was applincluded that voxel. The pseudocode for the searchlight procedure is shown in Algorithm Finally, we assigned to each voxel the highest accuracy rate obtained for all the regions that The experiments were performed in three steps: First, we estimated the locations with different patterns in controls and ASC participants using the multivariate approach described in section 2.2. Secondly, we followed the same procedure to differentiate between controls and unaffected siblings of ASC participants. Finally, we estimated the similarities between the two maps computed in previous steps by finding the regions of significant difference common for both. The result of the first two steps is shown in Figure In order to test if regions marked as common for both classifications indeed have the same pattern, an additional experiment was performed. For each significant region in the first classification, a SVM classifier was trained using controls and ASC participants, and the positive rate (percentage of ASC correctly classified) was then estimated through CV. Subsequently, the sibling data was evaluated with that trained classifier. For about 20% of the regions, the number of ASC individuals correctly classified as such was approximately the same  as the number of siblings classified as ASC. This reveals the existence of a common pattern for ASC and siblings in those regions and strengthens the suggestion that they are endophenotypes of ASC. Figure Regardless of the regional analysis it is reasonable to expect that classification of controls vs. ASC participants would achieve higher accuracy rates than classification of controls vs. siblings of ASC participants. After all, the siblings have not developed the condition and should be more similar to controls and thus separating these groups should be expected to be relatively more challenging. However, our experiments indicate the converse. Figure The results presented above demonstrate that structural differences exist in gray matter maps derived from neuroimaging data comparing controls and ASC participants, as well as between controls and unaffected siblings of ASC individuals. In the first case the regions containing differences are mainly located in temporal gyrus, cerebellum, right cingulate gyrus, right precuneus, left occipital and vermis, whereas differences for the second comparison are mostly located in cerebellum, left frontal gyrus, right temporal gyrus, left lingual gyrus, left occipital, and insula (a complete list of the regions is shown in Table 3 were found in this region). Smaller vermis volume in ASC participants than in controls was found in Kilman et al. (The vermis is also a candidate region as a neuroendophenotype of ASC (group differences in both ASC compared to controls and siblings compared to controls covering 23 mmn et al.  and, morn et al. . Figure Other previous works that looked for neuroendophenotypes of ASC reported that the amygdala was smaller in adults with ASC relative to the unaffected parents of children with ASC and age-matched controls (Rojas et al., In general, it worth noting that an important part of the regions highlighted in our analysis and enumerated in Table The results presented also suggest that our initial hypothesis on the enhanced ability of multivariate approaches to finding differences between groups of neuroimaging data is substantiated. The proposed method found significant differences in a dataset in which VBM had previously found no significant differences at levels of significance controlling for multiple comparisons. Furthermore, the locations of the observed differences match those reported by univariate studies using other, larger datasets.Finally, some considerations about the size and shape of the regions, and the manner of exploration associated with the searchlight approach can be drawn. The original searchlight approach proposed by Kriegeskorte et al.  used sphWe have presented an original analysis of MRI images by means of a multivariate approach in order to identify candidate neuroendophenotypes of ASC. To this end, we first looked for differences between controls and ASC participants, and then compared these differences to those resulting from comparing controls and unaffected siblings of ASC participants.The main novelty presented in this study is the algorithm used in the discovery of those differences: a multivariate approach that consists of performing an exhaustive examination of the brain space by means of a searchlight methodology combined with a support vector machine classifier.The results reported here indicate that differences in cerebellum, parietal lobule, left occipital, left angular gyrus and, to a lesser extent, other regions listed in Table 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.


It seems to be an exciting moment for the ASEAN countries to enter the era of the ASEAN Community. For the ASEAN 600 million people (8.6% of the World population), this regional initiative is expected to bring about economic prosperity and development in socio-cultural well-being of the people. However, development policies do not always complement one another as we promote economic growth and improve quality of life of the people. As part of the ASEAN Social and Cultural Community (ASCC) to promote equity in healthcare access across the region, the progress towards universal health coverage (UHC) becomes a key challenge. Different countries are at different stages of UHC development . I agreeThe health coverage for migrants should also be focused. As the AEC would promote economic prosperity of the region, it could be expected that labor migration would continue. Cross-border health services and migrant workers – both documented and undocumented – could considerably increase service workloads for providers in the receiving countries. Although they might become income opportunities for some hospitals in certain well-to-do areas, the uninsured frequently result in uncompensated care in public hospitals , 5. The The ASEAN integration and its impacts on health services, particularly on health coverage for the population, is obviously a challenging situation. Given the diversity among the ASEAN countries, policies on health services and health coverage after the ASEAN integration should be carefully planned such that every nation can benefit. There are choices for approaching UHC in terms of whom to be covered, what services to be covered and at what level of payment. In light of the constraints, we may need building blocks and roadmaps that could align the region and each ASEAN country. Still, the key is collective commitment among the ASEAN members in income and wealth distribution, and health equity. To make it financially feasible for ASEAN, I would like to propose that ASEAN starts UHC with the coverage for selected basic health services for everyone, such as traffic accident and some epidemic-prone communicable diseases, rather than beginning UHC talk focusing on coverage for everything for selected groups, or UHC for all of the population. The step-by-step approach helps ensure the minimal standardized package of UHC for all ASEAN countries to address critical public health issues, allows for insurance portability, and makes it practical to manage reimbursement. This also helps address the issue of health coverage for undocumented migrants.


Clostridium perfringens by the use of microbes or microbe-derived products. Microbes produce a plethora of molecules with antimicrobial properties and they can also have beneficial effects through interactions with their host. Here we review recent developments in novel preventive treatments against C. perfringens-induced necrotic enteritis in broiler chickens that employ yeasts, bacteria and bacteriophages or secondary metabolites and other microbial products in disease control.Since the 2006 European ban on the use of antibiotics as growth promoters in animal feed, numerous studies have been published describing alternative strategies to prevent diseases in animals. A particular focus has been on prevention of necrotic enteritis in poultry caused by  Clostridium perfringens is a spore-forming, anaerobic, Gram-positive bacterium, found in the environment and also in the gastro-intestinal (GI) tract of humans and animals , especially in pigs and poultry , recently reviewed by Uzal et al. , which took effect in January 2006, alternatives to antibiotics became essential in order to prevent NE occurrence and the consequent economic losses for the poultry industry. Preventive treatments can take the form of actions on predisposing factors, such as coccidiosis prevention, diet modifications, or improving overall cleanliness and hygiene. Alternatively they can directly target the causal agent of the disease by controlling the proliferation, colonization and persistence of virulent strains of C. perfringens or interfering with virulence and pathogenicity factors , plants  of chickens with NE often prevents the treatment of the disease. Antibiotics have been commonly used worldwide as growth promoters and for prophylactic treatment of C. perfringens and NE in poultry  and to prevent or reduce the incidence of diseases caused by pathogenic bacteria , which were active at low concentrations  with activity against C. perfringens in vitro   from pig intestines that had antagonistic action against C. perfringens, with an L. amylovorus strain presenting properties amenable to be a potential probiotic candidate  are also very good probiotic candidates, as they display antimicrobial activities, but also have beneficial effects for the host. Cao et al.  showed tin vitro studies that report the isolation of potential probiotic strains almost always test the strain for their ability to survive in the host and exert their action in vivo, through assessment of acid and bile resistance, auto-aggregation and adhesion to epithelial cells. A strain of Lactobacillus species that reduced C. perfringens numbers in chickens was shown not to affect the commensal flora . This strain was able persist in the chicks for the duration of the experiment, caused a reduced colonization by C. perfringens after 15 days, although no direct anti-C. perfringens activity was evident in vitro  was originally described by Nurmi and Rantala in 1973, when feeding young chicks with bacteria isolated from a healthy adult chicken prevented colonization by Lactobacillus, Streptococcus faecalis, S. faecium  and Bacteroides hypermegas  in combination with a prebiotic  and observed a reduction of mortality by half compared to the untreated animals, with effects comparable to those of bacitracin  and had improved performance (measured by body weight gain and feed conversion ratio), which are consistent with the known beneficial effect of yeast extract on broiler performance. Moreover, the animals treated with Saf-Mannan had a 5 log reduction of C. perfringens numbers in the small intestine in comparison to the untreated animals  that was highly active against C. perfringens in vitro (MIC = 75 μg/ml)  of 12 kDa, which was active under the physiological conditions expected in the GI tract  . Nanoparticles could also be used as vectors for delivery of these new antimicrobial molecules, thus avoiding the expression and regulatory issues that arise with the use of live cells and GMOs.A number of studies have now shown that the use of live micro-organisms and molecules produced by microbes represent potential alternatives to the use of conventional antibiotics for the prevention of C. perfringens molecule and a prebiotic product would constitute a robust formulation that could prevent the overgrowth of C. perfringens in vivo and maintain a healthy GI tract flora at the same time.It is difficult to identify a single “ideal” solution within this wealth of options for NE disease control. Several microbes and molecules of microbial origins, some already available commercially, represent promising agents that conceivably could be used in conjunction with one another to formulate highly effective synergic antimicrobials. For example, a product consisting of a CE culture, a probiotic strain producing a targeted anti-C. perfringens and other bacteria are highly adaptable micro-organisms. It is thus of high importance to develop and use products in a rational manner in order to avoid the appearance of strains resistant to these novel antimicrobials, as has occurred with conventional antibiotics.Several criteria must be taken into account when developing feed additives or preventive treatments for the animal industry. The financial cost of the product is a major criterion, especially for small animals with low market value, like broiler chickens. A thorough genetic characterization of candidate strains is essential in order to confirm the safety of the bacterial strain and ensure the lack of virulence and antibiotic resistance genes. The chosen molecule or strain must be able to stay active in the host and withstand industrial treatments. One must also keep in mind that the GI tract is a highly complex environment with numerous bacterial species that can affect the efficacy of these antimicrobials, perhaps in a different manner from one animal to another. Moreover, DC, RD, EA, and DD contributed to the conception and the design of the review and researched and wrote the review.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.


Due to rapid changes of technology and scientific advances in health systems and need for fast planning in health care, entrepreneurial spirit among employers and employees is a crucial element. According to the field of entrepreneurship research has not been solved and where learning and innovation for healthcare organizations due to the nature of the work required.This study aims to examine the entrepreneurial activities within the hospitals affiliated to Tehran University of Medical Sciences, Iran. To achieve the aim of the study, a questionnaire containing 29 items regarding the areas of innovation, creative behavior, flexibility, empowerment, rewarding systems and the management support was distributed among the hospitals’ managers. Establishment of a culture of entrepreneurship in healthcare organizations led to the development unit controlled, changing the culture of the hospital.The analysis of the data showed that the majority of the managers agreed with all five areas of entrepreneurship namely the existence of innovation and innovative behavior, flexibility, decision making, rewarding and encouraging system, as well as management supportive system of personnel’s new ideas. In fact, the managers generally had positive attitude towards entrepreneurship in their organizations The Pearson correlation test also showed that there is a significant relationship between the areas of entrepreneurship and the managers’ age as well as their working experience (P<0.05).Entrepreneurial activities in healthcare can be improved through providing a suitable environment, adjusting reward and encouragement systems, giving more authority to subordinates, promoting awareness and education, and mobilizing managers to attract appropriate opportunities for organization. Further active involvement of employees, more stable in front of changes and increased ability managers to capture opportunities in domestic and foreign situation. Today, organizational environment is so complex and uncertain that institutions can no longer survive through superficial changes such as changes in the method, system and structure . In the Entrepreneurship is a significant source of social mobility that covers various subjects, but the problem is that many areas of entrepreneurship in research are still virgin . Some stLearning and innovation are fundamental requirements for organizations that are seeking effectiveness and survival. Many organizations are also looking for highly innovative and entrepreneurial approaches to improve their effectiveness, efficiency and flexibility . Based uDue to rapid changes in technology and scientific advances among health care provider organizations, determining the future needs and planning them appropriately are very difficult. Health care systems like other economic organizations in the world are very complex and chaotic in which traditional approaches no longer apply. Lack of accurate planning and management in these systems will limit the expectations and creativity which is required to solve complex and new prospective problems of health care. Accordingly, for the conservation and sustainability of the organizations in the era of development and reconstruction of health care systems, innovation and entrepreneurship are a prerequisite .Factors such as increasing costs of services, competition, expensive equipment, old population and high cultural diversity affect health services environment. Healthcare related organizations exposed to these challenges are more complex; therefore, they seek solutions for their long-term survival. Achieving such solutions wont be possible without change, innovation and an entrepreneur attitude . DiffereThis cross-sectional study was conducted among senior and middle managers in 10 selected hospitals affiliated to Tehran University of Medical Sciences (TUMS), Iran. Study population was all senior and middle executives, including chairmen and chief executives, directors of hospital financial departments, directors of administrative-support departments, senior supervisors, as well as training and clinical supervisors in the hospitals affiliated to TUMS. Ten hospitals were randomly selected from among all 26 hospitals affiliated to TUMS. Data collection tool was a reliable and validated questionnaire consisting of two main parts. The content validity and face validity of the questionnaire were checked by two experts in the field based upon two designed forms . Moreover, to see the internal reliability of the questionnaire, Cronbach’s alpha coefficient was calculated. The coefficient was found to be 0.77 . The obtThe first part of the questionnaire deals with the respondents’ demographic information including age, sex, years of working experience and education level. The second part included 29 items in the areas of innovation, creativity, flexibility, empowerment, reward systems and the management support. The items were designed on a five-point Likert scale of agreement, where 1 = strongly disagree, 2 = disagree, 3 = undecided, 4 = agree, and 5 = strongly agree. While distributing the questionnaires, more explanations were given to the respondents regarding the aim and scope of the study, as well as how the questionnaire should be filled out. Furthermore, if the respondents were interested in the research results, they were assured that the findings will be sent to them after analyzing the obtained information. Moreover, the respondents were given enough time to fill out the questionnaire. At the end, the collected data was entered into the SPSS software, version 18, and then data analysis was performed using the t-test, two-way ANOVA and Pearson correlation test.This study was conducted in 10 hospitals affiliated to Tehran University of Medical Sciences. In total, 120 questionnaires were distributed among the managers but 95 questionnaires were returned. About 70 % of the respondents were female and the rest of 30 % surveyed managers were male. The age distribution showed that about half of the surveyed managers were in the age range of 40-49 (45.6%). Most of the respondents had bachelor’s degree and they had managerial experience between 10 to 20 years see .The results showed that the majority of the managers agreed with all five areas of entrepreneurship namely the existence of innovation and innovative behavior, flexibility, decision making, rewarding and encouraging system, as well as management supportive system of personnel’s new ideas. In fact, the managers generally had positive attitude towards entrepreneurship in their organizations see .The t-test did not show any significant relationships between the managers’ gender and the areas under investigation. The Pearson test showed that, except for the second area namely level of flexibility, there is a significant relationship between managers’ working experience and the areas under investigation see .The Pearson negative value indicates a negative relationship between the areas under investigation and the managers’ working experience. In other words, younger managers agree much more with entrepreneurship within their organizations.In this area, less than half of the respondents (46.52%) agreed with the innovation and innovative practices in their organizations. However, about one-fifth of the surveyed managers (21.12%) disagreed with this level of entrepreneurship in their organizations. Therefore, this factor can be regarded as an important factor in entrepreneurship in the hospitals. The results of this study are in accordance with the findings of Reisi et al. (2008) in which they found that creativity and innovation are effective factors in entrepreneurship. Moreover, In this area, more than half of the surveyed managers (55.60 %) agreed with the flexibility in their organizations. Sean (2005) also referred to a direct relationship between flexibility and improvement of organizations’ performance and considered it as an effective factor in innovation and doing innovative practices. The concept of flexibility in the last decade has attracted a great deal of researchers’ attentions. This concept has been defined as the organization’s ability to respond to the diverse demands of its dynamic competitive environment . AlthougIn the area of considering empowerment as an encouragement to the employees, about two-third (63%) of the respondents agreed to give authority to managers and lower level employees. In his study, With regard to the hospitals equipped with rewarding and encouraging systems for the entrepreneurial ideas, less than half of the surveyed managers (45%) welcomed the presence of this system. However, 22.13% of the respondents disagreed with this system in the hospitals. In general, rewarding system in entrepreneurial organizations has its own characteristics. Practicality and feasibility of the considered reward is one of them. For example, bonuses considered for the employees should be payable. The rewards should also be available for the employees. In this regard, various incentives should be employed. Both financial and non-financial incentives are important, but more intrinsic encouragements should be used . Sykes aIn this area, less than half of the surveyed managers (45.39 %) believed in the presence of management supportive system of personnel’s new ideas in their organizations. According to Paolini (1991), supporting the personnel is considered as one of the five major steps of entrepreneurship development process within organizations. In his study, In their study, It can be concluded that the more hospitals’ managers strengthen the characteristics associated with entrepreneurship by giving value to their entrepreneurial ideas, the better they can develop entrepreneurial activities within their respective hospitals. This also leads to more staff participation within the hospitals. The process of entrepreneurial activities can be improved by changing the culture of hospitals through providing a suitable environment for creative people, creating a system of reward and encouragement, giving more authority to subordinates, promoting personnel’s awareness, training the personnel in the field of working values and responsibility, and increasing managers’ ability to absorb appropriate opportunities for organization. In the areas such as healthcare services, organizations can be more irresponsive against changes, because the entrepreneurial organization is an organization that is capable to strengthen creativity and innovation according to environmental changes and structural complexity. In organizational entrepreneurship, the structural dimensions are regarded as the important issues that seriously prevent the spread of entrepreneurship and act as a barrier against the employees. Several studies have shown that there is a negative relationship between entrepreneurship and complexity in the organization because complexity reduces the relationship among the group members within the organization. Moreover, there is a negative relationship between entrepreneurship and formality because the personnel’s formality reduces the flexibility and freedom within an organization. For creating entrepreneurial activities within the organizations such as the hospitals, it is required to remove the barriers, such as structural complex aspects. Bureaucracy in organizations must be at the lowest level; however, due to the existence of bureaucracy in most of the Iranian organizations, it may be a little hard to imagine basic change in their structures. Nevertheless, in order to keep pace with the changes, particularly the global changes, considering the above mentioned entrepreneurial activities and their interactions seems inevitable.


In 2009, the Chinese government launched a national healthcare reform programme aiming to control healthcare expenditure and increase the quality of care. As part of this programme, a new drug pricing reform was initiated on 1 June 2015. The objective of this study was to describe the changing landscape of drug pricing policy in China and analyse the potential impact of the reform.The authors conducted thorough research on the drug pricing reform using three Chinese databases , Chinese health authority websites, relevant press releases, and pharmaceutical blogs and discussion forums. This research was complemented with qualitative research based on targeted interviews with key Chinese opinion leaders representing the authorities’ and prescribers’ perspectives.With the current reform, the government has attempted to replace its direct control over the prices of reimbursable drugs with indirect, incentive-driven influence. Although the exact implementation of the reform remains unclear at the moment, the changes introduced so far and the pilot project designs indicate that China is considering adaptation of some form of internal and external reference pricing policies, commonly used in the Organisation for Economic Co-operation and Development countries. Several challenges related to the potential new mechanism were identified: 1) the risk of hospital underfunding, if hospital funding reform is not prioritised; 2) the risk of promoting the use of cheap, low-quality drugs, if a reliable quality control system is not in place and discrepancy between the available drugs is present; 3) the risk of increasing disparity in access to care between poor and rich regions, in case of country-wide price convergence; and 4) the risk of industry underinvestment, resulting in reduced competition, issues with quality and sustainability of supply, and potentially negative social impact.Foreign pricing policies cannot be transferred to China without prioritising historical, cultural, and economic contextualisation. Otherwise, the new policy may be counterproductive and affect the whole healthcare chain, as well as the health outcomes of Chinese patients. At the same time, total healthcare spending as a proportion of gross domestic product (GDP) increased by only one percentage point – from 4.6 to 5.6% (0.07% per year on average) . For other Asian countries, like Japan and South Korea, the relevant numbers were also substantially lower – 20.6 and 25.1%, respectively   initiate015 No. 9The objective of this article was to describe the changing landscape of the drug pricing policy in China, including future trends. In addition, this study aimed to analyse the potential impact of the reform on various healthcare stakeholders, essentially on patients and their access to pharmaceuticals, and put it in the context of international experience with reference pricing.www.cnki.net), Wanfang Data (www.wanfangdata.com.cn), and Weipu (www.cqvip.com). In order to retrieve only the most recent and relevant articles, we applied a time limit of 1 January 2012 and used additional keywords limiting the results to China-related articles (see Supplementary Table 2). The database search was performed on 17 April 2015. In addition to the databases, we searched Internet resources: Chinese government and healthcare authority websites , the grey literature, relevant press releases, blogs, and common pharmaceutical discussion forums. An additional search was concluded by the end of April 2015. We developed an extraction table to ensure all relevant information was organised in a format that was easy to access and analyse. For redundant information we saved the most reliable source, applying the following ranking for reliability of sources: healthcare authority website, scientific article, official newspaper, press release, blog, discussion forum. Information was consolidated and reported initially as a PowerPoint presentation.As the first step, we conducted thorough research aiming to collect all publicly available information related to the current Chinese drug pricing reform and pilot programmes. We used the keywords ‘pricing’, ‘reimbursement’, ‘policy’, and ‘reform’ to search the three main Chinese databases: China National Knowledge Infrastructure  representing either the authorities’ or prescribers’ perspectives. The interviews aimed to fill the information gaps after the secondary research and to understand appreciation of the current pricing reform among relevant stakeholders. We designed two questionnaires: one for the authority representatives and another for prescribers. Both questionnaires contained three main sections aiming to do as follows: 1) obtain interviewees’ insights on the general environment of the reform; 2) validate information collected through the secondary research and fill information gaps; and 3) obtain interviewees’ opinions on the future drug pricing approach. The authorities’ questionnaire contained, in addition, a section aiming to collect interviewees’ insights on the international experience in drug pricing and its potential applicability to China. We interviewed nine KOLs in total: six authority representatives and three prescribers (see Supplementary Table 3 for the interviewees’ profiles). All interviews took place between 20 and 25 May 2015. They were conducted in a one-on-one fashion, during face-to-face meetings, or over the phone and lasted on average 1 hour each. The interviewees’ answers were combined with the results of the secondary research in order to provide the most comprehensive overview of the current situation in China and an appreciation of the forthcoming changes.Finally, at the stage of preparation of the manuscript, additional interviews were performed to clarify all outstanding issues, and secondary research was updated on 26 June 2015. The results were split between the national pricing reform concept and pilot programmes that were already implemented or announced.reimbursement standard was provided in the announcement and, at the time of writing, Chinese local administrative divisions had autonomy to apply their own methodology before introducing final regulations at the national level . For these products retail prices will be established by multilateral negotiations involving the pharmaceutical industry and other stakeholders. For blood products not included in the HIF and drugs procured and subsidised by the government , retail prices will be generated either through tenders or established by negotiations. However, the announcement did not specify the framework for price negotiations. The local tendering system was not abolished by the new law. Therefore, at least at the moment, the prices of most drugs are still affected by the competitive local bidding process.At the beginning of May 2015, the NDRC announced implementation of changes to the current pricing model with effect from 1 June 2015 . The coral level . ReimburChina is currently running several pilot projects to inform the implementation of the drug pricing reform.Sanming – a prefecture-level city in Fujian Province (South of China) – is piloting a form of IRP for drugs with the same active ingredient and dosage form. The reimbursement standard is set at the procurement price of the cheapest generic from the group and patients are liable to cover an excess amount in addition to any other applicable co-payment .The pilot was introduced on 1 June 2014 and follows a series of earlier local policy changes aiming at increasing the use of generics, reducing malpractice and overprescription, and optimising the use of the healthcare budget. It was initiated in 22 public hospitals and applied to 16 top-prescribed molecules and dosage forms. According to the initial announcement, the selected drugs were supposed to display ‘a minimal difference in terms of quality and a big difference in terms of price’ (5)  . This wa5) . Some hiChongqing – the municipality directly under the Central Government (Southwest of China) – announced the initiation of the drug pricing pilot project on 1 January 2015 . HoweverDifferent piloting approaches have been under discussion since the time of announcement , 25. BasIt is expected that most locally produced generics, which are normally much cheaper than imported off-patent originals, will enter Scenario 1. It was not explicitly stated in the announcement, but it seems that the difference between the actual procurement price and the reimbursement price will constitute the hospital's profit. The patients’ co-payment will be the same regardless of the product they are prescribed, because it will be derived from the relevant NAPP. Imported drugs and drugs previously under individual pricing will more likely enter Scenario 2 . If theiThe methodology of the Chongqing pilot project is perceived as complicated and sensitive to the potential lack of pricing data from other local areas, which is required for calculation. The impact upon its actual implementation is still yet to be seen.Shaoxing – a prefecture-level city in Zhejiang Province (Northeast of China) – is piloting an approach called ‘second price negotiation’, which allows hospitals to negotiate discounts directly with suppliers . Local pth People's Hospital discontinued or limited the use of 14 drugs, most of them being imported products from multinational companies   .Shaoxing is not the only city piloting the second price negotiation. The province of Anhui initiated a similar project in March 2015, with the difference that the discounts obtained through negotiation are to be awarded directly to the involved hospitals . Until JThe reform lacks systemic design and adequate supporting policies.Clear regulations for introduced changes and coordination mechanisms between responsible bodies are not established.The quality of generic drugs is not ensured.The Chinese pharmaceutical market in China is not mature.The change in the pricing paradigm was perceived by the interviewed KOLs as a step towards a market economy and a more efficient healthcare system; however, they reported several challenges and concerns:Appreciation of different piloting approaches varied. In general, the Chongqing approach was more widely supported and considered suitable for China countrywide; however the methodology for the reimbursement standard calculation was considered too complicated and potentially limited by lack of data from other local areas required for calculation. Setting the reimbursement standard at the average rather than at the lowest procurement prices was considered more appropriate. In addition, in contrast with Sanming, the Chongqing approach was perceived as taking into account differences in drug quality and price levels . The second price negotiation was considered an approach that can temporarily decrease drug prices but can be harmful in the long term as it may generate the risk of corruption.When asked about their insights on the international experience in drug pricing and its potential applicability to China, KOLs judged that ‘setting IRP groups for drugs with the same active ingredient and setting the reference price at the average price of drugs from the group’ was the most applicable and relevant approach for the Chinese market. Some of them were also in favour of setting an average price at ‘weighted average’. Most of the KOLs expressed that ‘using ERP to set prices of reimbursable drugs not included into the internal reference price group system’ was relevant and applicable to China (see Supplementary Table 6). The interviewees did not indicate any specific country that China could or should follow.With the current reform, the Chinese government attempts to replace its direct control over the retail prices of reimbursable drugs with a more indirect influence. The abolishment of GP and GGP for most pharmaceuticals gives manufacturers, in theory, more freedom to set retail prices. However, in practice, prices are expected to continue to be constrained mainly by tenders and other factors, such as hospital budgets and controlled reimbursement levels. To maintain an indirect influence over drug prices, the government seems to consider adaptation of some form of the IRP or ERP policies commonly used in the OECD zone. Implementation of the reimbursement standard as a tool to guide the market prices of drugs included in the HIF clearly resembles IRP policies successfully practised in Germany, the Netherlands, Denmark, and many other foreign countries. Comparison with prices of the same drug in other local areas  bears some characteristics of ERP. However, in this case, the comparison does not involve foreign countries, as per the definition, but other big and relatively autonomous areas within the same country. The role of the second price negotiation in the overall process remains unclear at the moment; specifically, it is unknown if it could be considered as the only pricing tool or if it would be used in conjunction with other mechanisms, like IRP or ERP.Many elements of the new drug pricing reform remain unknown and will likely depend on the pilot project outcomes. Nonetheless, based on current knowledge and our understanding of the government's main assumptions underlying the reform, we undertake an attempt to predict and discuss its potential impact in terms of challenges and consequences.An important characteristic of the Chinese system is that most healthcare utilisation – in some cases even 80% – occurs at the hospital level . MoreoveIn contrast, second price negotiation seems to be contradictory to the goal of reducing reliance on drug sales and reinforcing the non-profit nature of public hospitals. It may be seen as an alternative way to generate revenue after introduction of the zero mark-up policy, providing hospitals are directly granted the discounted amount.Another important issue in China is the therapeutic interchangeability of drugs –39. The The Chongqing pilot suggests that the new pricing strategy may involve a comparison with other local areas to set or adjust the reimbursement standard. Given the size and administrative structure of China, this approach bears some characteristics of ERP policies practised by many foreign countries, although the comparison is being made within the same country. It has been suggested that ERP, through its spillover and circular (re-referencing) effect, leads to convergence of prices across countries , 18, 19.Finally, IRP policies are recognised as effective cost-containment tools, reinforcing price competition and favouring generic penetration –17. ThisThe results of this study should be interpreted in the context of its limitations. The current situation in China is very dynamic. Limited information is available. The universal healthcare system reform initiated in 2009 targets different sectors, and changes to the pricing paradigm are one of many. This adds complexity to the overall situation. Therefore, the pricing reform should be seen as an evolving process and its future ‘shape’ is to be further investigated.Although many elements remain unknown and will likely depend on the pilot project outcomes, we are already able to identify the critical assumptions underlying the reform: creating incentives for hospitals to be more efficient in managing drug expenses and treating all products with the same active ingredient as equivalent in terms of quality, efficacy, and safety. However, with hospitals economically depending on profit generated from drug sales and drug quality issues, these key foundations of the reform may distort the piloting exercise and lead to biased conclusions. The risk of hospitals underfunding does not seem to be adequately balanced and the quality assurance system is still under development despite the fact that it has been improving. Moreover, comparison with other local areas, understood as a form of external reference pricing, may have potentially deleterious consequences on supply and equity towards poorest regions. Abolishment of GP and GGP, as such, is not expected to affect drug prices, as other mechanisms of price control remain in place. Some elements of the reform seem not to be well aligned or even contradictory, like introduction of the reimbursement standard and maintaining the tendering system. This indicates that, given complexity of the market, foreign pricing policies cannot be transferred to China without being properly adjusted for local healthcare specificities.A comprehensive and consistent reform that integrates the full chain of healthcare services delivery, including pharmaceuticals, is required. Finally, the current hospital-centric system should evolve towards a more patient-centric approach. This will likely lead to a reduction of the hospital role in the overall system compensated by a light, decentralised, agile and effective ambulatory care unit and office-based medical practice. Such change would significantly reduce management costs and allow allocation of the current heavy administration cost to healthcare services and pharmaceuticals.Click here for additional data file.