The emotional consequences of patient deaths on physicians have been studied in a variety of medical settings. Reactions to patient death include distress, guilt, and grief. Comparatively, there are few studies on the effects of patient death on physicians and residents in the Emergency Department (ED). The ED setting is considered unique for having more sudden deaths that likely include the young and previously healthy and expectations for the clinician to return to a dynamic work environment. To date, no studies have looked at the effects of patient deaths on the more vulnerable population of medical students in the ED. This study examined aspects of patient deaths in the ED that most strongly influence students’ reactions while comparing it to those of an inpatient setting.Semi-structured qualitative interviews were carried out with a total of 16 medical students from the American University of Beirut, Medical Center in Lebanon who had recently encountered a patient death in the ED. Questions included their reaction to the death, interaction with patients and their family members, the response of the medical team, and coping mechanisms adopted.The analysis revealed the following as determinant factors of student reaction to patient death: context of death; including age of patient, expectation of death, first death experience, relating patient death to personal deaths, and extent of interaction with patient and family members. Importantly, deaths in an inpatient setting were judged as more impactful than ED deaths. ED deaths, however, were especially powerful when a trauma case was deemed physically disturbing and cases in which family reactions were emotionally moving.The study demonstrates that students’ emotional reactions differ as a function of the setting (surprise and shock in the ED versus sadness and grief in an inpatient setting). Debriefing and counseling sessions on ED deaths may benefit from this distinction.The online version of this article (doi:10.1186/s12909-017-0945-9) contains supplementary material, which is available to authorized users. Medical professionals dedicate their lives to the treatment of patients in an attempt to cure, all the while knowing that any cure is temporary. Despite being a prevalent experience, a relatively small number of studies have shed light on death’s emotional effects on physicians . PerhapsStudies addressing the effects of death on physicians in the emergency department (ED) are similarly minimal. It is recognized, however, that the ED is a unique setting: there is generally no previously established relationship between the patient and the physician, deaths are likely to be sudden, and could include the young and previously healthy. Moreover, after a death, ED physicians are often expected to function in a dynamic work environment almost immediately, care for other patients, and handle a grieving family . Deaths One study found that 28% reported they sometimes considered quitting their jobs, 32% changing professions, and 14% seeking counseling . I cried a couple more times. Towards the end of the year, I stopped crying.”“It was the first time I saw death … I thought about the family because the death was unexpected, so I started to relate it to my family, I thought about death, the idea of death.”Students were asked about the contextual details surrounding their experienced deaths. These included the patient’s age, expectation of death, if it was the student’s first death, and whether or not the student related the patient death to personal experiences with death. In general, students reported a ‘sudden’ and ‘unexpected’ death when talking about deaths in the ED. By contrast, deaths in the inpatient setting were more likely to be described as ‘expected.’ Death of the young was viewed as unexpected whereas death of the old was expected. As a result, in a few cases, deaths in the ED were labeled as ‘expected’ when older patients were involved. Generally, deaths that are unexpected and involve the young were described as more emotionally moving. In some cases, experiences of first deaths appeared to be more impactful:“I noticed mainly that it's a matter of age, 40s, my parent’s age, I’d be devastated.”“She was already terminal… but you relate more to this. You start thinking of your grandma and your aunt.”Relating death to personal experiences, including thinking about death of relatives as well as thinking about death generally, increased students’ emotional reaction, as illustrated in the second quote and the following:“…Once I enter the room I just change everything in my mind because I know I care about them”.In relation to student interaction with patients, subthemes were characterized as active involvement and passive or minimal interaction. Greater interaction generally led to greater emotional investment. Regarding active involvement with patients in the inpatient setting, students’ behavior included: being caring, fighting for the patient, emotional attachment, closeness, and being there for the patient and family. One student says of a patient on the floor:“Well it’s because first of all, you know the patient. You’ve talked to them more. I had zero interactions with the ones in the ER or with their families. On the floor you’re more involved. You’ve talked to them; you’ve talked to their families you’ve followed them for weeks.”In the inpatient setting, students’ interaction with the patients was noticeably more extensive. Interaction with patients in the ED, on the other hand, was described in many cases as minimal, restricted to performing CPR, and observing. This, in turn, led to a less pronounced emotional reaction:“I got to know the family. I got to know his son, his wife, they spent all day there, every day and I spent all day there, every day.”In general, greater interaction with the family of the deceased was associated with a stronger emotional reaction. A similar trend was detected whereby family interactions are more extensive and heavier in the inpatient setting when compared to the ED. Specifically, students in the inpatient setting described their interaction with the family as supportive, empathetic, and many ‘got to know the family very well.’“They were shocked, they were crying. It was overwhelming. I had tears in my eyes again.”“Seeing her [the wife] cry was more disturbing than the patient’s death.”By contrast, in many cases, family interactions within the ED were minimal. Nevertheless, cases in the ED where the family reaction to the death was witnessed also triggered emotional reactions:“I did not know how to phrase it, how my expressions should be…”.The experience of accompanying attending physicians as they inform the family of death was also particularly stressful and confusing:“There was really no emotion, I felt.”“I didn’t have any reaction from the rest of the team concerning the emotion.”When commenting on the behavior of the emergency department team, students rarely mentioned witnessing emotional reactions to patient death. In cases where they were raised, students reported no emotional reaction from the team and even a sense of detachment:“I did not discuss that with them directly, I did not ask them how would they feel … they seemed sad but I can’t tell for sure.”In one case, a student assumes the attending was sad, but was unsure since no direct discussion took place:“It affected me positively in the way they completely forgot about everything going on and were focused on the patient.”“I realized that medical-wise, it was business as usual…”.The team’s behavior was instead most commonly described as professional, organized, systematic, calm, and efficient in both the ED and inpatient setting. This was regarded as a positive influence:“It was stressful. We did cry...The guys were bummed. 3 girls started crying for like 20 minutes.”The psychological consequences of patient death are divided into three broad categories: emotional, physical and cognitive reactions. A wide range of emotional reactions was expressed in the inpatient setting including: sadness, helplessness, grief, disappointment, sympathy, crying, feeling disturbed, emotional, heartbroken, irritated, overwhelmed, traumatized, upset and anxious:“Till now I still don’t understand what happened. It’s more shocking, because nothing happened, and he had nothing… I just felt a bit more powerless.”“That impacted me a lot. Just seeing the expression or lack of expression on her face… She had a blank look on her face. Her hands and arms were hyperextended at the elbow. The thighs were twisted... it was a very graphic scene… I still have a very vivid image of her in my head.”In the ED, emotional reactions were of a different nature including: frustration, shock, powerlessness, confusion, surprise, and being affected by the imagery:“So I was just, I don’t know, practicing CPR. That’s it. I wasn’t feeling anything. I wasn’t affected by the death… I was just learning something new.”“It was exciting. I remember being happy that it happened on my shift. If it has to happen, then I would rather see it.”“This time I was completely detached and because I did not have to tell the family. It was not my patient so just a guy who came to the ED.”Notably however, four students reported being unaffected and regarded the death as part of the job. This occurred more so in the ED than in the inpatient setting. In the ED setting, not being involved in the care of the patient for a lengthy period of time helped students view the incident as an ‘experience on the job’, improved their ability to detach and lessened the overall impact.Despite this, some students expressed guilt about feeling numb and detached and uncertainty about the proper reaction to have. It was also acknowledged that having no direct responsibility for the patient decreased the expected unpleasant feeling after the death. Increased exposure to death also had a similar effect.“It felt weird watching my hands because I had touched the person. I had a weird feeling in my hands. I felt they were tingling.”Physical reactions to patient deaths were comparatively rare. These included an inability to sleep in some cases and a sensation of tingling in the hands.“For the first 3 hours I was just sitting there and thinking about what happened.”“Sometimes I get flashbacks when I see a situation that reminds me of that moment.”With regards to the cognitive aspect, thinking about the death and the idea of death seemed to be a recurring theme for some students. For more traumatic cases, the imagery of the patient death was remembered vividly and flashbacks were experienced when similar cases appeared.“I can't have emotion, too much emotion, or it will devastate me. So it made me try to protect myself and be more distant.”Students commonly reported wanting to distance themselves and detach as a way to lessen the emotional impact; one student labeled this as a form of defense mechanism. A minority of students opted to talk to colleagues, friends and family, and ‘try to be involved in other things’ as coping methods. Another student stated that experiencing the worst helps in adapting to and coping better with future deaths.“It severely grounded me form the beginning so now I’m prepared for the easier things.”A large number of students (7) cited the ability to regulate emotions as a learning experience as well as a coping mechanism. Specifically, learning how to become less attached and expecting the worst. Students felt more prepared, confident and in some cases desensitized.Becoming more empathetic and gaining experience on how to deal with the family were also considered valuable learning experiences.As expected, students expressed distress and sadness in both settings. The reaction and the extent of the effect was determined by contextual factors including the patient’s age, the expectation or suddenness of death, the first death experience, if the death was relatable to personal experiences, the extent of interaction with the patient and their families, the presence of a family reaction, and the coping mechanisms adopted. Students generally reported inpatient settings as more impactful. This was attributed largely to the high level of interaction and involvement with patients and their families that is normally not present in the ED. Cases in the ED, however, were categorized as impactful with some additional conditions: if the trauma and imagery was visibly disturbing and if the family reaction was emotionally moving.Although there is some data on medical students’ responses to patient death in various inpatient settings, the present study illustrates that dealing with death in the ED for students produces reactions of a different nature, with the above-mentioned variables moderating this reaction. This is most visible in the spontaneous differences that emerge in the emotional labels expressed in each setting. Deaths in the inpatient setting elicited words such as grief, sadness, feeling heartbroken and upset. Deaths in the ED triggered reactions relating more to the suddenness that is common in the ED including: shock, confusion, surprise, and specific reactions to the imagery of trauma cases. As such, dealing with deaths in the ED may require or demand a different set of skills from the student. Debriefing and counseling sessions on ED deaths may also need to be tailored accordingly. In similar fields where traumatic deaths are often encountered, tailored interventions such as critical-incident stress debriefing (CISD), a widely used group intervention to reduce post-traumatic stress in high risk occupations, such as disaster response and fire fighting, has been introduced . Future Another notable differentiating characteristic is the impact of the imagery of trauma cases seen in the ED. Students offered more vivid descriptions and recollections of these patients as a result. Remarks were most commonly made on the goriness and graphic nature of the image.Students found patient deaths in the ED more impactful if they witnessed the family’s reaction to the death, even if no direct interaction took place. In one case, a student explains that watching the family’s reaction was more disturbing than dealing with the patient death itself.Several explanations have been put forth to understand physician reactions to patient death . One is Notably, emotional reactions to death are influenced by culture. Individuals of non-western groups tend to view emotions as highly pertinent to beliefs, with emotions more readily causing belief change when compared to western cultures. Typically, non-western groups tend to endorse an interdependent self-construal, a self-concept which places higher value on relationships and emotional connections and is strongly shaped by the feelings of others , 21. As Most students expressed an interest in either pre- or post-counseling to help manage death’s effects, with more preferring post-counseling or debriefing. Some argued that anticipating the emotions students might encounter is not possible and so pre-counseling will not be as effective. None of the students interviewed reported discussing a patient death or an emotional reaction with an attending.Appropriate emotional reactions to patient deaths and coping mechanisms are often implicitly shaped by the hidden or unofficial curriculum. This is transmitted through the immediate environment and culture of the institution, including its attitudes and values, ultimately influencing students’ professional development . As evidThere were at least two interviewers in any given interview which may have increased the number of follow up questions asked, potentially confusing the interviewee. One of the interviewers was involved in teaching the students but all teaching and grading happened prior to the interview and after the end of their rotation thus attenuating significantly the possibility of a dependent relationship. Additionally, since the topic is sensitive, this may have prevented participants from sharing their emotions openly and honestly. Recall bias may have limited the generalization of the results further.The emotional impact of patient death on students in the ED was different to the inpatient setting as described. Future studies may wish to assess the long-term impact of ED deaths in comparison to deaths in an inpatient-setting. Importantly, developing and testing debriefing techniques and sessions to support students and physicians in the ED setting may be a beneficial next step.


School ethos refers to the school leadership’s purposive efforts to shape and direct the attitudes, values and behaviors needed in order to promote an active learning environment and to prevent the emergence of undesirable behaviors by creating shared meaning and common goals for the school. The aim of this study was to examine how teacher rated aspects of school ethos are linked with manifestations of bullying among 11th grade students. Five teacher-rated sub-dimensions of school ethos  were examined in relation to student-reported perpetration of and exposure to traditional school bullying and cyberbullying. The data material combines student and teacher information from two separate data collections performed in 2016, comprising teachers and students in 58 upper secondary schools in Stockholm. Analyses showed that bullying was associated with all but one of the five sub-dimensions of school ethos, namely structure and order for dealing with bullying behaviors at the school. Results are discussed in light of this counter-intuitive finding. Our findings nevertheless lend support to the idea that the social organization of schools, as reflected in their teacher-rated ethos, can affect individual students’ attitudes in a way that prevents the emergence of bullying behavior among students. An increasing number of scholars highlight the importance of taking school-contextual factors into account when trying to understand the causes and consequences of school bullying ,2,3. OneA frequently used definition of school bullying was initially phrased by Dan Olweus  . The Stockholm Teacher Survey (STS) was carried out by our research group through a web-based questionnaire sent to all upper secondary-level teachers  in the participating schools . The final numbers of study subjects varies between N = 6067 and N = 5657 depending on the type of bullying outcome that is analyzed. An overview of the process by which the final four study samples were selected is presented in The data material combines student and teacher information from two separate data collections performed in 2016, comprising 58 upper secondary schools. Student information comes from the Stockholm School Survey (SSS), a total sample of students in the second grade of upper secondary school (17–18 years) in all public and most independent schools in Stockholm municipality  this school year?” Here, the question is constructed in such a way that it is not possible to take account of the number of times this has occurred since the response categories are either “Yes”, “No” or “Don’t know”. This also leads to a higher share of students, 7.3%, reporting having experienced this.Descriptive statistics for all of the variables used in the analyses are presented in Have you taken part in bullying or harassment of other students during the past school year?” with the following response categories: “No”, “Yes, occasionally”, “Yes, 2 or 3 times a month”, “Yes, about once a week”, “Yes, several times a week”, and “Don’t know”. Altogether, 5.0% of the students belong to this category. Finally, we also identified students who reported having been involved in perpetration of cyberbullying during the past school year through the question “Have you taken part in the bullying or harassment of other students on the Internet or by text messaging this school year?”. Here too, the response categories are either “Yes”, “No” and “Don’t know”, with 3.0% admitting to having done so during the past year.The third indicator concerns perpetration of traditional school bulling on at least an occasional basis during the past school year by asking “Agree completely” to “Disagree completely”, and the remaining four according to a 5-graded scale ranging between “Strongly agree” to “Strongly disagree”.Five teacher-rated sub-dimensions of the school’s ethos constitute the main predictor variables in this study. The first was rated on a 4-graded scale ranging between “The first sub-dimension concerns the school’s degree of staff stability in terms of the level of sick-leave among teachers, staff turnover and the frequency of substitute teachers at the school. The second takes account of teacher morale in terms of whether the teachers’ have a strong work ethic, work with great enthusiasm, take pride in their school and feel confident as classroom leaders. The third concerns structure and order for dealing with unwanted behavior through questions about the schools’ value system, whether the school actively works on issues such as violence, bullying and harassment among students, whether teachers feel confident about what they may and may not do if violent situations arise among students, and whether the rules for order and conduct are clear at the school. A fourth aspect takes account of the teachers’ degree of student focus in terms of positive feedback to, and high expectations of the students, as well as whether the teachers take their time with students even if they want to discuss something other than schoolwork, and also whether the students are treated with respect. The fifth sub-dimension, finally, tries to capture the school’s academic atmosphere by asking the teachers to assess whether the school provides a stimulating learning environment and whether the students’ motivation is a stimulating part of work.The teachers’ ratings of the schools’ overall ethos and its’ five sub-dimensions were aggregated to the school-level mean, and then z-transformed to have a mean of 0 and a standard deviation of 1. Cronbach’s alpha for the five sub-dimensions were 0.55 , 0.93 , 0.92 , 0.79  and 0.89 . The overall measure of school ethos (17 items) had a Cronbach’s alpha of 0.94.Are you a boy or a girl?” Students who refrained from answering the question (3.4%) were kept as a separate category since they were much more likely to report being victims of bullying. Parental education was measured by the question “What is the highest education your parents have?” with separate response categories referring to mothers’ and fathers’ education. Four categories were singled out: students with two, one, or no university-educated parent(s) as well as students who refrained from answering the question. Migration background was captured by asking “How long have you lived in Sweden?” The response categories were: “All my life”, “10 years or more”, “5–9 years” and “Less than 5 years”. The two latter categories were merged due to small numbers.Some basic sociodemographic background characteristics of the students were included in the statistical analyses as control variables. Gender was assessed by the question “In the Stockholm School Survey, students provide no information on personal identification and hence the data are filled in anonymously. As a consequence, the SSS data are not subject to consideration for ethical approval according to a decision by the Regional Ethical Review Board of Stockholm (2010/241-31/5). The Review Board has provided ethical permission for the Stockholm Teacher Survey (2015/1827-31/5).xtmelogit command in Stata 14. By estimating an “empty model” it is possible to evaluate if there is variation in bullying across schools. Such a model does not include any independent variables, but assesses the variation in the outcome separately for each level . From this information, the Intra Class Correlation (ICC) can be calculated. ICC for binary outcomes gives approximate information about the percentage of the total variation in the outcome variable that can be attributed to the school-level.The data material consists of information collected at two different levels of the school structure. The teacher-rated measures take account of conditions at the school-level, whereas the background characteristics and outcome variables refer to individual students’ circumstances. Therefore, multilevel modelling in terms of two-level binary logistic regression analysis was applied, using the p = 0.021). With the exception of the sub-dimension meant to capture structure and order, the remaining aspects of school ethos still indicate a decreased likelihood of exposure to bullying as well, although none of these estimates reach statistical significance.structure and order, are significantly associated with students’ odds of being exposed to cyberbullying. The estimates are very similar to those of victimization from traditional bullying, but with narrower confidence intervals. Here too, the school’s academic atmosphere emerges as the sub-dimension most strongly associated with victimization , but staff stability , teacher morale  and student focus  demonstrate substantial effect sizes in the fully adjusted models as well. The overall measure of school ethos points to a decreased odds of exposure to cyberbullying corresponding to OR = 0.84 (p = 0.003) for each standard deviation’s increase in school ethos. Calculated the other way around, a standard deviation decrease in overall school ethos is associated with a close to 19% increased odds of cyberbullying victimization among the students at the school.staff stability, teacher morale, student focus and academic atmosphere, which demonstrate odds ratios in the range of 0.69–0.76 in the fully adjusted models.Perpetration of traditional bullying is even more strongly linked to teacher-rated aspects of school ethos . This isp = 0.032).Calculated the other way around, this corresponds to an increased odds of 31–45% of being a perpetrator of bullying for each standard deviation decrease in in any of these four indicators of school ethos. However, no significant effect of structure and order is seen here either. Taken together, one standard deviation increase in teachers’ overall ratings of the school ethos is associated with a decreased occurrence of self-reported bullying perpetration corresponding OR = 0.74 (p < 0.001) compared to staff stability , teacher morale  and student focus  in the fully adjusted models. Calculated the other way around, a standard deviation decrease in overall school ethos is associated with a 35% increased odds of being a perpetrator of bullying .Regarding self-reported perpetration of cyberbullying, finally, the picture looks pretty much the same as that for traditional bullying perpetration . For allThis study investigated how five teacher-rated aspects of school ethos corresponded with students’ experiences of bullying in 58 upper secondary schools in Stockholm, while taking individual sociodemographic covariates into account. Results showed that victimization from cyberbullying decreased significantly with increasing levels of schools’ staff stability, teacher morale, student focus and academic atmosphere. Although this pattern of associations were almost identical for victimization from traditional bullying, the confidence intervals were wider, which left only academic atmosphere as a significant predictor in the fully adjusted model. Teacher-rated aspects of school ethos were even more strongly related to students’ reports of bullying perpetration, once again with staff stability, teacher morale, student focus and academic atmosphere as significant predictors of both traditional bullying and cyberbullying perpetration. These findings corroborate with previous studies showing that teacher-rated aspects of school policies and practices  as well structure and order. This ‘non-result’ is perhaps the most intriguing finding of this study given the items that this sub-dimension takes into account, namely (1) At this school we have a value system which is clear to students; (2) At this school we actively work on issues such as violence, bullying and harassment among students; (3) At this school the teachers feel confident about what they may and may not do if violent situations arise among students; and (4) The rules for order and conduct are clear at this school. The complete lack of effect from this measure on peer bullying appears counter-intuitive, as this literally is what it is meant to do. In the study by Mujis [In one respect, however, our findings are in contrast to previous research in the field ,38. Thusby Mujis , teacherby Mujis ,40.A possible explanation to our findings could be related to the fact that Swedish schools, since 2006, are legally obliged to have an anti-bullying policy . To meetSweden has a history of very low bullying rates compared to other European and North American countries ,46,47, aThe school is an important social arena in young people’s lives where patterns of social relations are constantly negotiated and refined. Aspects of status and power are important components in the establishment of peer relations, and bullying can sometimes be an effective strategy to climb the status ladder. Status goals have in fact been put forward as an important driving force behind bullying behavior in previous research, especially during adolescence . To fostInterestingly, the four aspects of school ethos that emerged as most important for expressions of peer bullying in this study were largely oriented towards creating good conditions for students’ academic motivation and success. These findings are in line with a recently published longitudinal study on the causal relationship between school climate, school violence and student performance . Rather A major advantage with the current study is that our measure of school ethos were rated by teachers whereas manifestations of peer bullying were reported by students in the corresponding schools, thereby decreasing the risk of bias due to common method variance. The findings and interpretations of this study should nevertheless be considered with some study limitations in mind. Firstly, the data material is cross-sectional which means that we cannot address questions of causality regarding any of the observed associations. Secondly, there may be confounding due to other school-contextual conditions that we were unable to take into consideration, for example school-specific anti-bullying programs. Thirdly, due to social desirability the two measures of bullying perpetration may have lower validity compared to those reflecting victimization. The association between school ethos and perpetration of traditional as well as cyberbullying were, however, stronger than those for victimization. Fourthly, our findings are based on regional data, which means that they cannot be generalized to 11th grade students in Sweden as a whole, or to other national context. Finally, while the main focus of the present study was on the resulting effect of school ethos, future studies should further elaborate on the qualitative components of the concept as well as on the more precise reasons as to why they tend to differ across schools.The findings of this study are in agreement with the underlying assumptions of the effective school literature, namely that efforts at higher levels of the school structure are crucial for providing the necessary conditions for processes at lower levels to come into force. Our results lend support to the idea that the social organization of schools, as reflected in their teacher-rated ethos, can affect individual students’ attitudes in a way that counteracts bullying behaviors at the school. Improving school ethos in terms of academic atmosphere, teacher morale, student focus and staff stability should be considered as a viable complement to school-based interventions to address bullying.


Liquid biopsy analyses are already incorporated in the routine clinical practice in many hospitals and oncology departments worldwide, improving the selection of treatments and monitoring of lung cancer patients. Although they have not yet reached its full potential, liquid biopsy-based tests will soon be as widespread as “standard” biopsies and imaging techniques, offering invaluable diagnostic, prognostic, and predictive information. This review summarizes the techniques available for the isolation and analysis of circulating free DNA and RNA, exosomes, tumor-educated platelets, and circulating tumor cells from the blood of cancer patients, presents the methodological challenges associated with each of these materials, and discusses the clinical applications of liquid biopsy testing in lung cancer. The so-called “liquid biopsy” is quickly moving from research into clinical practice in lung cancer, as well as in other human malignancies. Although its full potential has not yet been reached, the “liquid biopsy” is no longer a promise but a reality that is allowing a better treatment selection and monitoring of lung cancer patients in hospitals and oncology departments worldwide. We can already foresee a day when “liquid biopsy”-based tests will be as widespread and useful as “standard” biopsies and imaging techniques, offering invaluable diagnostic, prognostic, predictive, and monitoring information. In this mini review, we will summarize the state of the art in this exciting area, placing a particular emphasis on the clinical utility of the “liquid biopsy” and the variety of applications, methodologies, and results that can be derived from it.“Liquid biopsies” are usually defined as tests done in blood samples or other body fluids. In the case of cancer patients, the objective of those tests is to detect materials originated in the tumor. Although the term “liquid biopsy” is universally used, many pathologists argue that it is incorrect. The so-called “liquid biopsies,” they claim, are not true biopsies. A “true” biopsy is usually performed by a surgeon or a pneumologist and involves the extraction of sample cells or tissues that are subsequently examined by a pathologist under a microscope, commonly after some kind of fixation and staining. Paraffin embedding is also widespread. In contrast, “liquid biopsies” are not obtained by surgeons; involve the extraction of blood or other fluids and not of solid tissues, pathologists only occasionally intervene and fixation, embedding, or staining are equally infrequent. In addition to the “biopsy” half, the “liquid” half in the term “liquid biopsy” can also be misleading. The materials originated in the tumor that are to be detected in such “biopsies” are never liquid. Some of them are cells or fragments of cells, such as circulating tumor cells (CTCs), exosomes, or tumor-educated platelets (TEPs); others are nucleic acids dissolved in the blood, such as circulating tumor DNA or RNA . Each of these materials offers unique opportunities to test different biomarkers and analyze particular characteristics of the tumors Table .The differences between a “real” and a “liquid” biopsy—or “liquid sample,” as the pathologists would probably prefer to call them—explain the advantages of the latter. “Liquid” biopsies will never replace real biopsies, which are irreplaceable sources of information that cannot be obtained by any other means, such as tumor type and histology. However, they offer all sorts of additional data that cannot be obtained in any other way. In patients who cannot be biopsied, or where biopsies do not have enough tissue, “liquid biopsy” is the only alternative to perform genetic testing for targeted therapy. Also, in patients with advanced disease, it is not feasible to obtain biopsies of every metastasic site. But blood reaches both the primary tumor and the metastases, and materials coming from all can be found in a “liquid biopsy.” Finally, unlike “real” biopsies, blood can be repeatedly obtained without the risk of comorbidities and used to monitor the course of the disease, including early detection of response and relapse or emergence of resistance to a particular therapy.EGFR) or KRAS genes. This is particularly useful when no biopsy is available for genetic analyses and, in this setting, the European Medicine Agency recommends EGFR testing in liquid biopsies to select patients for tyrosine kinase inhibitor (TKI) therapy (Circulating free DNA (cfDNA) can be found dissolved in plasma and serum, at variable amounts. In the case of cancer patients, a fraction of the cfDNA is tumor derived, and ctDNA represents from less than 0.1% to more than 10% of the total cfDNA. This percentage has been shown to depend on stage, tumor burden, vascularization of the tumor, biological features like apoptotic rate and metastatic potential of the cancer cells, and factors affecting the blood volume of the patient . In addi therapy , 11.EGFR mutations in the cfDNA of cancer patients (Therascreen Plasma from Qiagen and COBAS Blood from Roche Diagnostics) are based on them. In our group, we have developed a quantitative PCR technique in the presence of PNA to detect EGFR, KRAS, and BRAF mutations in the cfDNA of advanced lung, colon, and cancer patients that achieves 75–80% sensitivity with 100% specificity   is present in the plasma of cancer patients and can be used for detection of the clinically relevant (RT-PCR)  and, usiEML4-ALK fusion transcripts in TEP RNA from advanced lung cancer patients with 65% sensitivity and 100% specificity , has been approved by the FDA for monitoring some type of tumors , based on filtration and cytological characterization, has shown an increased sensitivity in NSCLC  for positive selection or CD45 for negative depletion. One of such techniques, the CellSearchf tumors –84, but patients –87. Labepatients  or thosein NSCLC –92 with NSCLC  and immunochemistry in CTCs isolated using ISET (Finally, CTCs have also been investigated as a tool to identify clinically relevant genetic alterations in NSCLC Table . Using Nectively , 42, 105ing ISET  or othering ISET , 48. In ing ISET .All the authors contributed to the writing and critical revision of the review.The authors declare that this review was elaborated in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Health inequities are increasing worldwide, with mounting evidence showing that the greatest cause of which are social determinants of health. To reduce inequities, a lot of citizens need to be able to access, understand, appraise, and apply information on the social determinants; that is, they need to improve health literacy on social determinants of health. However, only a limited number of scales focus on these considerations; hence, we developed the Health Literacy on Social Determinants of Health Questionnaire (HL-SDHQ) and examined its psychometric properties.We extracted domains of the social determinants of health from “the solid facts” and related articles, operationalizing the following ten domains: “the social gradient,” “early life,” “social exclusion,” “work,” “unemployment,” “social support,” “social capital,” “addiction,” “food,” and “transport,” Next, we developed the scale items in the ten extracted domains based on the literature and included four aspects of health literacy  in the items. We also evaluated the ease of response and content validity. The self-administered questionnaire consisted of 33 items. The reliability and construct validity were verified among 831 Japanese adults in an internet survey.The scale items had high reliability with a Cronbach’s alpha of 0.92, and also adequate results were obtained for the internal consistency of the information-processing dimensions . The goodness of fit by confirmatory factor analysis based on the four dimensions was an acceptable value . Furthermore, the bivariate relationship between HL-SDHQ and the frequency of participation in citizen’s activities was similar to the theoretical results.HL-SDHQ clarifies the relationship between the ten domains of the social determinants of health and health in each domain and is able to measure whether it is possible to access, understand, appraise, and apply related information. The reliability and validity of the scale were adequate.The online version of this article (doi:10.1186/s12889-016-3971-3) contains supplementary material, which is available to authorized users. In recent years, although general health has improved with the development of medical and public health, health inequities continue to increase worldwide. According to final report in 2008 by the World Health Organization (WHO) Commission on the Social Determinants of Health (CSDH) , there iHealth differences that arise because of the society in which one is born are not the responsibility of the individual, but represent systemic gaps caused by the society. The factors that give rise to these differences have been referred to as the social determinants of health. In 1998, the WHO Regional Office for Europe announced “the solid facts” to improve awareness of the social determinants of health, which was later updated in the second edition in 2003. This publication shows ten relevant domains, organizing the evidence related to the relationship with health in a systematic manner [In the final report by the CSDH , it gaveHealth literacy is defined as the ability to access, understand, appraise, and apply health information . In receAt present, numerous scales do not measure health literacy with the latter meaning, and we are aware of few scientific evaluations of whether citizens can know about the social determinants of health and whether they can implement the health promotion initiatives. There are studies that are seeking to develop scales that take social determinants of health into consideration, including the All Aspects of Health Literacy Scale  and the “Health literacy refers to the ability to regularly update oneself on determinants of health in the social and physical environment and derive meaning, to interpret and evaluate information on determinants of health in the social and physical environment, and the ability to make informed decisions on health determinants in the social and physical environment and also engage in joint action”.For the development of the scale, we referred to the definition of health literacy for the domain of health promotion developed by Sorensen et al.  because Taking the definition by Sorensen et al.  as the s“The solid facts” outlines the most important aspects of new knowledge related to social determinants of health. This includes ten domains, “the social gradient,” “stress,” “early life,” “social exclusion,” “work,” “unemployment,” “social support,” “addiction,” “food,” and “transport,” Although we considered “stress” as one of the social determinants, we did not set stress as an independent domain but included topics on stress in other domains because people are subjected to many kinds of stress in daily life. For example, in the domains on “unemployment,” “addiction,” and “work,” we included topics on stress caused by job insecurity, social settings and work.the quality of social relationships and the existence of trust, mutual obligations and respect in communities or in the wider society” [. When we considered whether to add “social cohesion” to the domain, we found that the final form of the CSDH document, “A Conceptual Framework for Action on the Social Determinants of Health, [features of social organization, such as trust, norms, and networks that can improve the efficiency of society by facilitating coordinated actions” [On the other hand, we added “social capital” to the domains. The description of “social support” in “the solid facts” includes not only social support but also social cohesion, which is defined as “society” . When we Health, ” introduactions” . Althougactions” . ConsequIn “the solid facts,” we identified 33 items that covered the ten domains. Topics about the relationship between health and each domain were set as questionnaire items. Further, we referenced the HLS-EU-Q47  to identTo ensure the content validity of the question items for the ten domains, the items were examined and adapted through discussions with researchers from public health, nursing, and social sciences working in related fields. No questions were revised in this task.The score per question was rated 1–4 depending on the response, and the scores were summed. For example, one question was “On a scale from very easy to very difficult, how easy would you say it is to understand that the lesser the income the greater the tendency to become ill?” and were ranked on a four-point Likert-type scale . We also included the response “don’t know/not applicable” to help assess participants’ level of comprehension. Further, as in the HLS-EU-Q47, items with missing values were supplemented by the substitution of the average value of that item for the whole sample .Participants were recruited from registrants of an internet research service in Japan. The research company had approximately 2.5 million voluntarily registered participants at study onset, from which we sought to collect data from 1000 men and women aged 20–69 years. On October 30, 2014, potential respondents were randomly invited via email to complete the cross-sectional web-based health literacy questionnaire anonymously. Participants voluntarily signed an online informed consent form approved by our institutional review board. The present study received prior approval from the research ethics committee of St. Luke’s International University, Japan.We sought to match the percentages of participants by gender, age group, and region (divided into eight nationwide regions in Japan) to the results of the 2010 Japanese census . We acceThe HLS-EU-Q47  compriseWe also assessed the relationship between HL-SDHQ and frequency and number of participation in citizens’ activities. Nutbeam pointed out that “critical health literacy” reflects cognitive- and skill-development outcomes oriented toward supporting effective social and political action, as well as individual action. Thus, we considered that there might be a relationship between HL-SDHQ and the frequency and the number of participation in citizens’ activities including social and political action. Further, with regard to the frequency of participation in each citizens’ activity, we compared the Spearman’s correlation coefficient for the HL-SDHQ with the corresponding value for the HP-HL. We also considered that the correlation coefficient for the HL-SDHQ was higher than that for the HP-HL. This was because the HL-SDHQ, more so than the HP-HL, reflected the responses from the perspective of community health rather than individual health. With reference to the major classifications of legislation in Japan designed to promote specified non-profit activities, 25 activities were targeted, including community involvement activities. Questions were asked about the frequency of participation in each citizens’ activity, and four responses were available . For the number of participation in citizen’s activity, we calculated the score based on the frequency of participation in each citizens’ activity. If the response was “usually,” “often,” or “sometimes,” we recognized the respondent with an experience of participation and gave a score of “1”. Otherwise, respondents with no experience were given a score of “0”. We summed the score of 25 activities.We assessed the relationship between HL-SDHQ and health status. Self-rated health was measured by participants’ responses to the question, “Recently, how would you describe your state of health?” with five outcomes . This was the same question and response option that appeared in a survey administered by the Ministry of Health, Labour and Welfare .The following demographic and socioeconomic characteristics were analyzed: gender, age groups, highest level of education, annual pre-tax household income in millions of yen, self-assessed living conditions, occupation, and municipality size  was conducted. The number of factors was set to four, which related to the four information-processing dimensions . In the CFA, we used the comparative fit index (CFI) and the root mean square error of approximation (RMSEA) as the model fit indices. A CFI value ≥0.90 was considered to indicate acceptable model fit. For the RMSEA, a value <0.05 represented good fit, and a value <0.08 was considered acceptable . ConstruWe also compared the mean and standard deviation of the HL-SDHQ by demographic and socioeconomic characteristics . Data were analyzed by IBM SPSS and Amos version 23.0.Table The sample distribution in terms of age and income was almost in accordance with the distribution of these metrics in the Japanese population (not tabulated), but men and college/university or higher overrepresented in the studied population . RegardiThe wordings of the 33 items, and the empirical answer patterns, are displayed in Table Regarding the total difficult (“very difficult” + “fairly difficult”), Q26 “Involve oneself in politics and public administration to protect the health of workers both institutionally and legally” (86.0%) is the most difficult item. Many items of the ability to apply information related to the social determinants are recognized as more difficult. By contrast, regarding the total easy (“very easy” + “fairly easy”), Q12 “Understand that work that is not stable becomes a huge stress” (66.1%) is the easiest item. Many items of to understand are recognized as easier.The Cronbach’s alpha coefficient values were calculated to examine the internal consistency of the scale and its component subscales. For the questionnaire, Cronbach’s alpha was 0.92; the subscale values were 0.82 for accessing, 0.91 for understanding, 0.84 for appraising, and 0.92 for applying items. For all scales, the reliability of ≥0.8 was achieved and the item-total correlations were all positive.CFA was conducted to assess factorial validity, revealing CFI and RMSEA values of 0.901 and 0.058, respectively. Four-factor models for the questionnaire item fitted the data reasonably well.r = 0.74, p < 0.001), as well as health status , gender , and self-assessed living conditions  (Table Bivariate relationships between the HL-SDHQ scores and other parameters are shown in Tables r = 0.22 for each). Further, the correlation coefficient between these activities and the HL-SDHQ was higher than the corresponding value for the HP-HL .In addition, we also found significant relationships between the HL-SDHQ and the frequency of participation in citizens’ activities Table . The resr = 0.20; data not shown) was also obtained between the HL-SDHQ and the number of participation in citizens’ activities.A significant correlation  and an adequate goodness of fit. In the bivariate relationship, a valid result was obtained for the relationships with the HP-HL, the frequency and the number of participation in citizens’ activities, and the self-rated health. The correlation coefficient between the HL-SDHQ and HP-HL was high at 0.74, indicating the validity of the HL-SDHQ to measure health literacy required for health promotion. Further, when we compared the Spearman’s correlation coefficient between the frequency of participation in citizens’ activities and the HL-SDHQ with the corresponding value for the HP-HL, the HL-SDHQ rather than HP-HL had a much strong relationship with activities such as “Support activities for mother and child related to natural childbirth and child rearing” or “Group purchase of pesticide-free vegetables” in which health was an objective that changed society. This result not only supports the theory critical health literacy proposed by Nutbeam  but alsoAlthough the HL-SDHQ is different from health literacy scale already developed because it does not focus on the realization of the health of a specific individual, but is instead directed toward the realization of the health of the community or society through modifications to the social determinants of health, a positive correlation was obtained for the relationship between HL-SDHQ and self-rated health. Generally, similar results are obtained from studies reporting health literacy and self-rated health . AccordiIn the relationship with basic attributes, no relationship was seen with objective indicators of social position, such as education or income, but there was a significant relationship with subjective life circumstances. This result is similar to the results of the HLS-EU-Survey in the Netherlands . An impoAlthough no significant relationship was observed with age, it is important to note that the HL-SDHQ score was high for those aged over 60 years. In a previous study, it was conceivable that because cognitive ability may decline when one becomes older, health literacy could also decline; however, the results of this study do not support this argument . The reaIt is important to note that this study has some limitations. First, it is possible that there was some selection bias. The Japanese cohort may have been skewed toward including those with a high level of internet literacy because of the use of a web-based survey. Also, the recruitment of respondents was based on self-selection from among a group of individuals who had previously expressed a desire to participate in research projects. Moreover, responses were limited to the first 1000 people, and may therefore have only included those who were most active on the internet. When we confirmed the representativeness of the study sample to the general population in terms of age, gender, income and educational level, participants included a more men and a higher education level. Perhaps, these factors might positively influence internet literacy. This suggests that the HL-SDHQ may be validated for web-based studies.Second, our findings may be limited to Japanese settings, and care must be exercised especially when generalizing them to European and American countries. Given that the development and research for the HL-SDHQ has been implemented in Japanese, the validity and reliability of an English version need to be assessed in future research.In this study, we developed a reliable and valid health literacy scale on the social determinants of health in Japan. We operationally identified ten domains of the social determinants of health and confirmed their content validity. Moreover, a high goodness of fit was obtained and we showed a clear bivariate relationship between the HL-SDHQ and the frequency and the number of participation in citizens’ activities, supporting the validity. In the future, there is a need to confirm the usefulness of each question and to confirm the validity of the questionnaire in other cultural settings and languages.


Most life scientists have relentlessly recommended any evaluative approach of agri-food products to be based on examination of the phenotype, i.e. the actual characteristics of the food, feed and fiber varieties: the effects of any new cultivar  on our health are not dependent on the process(es), the techniques used to obtain it.The so-called “genetically modified organisms” (“GMOs”), on the other hand, are commonly framed as a group with special properties – most frequently seen as dubious, or even harmful.Some social scientists still believe that considering the process is a correct background for science-based understanding and regulation. To show that such an approach is utterly wrong, and to invite scientists, teachers and science communicators to explain this mistake to students, policy-makers and the public at large, we imagined a dialogue between a social scientist, who has a positive opinion about a certain weight that a process-based orientation should have in the risk assessment, and a few experts who offer plenty of arguments against that view. The discussion focuses on new food safety. We are in a food analysis laboratory. The “prototype” of a new variety of sweet pepper has just been put on the table. A few people are there: the lab manager, who is a toxicologist; her assistant, an expert in food-related allergies and intolerance; an agricultural biotechnologist from the philanthropic research unit where the cultivar has been developed; an epistemologist of life sciences who specializes in agri-food biotech regulation and policies. The last attendant is a professor of social sciences, who heads a “Genetic Engineering and Society Center” at a university: since she is convinced that it is necessary to “reboot the debate on genetic engineering”, their discussion is very interesting.The social scientist starts by affirming that “framing the debate around ‘product versus process’ is neither logical nor scientific” . The social scientist quickly seizes her opportunity, underlining that such experiences show how certain processes should be considered significant for stricter regulation! Timidly, the lab director’s assistant says that no, those noxious cultivars were not “GMOs” but unfortunate outcomes from traditional hybridization! With a touch of irony, the biotech expert asks the sociologist whether she thinks that any older method should be strictly regulated, since bad results may emerge… Noting the amused look of the lab director, the sociologist realizes that they have played a little trick on her.Yet, the lab director recalls that a few genetically engineered cultivars had proved to be very harmful: a squash with toxic properties; a celery made resistant to certain insects, which would bring out rashes in whoever handled it; a very toxic potato, commercial name Lenape (Haslberger http://cls.casa.colostate.edu/transgeniccrops/defunct.html): they were discarded, plain and simple. It happens all the time: breeders, taking advantage of previous experiences and accumulated knowledge, try and see, relying on competence and luck; that’s the way science and technology work, even more so for “green” produce enhancements. In agri-food labs, experimental greenhouses and open field plots, the waste bin is never empty ☹The researcher – this time seriously – points out that also quite a few genetically engineered cultivars came out as unsatisfactory, even unsafe  used to create it, that must be evaluated on its own unique profile of pros and cons related to health, environmental impact and commercial value. Many position statements were issued by several scientific societies all around the world, says the epistemologist; let’s just quote a petition signed by 3,400 scientists – inter alia 25 Nobel laureates: “The risks posed by foods are a function of the biological characteristics of those foods and the specific genes that have been used, not of the processes employed in their development.”  and does not consider ex-ante the technique(s), the process(es) used during the experimental manipulations. The new pepper variety that is sitting on the table in front of us may have been derived from mutagenesis, either physical (irradiation) or chemical (exposure to certain substances that change the genome), or from RNA interference, having had some of its traits modified without even changing the DNA structure; it may even come from Mars. The technicians in charge of its safety assessment don’t know and don’t care: their only focus must be on the actual properties of the submitted “prototypes”, following adequate methods for their analyses.The actual any food, according to different risk profiles, because there is no reason to think that “GMOs” should be treated differently. The committee did its job properly, although it simply repeated that certain kinds of genetic engineering are not in themselves riskier than others: a little waste of public money…That’s why, the epistemologist points out, the Codex ad hoc committee which was established to write the guidelines for the safety assessment of foods derived from biotechnology  mix of product and process; it is false that both standpoints are similarly correct or useful. Please consider this again: regulating the processes (“GMOs!”) even before asking the question – the only rational one – whether this or that product, individually considered, is more or less safe or unsafe. Their ongoing embarrassment when new techniques emerge that cannot be placed inside, or outside, their nonsensical rickety fence, is not surprising , but accurate examination of each “prototype” – such as our pepper on the table – once created and selected from many unlucky outcomes (ex-post): if it is safe, hooray!, we will clone and propagate it in millions of copies to be sold on the market; in many parts of the world, it will be crossed with local varieties, well adapted to different climates and soils. Alas, not every new cultivar will be available soon and everywhere, the lab director reminds us: if it is a “GMO”, in many countries there will be lots of added controls, never-ending red tape, legal hurdles, inflated costs or even straight prohibition. , i.e. the EU agency in charge of scientific risk assessment, has a section which is explicitly dedicated to “GMOs”, with a goodly number of scientists on the expert panel, detailed guidelines and precise instructions for breeders who want to submit an application for the authorization of a rDNA-derived product (www.efsa.europa.eu/en/science/gmo); very similar new foods which are obtained with slightly different biotech methods are completely exempt, and are not even mentioned. Where’s the rationale for this?The social scientist adds that “product-based arguments lead to one of two conclusions: if all products (GE or otherwise) are to be treated the same, then either all products – GE and conventionally bred – should be regulated, or neither should be. The first option is impractical and the second inadvisable given that some products could be harmful.” What do you mean “impractical”, asks the lab director: since we know that any new process(es), instead of the actual characteristics of each product, results in really bizarre consequences: I can offer two examples, among many. 1. One of the most common traits obtained via recombinant DNA is crop tolerance to herbicides: farmers find it convenient to buy seeds of maize or soybean or other crops coupled to a weed-killer substance that prevents weed growth but leaves the valuable plants intact. However, there is another series of varieties of the same crops  that, similarly, have been made tolerant to proprietary herbicides, and consequently are used together with them; but the desired trait has been obtained through tissue culture and/or induced mutagenesis or selection of natural mutants which are then crossed with other varieties and so – legalistically speaking – without creating “GMOs”: consequently, the producer has legitimately and happily avoided the very major barriers which it would have had to face if the technical staff had directly pinched the DNA of the new varieties of wheat, rice, sunflower, lentil, corn and canola (BASF http://en.wikipedia.org/wiki/Amflora). It was genetically engineered in order to inhibit the production of one of the two kinds of starch which are typically present in the tuber. This modification is useful for many industrial applications  and avoids a costly and polluting process: the inactivation of a certain gene solves the problem at source. The push and shove between the European Commission, the ministers of various recalcitrant European states, and the challenges of “anti-GMO” organisations concerning authorization of the new cultivar lasted 17 years and eventually convinced the producer to give up marketing the product in Europe , case by case, obviously before starting mass production. Note again that the present situation is very unbalanced almost everywhere: obsessive tests and redundant analyses are mandatory for “GMOs”, almost no supervision is requested for the “prototypes” of all the other products.Therefore, the new foods developer says to the sociologist, you have already drawn the correct conclusion – which may be surprising for laypersons and quite a few social scientists, not for geneticists, biologists and breeders: as far as agricultural products are concerned, no special precautionary safety regulation is necessary for the ex-post criterion of controls, given that some inadequate, or even harmful, trait can escape scrutiny? Well, some risks may always exist. But, again, we must be aware that a higher or lower level of possible unsafety is not related to the process(es) used to create new cultivars: therefore, any ex-ante regulation of agri-food biotechnique(s) does not add anything interesting or useful to the safety issue.I anticipate a possible objection, says the lab director: isn't it risky to rely on an Thus, says the biotechnologist, reading quotes from an article written by the sociologist, asking “what classes of GE products or processes should receive greater regulatory scrutiny” is simply a groundless question if related to the agri-food area, and the alleged “need to consider a mix of product and process issues to capture product groups that are likely to be of greater concern” is utterly misplaced.risk assessment and risk management: the first is definitely a technical issue, the second is a policy matter – although decisions (management) should be based on the best scientific evidence available (assessment). This is a bedrock of the guidelines for risk analyses, as accepted at the widest international level: “There should be a functional separation of risk assessment and risk management, in order to ensure the scientific integrity of the risk assessment, to avoid confusion over the functions to be performed by risk assessors and risk managers and to reduce any conflict of interest.”  management of it: how could it be otherwise?The sociologist poses another problem: “it is impossible to be completely ‘science based’ in a regulatory system. Value judgments are embedded in all risk and safety assessments. For example, the dose–response curve for a certain food additive might be known, but such data do not by themselves tell regulators where to set an acceptable safety limit.” There is a chilly moment: the lab director and the epistemologist stare at each other. Please, colleague, the latter slowly says, be aware that you are confusing In a seminal text NAS-NRC , the epiwww.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/ucm081825.htm) or allergenicity (USA: http://www.jaad.org/article/S0190-9622(10)02126-2/abstract; UK: www.nice.org.uk/guidance/CG116) effects are concerned: and let me tell you, although we are not omniscient, our tools and procedures are “science-based”, while we follow the risk assessment policy as established by risk managers.In labs like mine, adds the director, we are in charge of evaluation of new agricultural products, as far as possible toxicity  to assess the qualities – or defects – of a product, we’ll be very disappointed… ☹The epistemologist looks the now impressed sociologist directly in the eye, saying: if these examples do not delete in your mind the very notion of the supposed relevancy of the science-based path, applying the necessary scrutiny to each and every new agri-food product – “GMO” or otherwise – before its multiplication and commercialization.Therefore, the biotech expert hopes to conclude, we don’t need to “reboot the debate on genetic engineering”, starting once again on the wrong foot. All we need is to follow a rational, science-based technical-legal framework is already available (Conko et al. ex-post, i.e. when each agri-food invention has been put on the lab table. The creators of these guidelines emphasize that it is not a mere theoretical hypothesis, but it draws inspiration from similar experiences which are already well tested in the real world: it is analogous to existing regulatory regimes, such as those for quarantine regulations for plant or animal pests. The approach is not fundamentally new and has worked well in practice for decades.The epistemologist adds that if lawmakers wanted to reconsider the existing “green” biotechnology regulations, which are almost always warped, a rational and Therefore, the biotechnologist declares with a slight but evident provocative tone, the public should not be lured into a frequent delusion: the pressing problem is not the relationship between “GMOs” and society, because this is a misleading approach.The social scientist is now a little upset: should I shut down my “Genetic Engineering and Society Center” then, she asks?! No ma’am, the epistemologist quietly replies, in our humble opinion you should reassess the scope of your department, making it a “Biotechnologies and Society Center”: this way, if you allow us, the narrow focus on the botched “GMO” pseudo-category would be widened to a real societal big issue…product has been obtained: everybody knows that the processes are irrelevant.P.S. – One year after, bad news: the delicious new pepper variety, as good and safe as it was, has given unsatisfactory yield results, some 15–20% lower than its competitors which are already on the market. At the research department, after a moment of depression, breeders are ready to try again: one group of developers thinks that a hybridization with an “heirloom” cultivar of pepper may be successful, adding better organoleptic qualities to high productivity; another group imagines that inserting into the pepper’s genome a certain DNA sequence taken from an orchid could do the trick. Hopefully, in a few months they will show up again at the food analysis lab to assess the safety of some new prototypes. There, technicians will perform the relevant tests again, without even asking how the new P.P.S. – This is just a fantasy, because the first outcome of the next experiment – the hybridized cultivar – would be quickly examined, while the second approach would create a “GMO” and therefore start a long, costly path.


End-of-life decision making constitutes a major challenge for bioethical deliberation and political governance in modern democracies: On the one hand, it touches upon fundamental convictions about life, death, and the human condition. On the other, it is deeply rooted in religious traditions and historical experiences and thus shows great socio-cultural diversity. The bioethical discussion of such cultural issues oscillates between liberal individualism and cultural stereotyping. Our paper confronts the bioethical expert discourse with public moral attitudes.n = 82). Considering the respective socio-political and legal frameworks, the thematic analysis focuses on moral attitudes towards end-of-life decision making and explores the complex interplay between individual preferences, culture, and religion.The paper is based on a qualitative study comprising 12 focus group discussions with religious and secular persons in the USA, Germany, and Israel (situatedness of religious beliefs and cultural communities becomes visible: Their status and role in individual situations, for example, as consensual or conflicting on the level of personal perspectives, family relationships, or broader social contexts, e.g., as a majority or minority culture within a political system.Our findings draw attention to the variety and complexity of cultural and religious aspects of end-of-life decision making. Although there is local consensus that goes beyond radical individualism, positions are not neatly matched with national cultures or religious denominations. Instead, the relevance of the specific As the group discussions indicate, there are no clear-cut positions anchored in “nationality,” “culture,” or “religion.” Instead, attitudes are personally decided on as part of a negotiated context representing the political, social and existential situatedness of the individual. Therefore, more complex theoretical and practical approaches to cultural diversity have to be developed. At the onset was a conflict between her husband and parents about removing her feeding tube after more than a decade in a persistent vegetative state. In the course of the controversy, however, the case engaged several levels of jurisdiction, the US-Congress, President George W. Bush, the US-Supreme Court, and even the Vatican. A great variety of political and ideological groups accompanied the whole process and voiced heterogeneous, at times completely incompatible views and agendas. Civil liberties movement representatives underlined the right to an autonomous decision and a dignified death  self-determination of humans, that he can decide what he wants (F-sec GE).Participants in the German and the US FGs showed a rather strong tendency to emphasize the relevance of individual autonomy in EOL decision making, especially regarding the validity and binding character of ADs. In the corresponding discussions, different intellectual traditions of conceptualizing autonomy seemed to come into play. Thus, in line with a Kantian understanding of autonomy, a person’s will as put down in an AD was often considered as strictly “, many speakers expressed the conviction that there is not only a right, but actually a moral responsibility towards one’s next of kin or attending physicians to hold an AD. Individuals were expected to take care of their own EOL matters, that is, to make up their mind, come to a clear decision, and finally complete “a precise document” in order not to “burden another person with this responsibility” (F-sec GE) of making serious proxy decisions regarding other people’s life and death.Furthermore, especially in the German FGsMany religious people believe that the time of death is written – that God knows when death will occur, and humans shouldn’t interfere. If that is true, how can anyone know when medical life support is appropriate, or when it merely prolongs dying? It is futile to man, but on the other hand – we are not the ones to do the work of nature, it would be taking a role that is conflicting with the creation and nature. (M-rel IL)The Israeli groups, by comparison, were much more reluctant and ambivalent in this regard. Participants frequently suggested that the application of ADs has to be coordinated with other formal requirements including a restriction of the options that can be chosen. However, there were additional differences underlying this “Israeli” stance. Secular speakers mainly discussed the tension between individual self-determination and moral responsibilities towards others, e.g., relatives or attending physicians. The latter should not be burdened with executing problematic directives, especially if they have lethal consequences. The religious speakers, on the other hand, also pointed out further preconditions and limitations of individual self-determination, such as divine will, creation, and the natural order of things:a great difference” (F-rel GE) between withholding and withdrawing medical treatment when it comes to ADs. The underlying intuition seemed to be that a purely consequentialist, outcome-oriented moral perspective ignores that it makes “a major difference if I omit something, or if I act directly” (F-rel GE). Especially the Israeli religious participants were practically unanimous in this respect. In consequence, they frequently contested the validity of ADs if these demanded a withdrawal of life support. Such demand was considered illegitimate and repeatedly equated with “promoting suicide” or even killing:I agree, the directives in this case are not binding for the doctors. Generally speaking […], nobody can determine the fate of another person. In this case particularly – disconnecting from life support machines is the same as killing. It is legally forbidden and it is prohibited by Judaism. (M-rel IL)In contrast to the secular speakers, many religious participants saw “Our findings thus indicate a certain tension between a secular emphasis on individual autonomy and more comprehensive religious perspectives. Thus, while many secular participants defended autonomy in the sense of unhampered self-determination, religious participants often complemented and weighed individual self-determination with other aspects such as responsibility for others or respect for divine creation or natural law. Furthermore, the distinction between withholding and withdrawing treatment played a decisive role in this context. Interestingly, however, it did not seem to be exclusively linked to Judaism as could be expected against the backdrop of the corresponding Halakhic teachings. Thus, while the participants at the Jewish Home San Francisco unanimously rejected the idea that there is a morally significant difference between withholding and withdrawing, the other religious speakers, including the Christian ones in Germany, expressed the sense that this difference should be taken into account.I believe in … euthanasia. … I have had so much experience in my own family with death directly, uh, to the point of uh, holding my sister when she died, and feeling her life spirit leave her body, that my attitude has changed a great deal on that score. … I think it’s very important even that the families change their attitudes and let people go (F-rel US).We also found a complex array of moral stances towards termination of life-sustaining treatment and euthanasia amongst our respondents. In line with a liberal understanding of autonomy, many participants in the German and US-groups applied the right to self-determination to include withholding or withdrawing life-sustaining treatment. In the groups of aged residents at the Jewish Home San Francisco, this attitude was also backed by a sense of urgency due to being personally affected:But one must also consider who can be burdened with that. I think, well even if one could talk about it with someone, a relative: “I want this and this not so,” but then one still has to stand up for this decision before the doctor: “Please turn the machine off, he shall die.” This is indeed a heavy burden. To burden one person with all of that … (F-sec GE).By contrast, especially in the German groups, moral responsibilities towards other actors involved, such as relatives or medical professionals, were frequently weighed in and played out against individual self-determination. The underlying concern was that it is not legitimate to burden other persons with the responsibility of executing one’s own dying wish:According to Jewish religion it is forbidden to hasten death, that would be equivalent to murder, and allowing doctors to decide about hastening death can lead to incorrect decisions and recklessness bordering on murder. M-rel IL: Yes, I also agree with this prohibition … We have to let nature take its course. (M-rel IL)The Israeli FGs generally expressed strong reservations against euthanasia. Thus, especially the religious speakers were strictly opposed to euthanasia and – although to a lesser degree – also to termination of life-sustaining treatment. Theological doctrines and interpretations figured prominently as a basis for the arguments expressed. Thus, for many Jewish Israeli respondents, life is given and taken by God, so that human decisions and actions are not allowed to interfere:actually quite curious” that “this concept never invaded Jewish thought, even though Jewish people suffered throughout history” (M-rel IL). This clear idea of a historical and cultural Jewish identity played an important role in the Israeli FGs. Thus, while the FG participants at the Jewish Home San Francisco articulated a rather lenient understanding of being Jewish – “you talk to … ten Jews and they probably have ten different ideas about that” (F-rel US) – the Israeli groups tended to formulate a much more compact, homogeneous conception:As Jews, modern religious or otherwise, we should value life and respect our bodies. Furthermore, we have the responsibility to care for ourselves and seek medical treatment needed for our recovery-we owe that at least to ourselves, to our loved ones, and to God. (M-rel IL)It is important to note, though, that the opposition to euthanasia was not necessarily attributed to Jewish religion or theology in a narrow sense, but often also to a broader notion of Jewish cultural identity. Thus, the idea of ending life was repeatedly described as being alien to one’s own cultural tradition and values, with one Israeli Jewish speaker finding it “I believe if one is thinking now that they possibly continue to live disabled, then this is actually…That will pretty soon go into the direction of [laughs] Auschwitz. Well, this is what the Nazis wanted too. That is only healthy people and so on. Life is not this way. (F-sec GE)Interestingly, in the German groups, references to the country’s Nazi past seemed to play a similar role. They created a presumed cultural identity which precluded overly liberal stances towards euthanasia. In this sense, the following speaker alluded to the historical Nazi “euthanasia”-programmes in a slightly embarrassed manner:Our participants’ responses to the moral problem of euthanasia confirmed the impression that attitudes towards EOL decision making do not so much depend on a specific “culture” and “religion” as such, but on many different and interlaced factors. Thus, a general idea of individual autonomy played a major role for participants in both the US and German groups, religious or otherwise. This stance could be supported by the perspective of being personally affected through advanced age or ailing health. At the same time, however, the idea of responsibility for others, as well as lessons learnt from national history such as the Nazi euthanasia programme suggesting slippery slope effects, could act as a counterbalance against overly individualistic and liberalistic interpretations of autonomy as unrestricted personal self-determination. Once again, participants in the Israeli groups – religious as well as secular – drew a somewhat different picture with regard to euthanasia. But even there, opposition to euthanasia was not based on theological arguments alone (not even in the religious group), but rather on the cultural interpretation of Jewish identity as centring on a high valuation of life.should draw up a recommendation” but “must not exert pressure” (F-sec GE). Respecting highly individual decisions, e.g., regarding the format of ADs, was also expected:Death is not a bureaucratic act, and neither is the way to it. And correspondingly, I would plead to keep the state as far as possible out of it. It can issue recommendations. It can lend a helping hand, especially with respect to such lists. …But otherwise it should stay out of it. Of course we want to make life easier for our doctors, but the patient comes first. (M-sec GER) It is ok for the state not to have a say. This is actually a condition. (M-sec GE)When it comes to the question how the state and political or legal regulations should deal with EOL decision making, rather clear-cut national differences emerged in the FGs. Thus, in the German groups, the state was mainly viewed as a neutral authority which should set general legal framework conditions, but stay out of concrete decision making processes regarding ADs or EOL situations. The state “There is a woman, who … was in a condition that she could not react or decide anymore. There existed an advance directive, but the husband did not want to switch off. He wanted that she will be helped and is given a certain medication. … And this was not possible in Germany. … Now he travelled with her to Switzerland where she, so to say, was put to sleep. And now he sued at the Federal Court of Justice, which has dismissed the suit, but the European Court of Justice has accepted it. Now it will be decided, if the doctors acted here wrongly in refusing this euthanasia. (F-sec GE)In addition, the participants in the German FGs discussed the political regulation of EOL-issues in a European context. Thus, they compared the German setting to the situation in the Netherlands or Switzerland which have more permissive legal regulations regarding assisted suicide or euthanasia. Participants also discussed issues of euthanasia tourism and the different legal and juridical situation between the national and the European levels, addressing the complicated questions arising from transnational standardisation:functions to maintain order and protect its citizens, and not leave it to the whims of everyone” (F-sec IL). It has the power to defend individual life and rights against majority pressure and religious influence and to enforce generally binding rules. In consequence, its impartial courts should decide in cases of conflict and doubt:You need to consider all views and take into account all the contexts of a situation. Probably every one of those who are involved will have arguments that are very convincing. In the end who I think need to decide – it’s the court because the court looks at things objectively – or at least that’s what it should do. (F-sec IL)The Israeli FGs reserved a much more central role for the national state, albeit with completely different motives: The secular speakers put great trust in the state and its bodies  as neutral, rational authorities which are above arbitrary individual preferences as well as partisan quarrels. The state “law was made in agreement with the rabbis; otherwise it would not have become a law” (M-rel IL). This was perceived as a relieving reassurance that legally permissible decisions will also be morally irreproachable.The Israeli religious speakers, on the other hand, articulated the almost diametric view that the Israeli state indeed embodies a substantial religious stance. Many participants expressed a rather strong belief that state regulations regarding EOL decision making are legitimate since (and inasmuch as) they are actually in accordance with Jewish law . Some participants were convinced that the national “primarily a Christian country” (F-rel US) which has also an impact on political regulations of EOL decision making “because here in the United States, we want to protect life, so much, that … you’re going to have some difficulty…, especially when it comes to … suggesting changes” (F-sec US). Since the mainstream Christian culture was seen as influencing political decisions and legal regulations that affect one’s own personal situation at the end of life, there was concern about ensuring individual autonomy and personal rights in EOL decision making among the Jewish Home residents:That’s just as important as how you end your life, having the right to end it. Unfortunately, we don’t have that right. Not legally anyway. And sometimes I worry about that. Cause I live with a lot of pain that I manage, but what if I couldn’t manage it? Would I be able to say I don’t wanna live anymore please say goodbye, I wanna call my family? No! I don’t have that right. That worries me, I wish I could go to Congress and change the laws. Or find a new Dr. Kevorkian to come into the world. [CHUCKLES] (F-sec US)By contrast, the attitudes in the US FGs at the Jewish Home San Francisco showed much more reservation towards the state. Speakers repeatedly expressed the experience of being members of a religious or cultural minority in a political culture dominated by Christianity. The US was perceived as “I mean um, Christians live to go to Heaven, and why, why is there such a fear of death? When Terry Schiavo died that was a big political case here, that was what, that’s what got me to do my first advance directive! And, as soon as she died, her brother went on the air, who was totally against pulling the tubes and said, “Well, she’s in a better place now.” […]: What’s wrong with this picture?! Why wouldn’t you let her go there, if she’s in a better place? (F-rel US)Maybe due to the experience of being marginalized in a predominantly Christian culture, there was a strong awareness of the cultural aspects and differences of attitudes towards EOL in the US groups. In Israel, the Jewish homeland, the strong nexus between religion and nationality could explain the support and trust expressed by many of the Israeli respondents toward the role of the state. By contrast, the US experience could have led to a sense of alienation from mainstream culture and the political governance of EOL. Indeed, this sense was sometimes articulated by way of grim sarcasm in view of the perceived perplexities and inconsistencies of the majority position:Our findings draw attention to the variety and complexity of cultural and religious aspects of EOL decision making. In contrast to stereotypical prejudices, e.g., about rational secularists and unthinking “religionists,” moral reasoning among those identifying as religious often proved to be rather varied and nuanced. Narrow interpretations of individual autonomy in the sense of personal self-determination were complemented with and sometimes relativised by other aspects, such as responsibility for others, natural law, or divine will. Furthermore, purely consequentialist views levelling the moral relevance between withholding and withdrawing treatment were put in perspective.situatedness of religious beliefs and cultural communities becomes visible: Their status and role in individual situations, for example, as consensual or conflicting on the level of personal perspectives, family relationships, and broader social contexts, e.g., as a majority or minority culture within a political system . Moreover, there was a slight bias towards higher education which might have influenced the way EOL-issues were perceived and discussed. Finally, our sample is not symmetrical as it does not include Jewish persons in Germany or Christian persons in the USA or Israel. Further, more systematic empirical research will be needed in order to draw a richer and more differentiated picture of the respective influences of and interactions between the religious commitments and the national situatedness of participants. Moreover, similar studies including additional countries and denominations could help to explore whether laypeople from other national or religious backgrounds and in different sociocultural settings would express divergent perspectives on EOL, e.g., Muslims in the US, Israel, and Germany .practical ethical level, our findings suggest that there are good reasons for being suspicious of academic positions, professional stances, and practical guidelines that seek to derive persons’ moral attitudes towards EOL mainly from their cultural or religious backgrounds. Cultural and religious perspectives seem to be far too complicated to predict individual preferences regarding limitation of care or euthanasia. As our findings show, this may not just be a pragmatic problem of dealing with complexity in the sense that we need more statistical information about additional factors potentially modifying cultural or religious convictions. Indeed, no statistical model, however complex, seems to do justice to the fundamental reflexivity of modern cultural and religious attitudes: the fact that people not just belong to certain cultural or religious communities, but frequently position themselves in relation to their respective commitments by interpreting, reviewing, modifying, or even abandoning them. In this sense, our speakers often explicitly articulate their own stances as “Christian” or “Jewish” while at the same time qualifying them with reference to particular authoritative traditions or cultural circumstances, e.g., as a Jewish minority in a Christian majority culture. Thus, rather than going through great pains to develop elaborate decision making algorithms, our findings suggest that the conditions and standards of actual decision making need to be improved. One important way of doing so would be by strengthening the reflexive and communicative practice of completing ADs [On a ting ADs , as neweting ADs .theoretical level, these findings can provide an important clue for a contemporary bioethics that is willing to engage seriously with cultural and religious diversity. It suggests that the discipline has to be informed by adequate theoretical conceptions and empirical insights. In this sense, culturally informed bioethics should not rely on a do-it-yourself approach to culture, but systematically take into account the approaches and results of contemporary cultural theory. This can help to question essentialist and monolithic conceptions in discussions about EOL decision making. Furthermore, it facilitates the differentiation between various factors that play into “culture,” as well as the analysis of their dynamic interaction and development, e.g., effects of migration, acculturation, collective history, family story, and individual biography [On a iography , 50. Theiography . Hence, iography .The theoretical implications of this study thus encourage bioethics to develop in a direction that can be called “comparative empirical bioethics” . In cont


Genomic research has revealed that schizophrenia is a highly polygenic disease. Recent estimates indicate that at least 71% of genomic segments of 1 Mb include one or more risk loci for schizophrenia . This extremely high polygenicity represents a challenge to decipher the biological basis of schizophrenia, as it is expected that any set of SNPs with enough size will be associated with the disorder. Among the different gene sets available for study , those based on brain co-expression networks represent putative functional relationships in the relevant tissue. The aim of this work was to identify brain co-expression networks that contribute disproportionately to the common polygenic risk for schizophrenia to get more insight on schizophrenia etiopathology.We analyzed a case -control dataset consisting of 582 schizophrenia patients from Galicia, NW Spain, and 591 ancestrally matched controls, genotyped with the Illumina PsychArray. Using as discovery sample the summary results from the largest GWAS of schizophrenia to date , we generated polygenic risk scores (PRS) in our sample based on SNPs located at genes belonging to brain co-expression modules determined by the CommonMind Consortium . PRS were generated using the clumping procedure of PLINK, considering several different thresholds to select SNPs from the discovery sample. In order to test if any specific module increased risk to schizophrenia more than expected by their size, we generated up to 10,000 random permutations of the same number of SNPs, matched by frequency, distance to nearest gene, number of SNPs in LD and gene density, using SNPsnap.As expected, most modules with enough number of independent SNPs belonging to them showed a significant increase in Nagelkerke’s R2 in our case-control sample after the addition of the module-specific PRS in a logistic regression model. Our permutation strategy revealed that most modules did not show an excess of risk, measured by increase in Nagelkerke’s R2, in comparison to equal number of SNPs with similar characteristics. But one module, M2c from Fromer et al., remained highly significant after multiple tests’ correction. Reactome pathways analysis revealed an over-representation of genes involved in “Neuronal System” and “Axon guidance” among genes from this module. Using the same protocol, we detected that the 84 genes from the neuronal system pathway at this module, representing less than 6% of the genes from the module, explained a higher level of risk than expected. “Voltage-gated Potassium channels” and “Neurexins and neuroligins” are overrepresented among the Neuronal System genes from module M2c.Here, we show that, in spite of the high polygenicity of schizophrenia, it is possible to identify gene sets contributing disproportionately to total risk, as it was the case for the M2c module from Fromer et al. These authors have previously reported that the M2c module was enriched in GWAS signals, as well as CNVs and rare variants associated with schizophrenia. Therefore, this module shows a disproportionately contribution to schizophrenia risk.Study supported by Grant PI14/01020 from Instituto de Salud Carlos III, Ministry of Health, Spanish Government.


In “Empathy and its discontents” Bloom  argues tI am often touched by things that I see happen”; , the same cannot be said for compassion. In the Trend in Cognitive Sciences article [1] it is “positive feelings toward others, a desire that others do well and do not suffer…”, but elsewhere it is defined by Bloom similarly as to what Batson  refers t” Bloom, . Adding Keltner, . This co” Bloom, , p. 24 aindividuals who encounter the suffering of large numbers of people (e.g. starvation in Sudan) are more likely to respond with sadness, distress or even apathy as a result of their inability to cope with suffering of such a large magnitude”  but is more in line with his definition of compassion. For instance, the work cited by Bloom on the identifiable victim effect  as the motivator of moral decisions  when making moral decisions. However, some form of emotion (regardless of how biased it is) may be a necessary, though not sufficient, condition for action by both individuals and societies. Zaki  points tAll authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.This research was funded by grants from National Science Foundation, Vetenskapsrådet, and Riksbankens Jubileumsfond.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.