Due to the aeging of the population, there is a societal need for workers to prolong their working lives. In the Netherlands, many employees still leave the workforce before the official retirement age of 65. Previous quantitative research showed that poor self-perceived health is a risk factor of (non-disability) early retirement. However, little is known on how poor health may lead to early retirement, and why poor health leads to early retirement in some employees, but not in others. Therefore, the present qualitative study aims to identify in which ways health influences early retirement.Face-to-face semi-structured interviews were conducted with 30 employees (60–64 years) who retired before the official retirement age of 65. Participants were selected from the Study on Transitions in Employment, Ability and Motivation. The interviews were transcribed verbatim, a summary was made including a timeline, and the interviews were open coded.In 15 of the 30 persons, health played a role in early retirement. Both poor and good health influenced early retirement. For poor health, four pathways were identified. First, employees felt unable to work at all due to health problems. Second, health problems resulted in a self-perceived (future) decline in the ability to work, and employees chose to retire early. Third, employees with health problems were afraid of a further decline in health, and chose to retire early. Fourth, employees with poor health retired early because they felt pushed out by their employer, although they themselves did not experience a reduced work ability. A good health influenced early retirement, since persons wanted to enjoy life while their health still allowed to do so. The financial opportunity to retire sometimes triggered the influence of poor health on early retirement, and often triggered the influence of good health. Employees and employers barely discussed opportunities to prolong working life.Poor and good health influence early retirement via several different pathways. To prolong working life, a dialogue between employers and employees and tailored work-related interventions may be helpful. Many industrialized countries are confronted with an aeging workforce, since the baby-boom generation ages, fertility rates have declined and younger workers enter the labour market later . The ratPrevious research on work disability pensions showed that workers with specific diseases, such as depression , rheumathow poor health may lead to early retirement. Second, little is known on why poor health leads to early retirement in some situations, but not in others. Third, the influence of good health on early retirement has barely been studied. More insight in the role of health in early retirement could be helpful to design interventions aiming to prolong persons working life despite health problems. Hence, the present study aims to identify through which pathways health influences early retirement.Although several longitudinal studies identified poor health as a predictor of early retirement, there is little understanding on This qualitative study was part of a larger qualitative investigation on why persons retire early. The present study focuses on health-related reasons of early retirement. Non-health related reasons of early retirement are described elsewhere .Face-to-face semi-structured interviews with Dutch employees who retired early were conducted. Early retirement referred to retirement before the official retirement age of 65, and excluded persons who retired early due to  compensated work disability or unemployment. Persons reporting compensated work disability or unemployment were excluded because previous research suggested that different factors underlie these transitions out of work .The participants were selected from the Study on Transitions in Employment, Ability and Motivation (STREAM) . The aimInclusion criteria for the present study were: (1) persons had a paid job as an employee at the time of STREAM 2010, (2) retired before the age of 65 in the last 12 months or were going to retire early in the next six months and already formally arranged this with their employer at the time of the interview, and (3) were aged 58 to 64 years at the time of the interview. Moreover persons had given permission in the STREAM 2010 questionnaire to be contacted for additional research.To ensure heterogeneity in the study participants, participants were purposefully selected  based onBetween July 2011 and October 2011, 221 persons were contacted by telephone to check whether they met the inclusion criteria  events, such as education, marriage, divorce, birth, death of family or friends, and periods of illness. The third part focused on the reasons why an interviewee had retired early, or had made arrangements to do so. Understanding of the reasons for early retirement was gained through in-depth follow-up questions. For example, if a person mentioned poor health as a reason for early retirement, the interviewer asked The interviews were carried out by the first author (AdW). The interviewer was familiar with interview techniques, such as clarification, paraphrasing and summarizing. During most of the interviews, a second interviewer was present who took notes (KR or DR). The interviewers did not have a prior relationship with any of the participants. The interviews were carried out in participants’ homes throughout The Netherlands, except for one person, who, upon request, was interviewed at work. Interviews were digitally recorded. All participants agreed to this procedure. On average interviews lasted 80 min (range: 40–156 min). During 9 interviews non-participants were present (spouse (N=7), spouse and daughter (N=1), and granddaughter (N=1)). In one interview the spouse helped the respondent come up with ideas about what was asked. In two interviews the spouse interfered substantially. Issues brought up by these spouses were interpreted with caution in the analysis.Analysis of the interviews took place in four steps. First, the interviews were transcribed fully verbatim. All interviews were listened to at least twice and compared to the transcriptions to check accuracy.Second, 10 interviews were independently summarized, using transcriptions and field notes, and open-coded by AdW and KR. The aim of this step was to understand why and how the transition from work to early retirement had taken place in these persons. Afterwards, AdW and KR discussed summaries, timelines, codes, and coding trees extensively, and reached consensus.In the third step, the remaining 20 interviews were summarized, and open-coded by either AdW or KR. Summaries and coded interviews were cross-checked, and AdW and KR regularly met to discuss findings. During these meetings, data saturation was monitored. No new information on reasons of early retirement was derived from the last interviews.In the fourth step, AdW extracted parts about health from the transcriptions of all interviews. AdW open coded these parts in more detail, and discussed the findings extensively with KR. The aim of this step was to investigate the role of health in the transition from work to early retirement in more detail.Parallel to the four steps described above, AdW and KR regularly met to compare interviews. Leading questions during these discussions were: (1) what similarities can be identified between the stories of the interviewees, and (2) why did certain processes take place in some persons, but not in others. To enhance robustness of the findings, main results were also discussed with other project members (MW and GG). In order to manage the data of the interviews, the computer package for qualitative analysis Atlas.ti 6 was used.The Medical Ethics Committee of the VU University Medical Center Amsterdam declared that no ethical approval was needed to conduct this study. Informed consent was obtained verbally from all participants during the telephone conversation, in which persons were invited for the interview.Characteristics of the study participants are shown in Table ‘Poor health’ was (one of) the reason(s) to retire early in 12 of the 30 participants. Most persons who mainly retired early because of ‘poor health’ experienced a gradual decline in health. Poor health was the main reason to retire in some persons, whereas it was one of a variety of reasons in others. Poor health resulted in early retirement through four different pathways.First, poor health resulted in early retirement in one employee who felt unable to work at all due to health problems, and felt there was no other possibility but to retire early. This 63-year old woman who had suffered from psychological disorders (ADHD and burnout) for many years had quitted paid employment after being granted a work disability pension four years ago. She explained:“In 2007, that was the last year, I became sick in June or July. I worked till autumn, although I said ‘It’s not possible, I am too tired’. The company doctor said ‘No you have to’. I said ‘I can’t do that’, however, I started again. In March I completely collapsed. And in May the general practitioner concluded that I was depressed.”However, during re-examination of her work disability pension, her insurance physician approved her for a 16 hour working week. Both this woman and her employer thought she was not able to work anymore, and together they concluded early retirement would be the best solution. She experienced early retirement as the only possible escape from work.Second, persons who experienced or expected that physical or mental health problems caused a decline in their (future) ability to work decided to retire early (N=5). Health problems made their work physically or mentally (too) demanding, which resulted in feelings of incapability to accomplish working tasks properly. A 63-year old male job coach in a social workplace with a history of heart disease and cancer explained that he retired early because of health problems. He stated that work had been very important to him. Besides, it offered day structure and social contacts. This man felt he was not able to accomplish working tasks properly and explained:“I was there to pump people up, to make them feel good, and now I got the feeling that I needed to be pumped up… and I thought that’s not good, because then you can’t help people in the way that you want to anymore.”This man also felt that he was a burden to his colleagues by being absent on a regularly basis.“The most important reason for me to stop was that I was sick…the work that you miss burdens your colleagues, because they have to take over.”In some persons, negative events at work or certain working conditions, such as aggression, high work pressure, and conflicts, underlied the influence of poor health on early retirement. For example, a 60-year old policeman explained that a traumatic experience when he just started working had bothered him during the rest of his career. He explained that he had suffered from increasing fears in stressful situations and a declining mental health. This was the main reason for him to retire as soon as possible.“I worked for the police for a year and a half, and then in a fight at a pub I got beat up so bad I had to go to the hospital. Well, I probably didn’t deal with that very well, because six weeks later I was working again. At that time they didn’t have a company support group, which luckily they do have now… I really experienced that as a burden during my whole career.”He reported that he did not always perform well due to his traumatic experience:“Just that in a violent situation, that could escalate I hid behind my colleague, or because of the violence I would intervene too quickly.”Third, poor health influenced early retirement in persons with health problems who were afraid of a further decline in health (N=4). For example, a 60-year old civil servant who had suffered from many health problems during his life  was afraid to become disabled if he would continue working:“Look, deciding to stop at 60… that was actually because I didn’t want to end up handicapped early.” […] “When I got that TIA and the oppression complaints, I said ‘60 is my limit’. I don’t want to think of being 62 or 63 and it going down hill from then on, and I get disabled. Then I'd have no one to blame but myself.”Although this man experienced health problems, these problems did not influence his ability to work:“Yes, but it didn’t limit me in my work. I had problems with walking to my work, or when I needed to walk up a lot of stairs. However, in my work it didn’t limit me at all.”Similarly, a 60-year old woman, who worked as a nurse, explained that fear of a further decline in health played a role in her early retirement. She said that she valued her (future) health more than her work:“Because my back is more important than work. That’s how I think about that. I don’t want to end up in a wheelchair in two years. So yeah, these things together made me retire.”In the second and third pathway discussed above, the decision to retire early was often triggered by the financial opportunity to do so. Participants either had personal savings, or could claim a special financial arrangement from their employers. The 60-year old civil servant, mentioned above, for example, explained it would be stupid to risk his health by continuing to work.“And that while I can get a nice arrangement from the age of 60 onwards.”No pressure was felt from the employer or colleagues to retire early. Most persons did not discuss opportunities to (further) adjust the demands of the job to their abilities with their employer. One person reported that she proposed job redesign to extend working life, but according to her employer there were no opportunities within the organisation to do so. Although early retirement was experienced to be voluntary, most of these persons originally had not intended to retire (this) early.Fourth, some employees felt capable of doing their job despite their health problems. Nevertheless, the employer suggested to retire early, sometimes even in a compelling manner (N=2). There was a threat of dismissal, or the employer caused a situation in which the employee felt it was not possible to continue working in an agreeable manner. This often occurred when organisations were restructuring. The push to early retirement by the employer was not directly caused by the health problems, but was related to the work situation that emerged due to these health problems. For example, a 61-year old man who worked for the largest part of his life for one company in various ICT-related jobs explained he retired early due to a complex interplay of “unwanted circumstances”. This man explained that work had always been very important to him. The largest part of his working life he worked 50 to 60 hours a week. Three years before he retired, he got a stroke. He recovered, but it took a year before he was able to start working again. His department had been sold to another company and his job did not exist anymore. He explained that he organized his own re-integration by arranging another job, and received little help from his employer:“I have been out of circulation for a year. When I came back to [company name] there was no work anymore for me. I searched for a job within the organisation and found something.” […] “I organised my own reintegration. Nobody from the personnel department was concerned about that. It’s a pity, but it was just like that.”He was overqualified for this job. The employer was not satisfied with this new situation. They made clear the company wanted to let him go, and proposed a financial arrangement for early retirement. This man was very disappointed in his company. Nevertheless, after tough negotiations, he accepted an adjusted financial arrangement. Although it was a choice to accept the proposed arrangement, it did not feel like a choice to him. The company at least did not create a situation in which this man could have decided to continue working in a pleasant way.‘Good health’ was (one of) the reason(s) to retire early in 5 of the 30 participants. This occurred also in persons who suffered from chronic diseases. These persons reported they wanted to enjoy life while their health still allowed them to do so. In most persons, the awareness of being in ‘good health’ arose, when they were confronted with the finiteness of life. This was caused for example by illness or death of a family member or friend, or death of a colleague immediately after retirement. A 62-year old administrative assistant expressed his fear to die or getting a handicap after years of hard working:“Too often I’ve noticed this in entrepreneurs: they worked themselves half to death until they are at least 65, sometimes older… and when they retire they just die or they got sick, or they get a handicap and can’t do anything anymore. Well, I didn’t want that, I want to do things while I still can.”This man also explained he wanted to spend more time with his wife:“And because my wife didn’t work anymore and was also at home. And I said, listen, I’m healthy and there are things that I still want to do together.”Persons were looking forward to having more time and freedom, and wanted to spend more time on hobbies, family and friends, and holidays. A 62-year old math teacher, who was very motivated to work, felt he had worked long enough and wanted to enjoy the time and the freedom of retirement now. About health he said the following:“But you can also turn it around and say you’d be better off stopping while you’re still healthy so that you can still enjoy it.”In these employees, continuing to work did not fit into their perspective of the future. What they wanted to do in life, while still in good health, did not match with what they expected to be able to do while working. These kind of processes occurred both in persons who enjoyed their work and found it important, and in persons who did not enjoy their work and merely did it for a living. Persons did not discuss opportunities to adjust certain job characteristics with their employer, such as working hours and flexibility, to reach a better fit between their job and private lives.Although ‘good health’ was reported as a reason to retire early, it was often not a primary reason. Besides, it was always accompanied by the financial opportunity to retire early because of savings or a favorable early retirement scheme. One men, in which good health was an important reason to retire early, explained:“And the fact that it was possible. Also financially.” […] “If it would not have been possible financially, I would have had to continue working.”The aim of the present study was to identify through which pathways health influences early retirement. Face-to-face semi-structured interviews with thirty Dutch employees who retired before the age of 65 were conducted. Both poor and good health played a role in early retirement. Poor physical or mental health influenced early retirement through four different pathways, i.e. (a) persons felt unable to work at all due to health problems, (b) poor health resulted in a self-perceived decline in the (future) ability to work, (c) employees were afraid of a further decline in health, (d) or employees with a poor health felt pushed out by their employer, although they themselves did not experience a decline in their ability to work. Good health influenced early retirement, since persons wanted to enjoy life while their health still allowed to do so. The financial opportunity to retire sometimes triggered the influence of poor health on early retirement, and often triggered the influence of good health.Earlier studies have shown that poor health is a predictor of early retirement . HoweverIn agreement with earlier studies, we found that the financial situation of the household and the opportunity to make use of various retirement schemes or financial arrangements played a role in early retirement . The impThe relationship between health and early retirement seems to be in line with the person-job-fit approach . This apEmployers and employees barely discussed the ‘person-job-misfit’. This could be illustrated by the fact that employees who retired early due to a self-perceived (future) decline in their ability to work or fear of a further decline in health, did not discuss these perceptions or anxieties with their employer. Similarly, employers who pushed employees with poor health out of work did not discuss their plans from an earlier phase onwards. A dialogue between employees and employers and measures directed to the prevention of (future) misfits might be helpful to prolong working life in good health and with good work ability. The different pathways by which health influences early retirement suggest that these measures need to be tailored to the individual. For example, it could be hypothesized that the 63-year old job coach, who retired early since he experienced a decline in his ability to work, could have continued working if he had received other responsibilities than “to pump people up”. Besides, it could be hypothesized that the 62-year old math teacher might have continued working if flexible working hours would have enabled him to enjoy the things he liked outside of work. We recommend future research to investigate why this dialogue between employers and employees is often lacking and what an effective dialogue should include.how health influences early retirement. Another strength of the present study is that we conducted interviews with persons who had retired early, or already formally arranged to do so within six months after the interview, instead of persons who only intended to retire early. Hence, we studied early retirement behavior. Previous studies often investigated the intention to retire early [A major strength of the present study is the qualitative design, which allowed us to explore re early ,22,23 orre early , but facre early .However, this study also has limitations. First, in qualitative studies the researcher is an important instrument, both in data collection and data analysis . This maTaken together, poor and good health influence early retirement via several different pathways. To prolong working life, a dialogue between employers and employees, from an early phase in the career onwards, and work-related tailored interventions may be helpful.The authors declare that they have no competing interests.All authors made a substantial contribution in the design of the present study. AdW and KR were responsible for data collection. AdW and KR analyzed the interviews and AdW, GG, KR, and MW regularly discussed the findings. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/292/prepub


To review the context of food insecurity in Greenlandic children, to review and compare the outcomes related to food insecurity in Greenlandic children, in other Arctic child populations and in other western societies, and to explore the measure used by the Health Behaviour in School-aged Children (HBSC) study.The study includes literature reviews, focus group interviews with children and analyses of data from the HBSC study. HBSC is an international cross-national school-based survey on child and adolescent health and health behaviour in the age groups 11, 13 and 15 years and performed in more than 40 countries. The item on food insecurity is “Some young people go to school or to bed hungry because there is not enough food in the home. How often does this happen to you?” .The context to food security among Inuit in Arctic regions was found to be very similar and connected to a westernization of the diet and contamination of the traditional diet. The major challenges are contamination, economic access to healthy food and socio-demographic differences in having a healthy diet. The literature on outcomes related to food insecurity in children in Western societies was reviewed and grouped based on 8 domains. Using data from the Greenlandic HBSC data from 2010, the item on food security showed negative associations on central items in all these domains. Focus group interviews with children revealed face and content validity of the HBSC item.Triangulation of the above-mentioned findings indicates that the HBSC measure of food shortage is a reliable indicator of food insecurity in Greenlandic schoolchildren. However, more research is needed, especially on explanatory and mediating factors. Food insecurity exists when people do not have adequate physical, social or economic access to food and is the opposite to food security, that is, defined as “a situation that exists when all people, at all times, have physical, social and economic access to sufficient, safe and nutritious food that meets their dietary needs and food preferences for an active and healthy life”.In 2004, the Greenland Home Rule Government published a national report on food and food policy. The report was meant to provide the basis for formulating a suitable food policy for Greenland. For the first time, it gave epidemiological evidence of food insecurity among Greenlandic children, by revealing that 11% of Greenlandic schoolchildren in grade 6–11 (11–17 years old) reported that they “often” or “always” would go to school or to bed hungry –6.Food insecurity is an important child public health problem. In the literature, in Western countries, the evidence also shows that food insecurity in children is associated with a range of adverse effects on health, development and academic performance, and is connected to behavioural and psychosocial problems –10. HoweWith this background, the aims of this study was: (a) to review the context of food security and insecurity in Greenlandic and Inuit or Aboriginal children in other Arctic countries; (b) to give the prevalence of food insecurity in children in Arctic countries with an Inuit population and comparing food insecurity in these countries and Denmark using the HBSC item; (c) to review associations to food insecurity found in indigenous Arctic child populations, in child populations in other Western countries, and to reporting hunger using the HBSC measure; and (d) to explore the validity of the HBSC measure on food security used in Greenland.The research design included literature reviews, focus group interviews and analyses of data from the international and the Greenlandic part of the HBSC study. HBSC is an international cross-national school-based survey on child and adolescent health and health behaviour in the age groups 11, 13, and 15 years. The survey collects comparable data on health and health behaviour in more than 40 countries and regions in Europe, North America and Israel, every 4 years .The HBSC item on going to bed hungry, or to school, was added in the international HBSC survey in the 2001/2002 study in acknowledgement of the fact that HBSC lacked a measure of very low socio-economic status. However, by wording, the HBSC item measures food insecurity, and not poverty. The issue is: “Some young people go to school or to bed hungry because there is not enough food in the home. How often does this happen to you?” .Aim I: To review the context of food security and insecurity in Greenlandic and Inuit or Aboriginal children in other Arctic countries: A literature search in PubMed on “Greenland” and (“food security” or “food insecurity”) and (child*) was performed. The search had 3 hits, 1 was relevant  and child*. Limitations included: Humans, English, All Child: 0–18 years. This search yielded 391 hits. A total of 49 reviews were selected; after reading the summaries, 5 reviews  to explore the content validity of the HBSC item, and Aim IVb) to explore outcomes associated to food insecurity in the HBSC study, compared to associations found in other studies. Aim IVa: To explore the content validity of the HBSC item in Greenlandic schoolchildren, 2 group interviews with children in grade 9 (aged 14–15 years) in a public school in Nuuk were analyzed. The interviews were carried out in Greenlandic and taped. The same interview guide, including questions about understanding of the question, thoughts about the question and its content, was used. The interviews were transcribed and translated into Danish by the interviewers. Analyses were performed following Kvale's work  were retrievable using the HBSC item. For the 8 domains revealed under Aim III, the following items were analyzed: (a) Dietary consumption and nutritional outcome: “Eating breakfast on all schooldays” and “Eating fruit and drinking soft drinks nearly daily (5–6 times a week or more)”; (b) Physical health and development: “Physical symptoms  nearly every week” and “Good or excellent self-rated health”; (c) Life satisfaction and mental health: “Psychical symptoms  nearly every week” and “Having the best possible quality of life”; (d) Behavioural and psycho-social functioning: “Never been bullied”, “Never bullying others” and “Feel accepted by classmates”; (e) Academic performance: “Good or very good academic achievement” and “Low pressure from schoolwork”; (f) Risk factors in the home environment: “Difficult to talk to mother or father about something that really bothers” and “Eating dinner with parents every day”; (g) Health behaviours: “Tooth brushing twice a day”, “Daily smoking” and “Have been drunk more than once”; and (h) Socio-demographic risk factors: “Age” (11–12 years old/13–14 years old/15–17 years old), “Gender” (boy/girl), “Low family affluence” (proxy for high/low economic access) and “Living in a settlement” (proxy for living remote). The exact wording of the item questions in English can be found in the International HBSC Study protocol (http://www.hbsc.org), and in Danish or Greenlandic in the national reports , have not been undertaken in Greenland, as opposed to Canada and the United States. In Greenland, the only data sources on the prevalence of food insecurity found were regarding food shortage (hunger) either using self-reported data from schoolchildren or parental reports in 0–14 year-olds , 6, 17. always went to bed or to school hungry, because there was no food in their home, and an additional 4% stated that it happened often, while the proportion that never went to school or to bed hungry was 69%  and the lowest in rural girls in grade 9–10 (23%)  , therebyoften or sometimes during the year prior to the study, compared to 7% for overall Canadian households . For always, the proportion in the 11-year-old Greenlanders was nearly 10 times the average of HBSC countries, while the 13 and 15 year-olds reported about 4 times the HBSC average. In all age groups, Greenlandic children had the lowest proportion reporting never going to bed or to school hungry.Analysing HBSC data  did confThe HBSC samples are national samples. The comparison cannot take the inter-country variation found by other methods into consideration. The data from Yukon  indicateIn indigenous Arctic populations and other Western child populations, the relationships between food insecurity and children's health, behaviour and development seem to vary according to the child's age, gender and ethnicity . As statshort on money before payday and that their children were aware of the situation, especially if short on food. The children expressed that they sometimes did not get enough to eat at home or did not bring enough food for lunch in school. They expressed complex strategies from giving up, lower their expectations, eat at family or friends or get a job. The motivation to get a job was connected to wanting to help the family economy and for them to be able to cover their own needs . However, for Dietary consumption and nutritional outcomes (Eating breakfast on schooldays); Physical health ; Behavioural and psychosocial functioning (Never been bullied and Never bullied others); Academic performance (Good or very good academic achievement and Not pressured by school work); Risk factors in the home environment (Eating dinner with parents); and Health behaviours (Tooth brushing twice a day), highly significant differences were found. Also, on Eating fruit 5–6 times a week or more, Physical symptoms  nearly every week and Having the best possible quality of life significant differences were found, while with regard to Drinking soft drinks, Psychical symptoms, Feel accepted by classmates, Talking to their father, Daily smoking and Being drunk more than once, no significant associations were found (Comparing outcomes on central items associated to food insecurity between Greenlandic children reporting having and never having experienced going to bed or to school hungry, because there was no food at home, was performed on the above-mentioned items and shown in re found .The background on which food security in Arctic populations must be evaluated is the rapid dietary transition . The shiFood and eating have important social, cultural and symbolic functions. What we eat is “a sign of membership”, social status and spiritual worth . TherefoFood insecurity was found to be associated with economic access to healthy foods and to socio-economic factors. However, the relation between traditional food consumption, food insecurity, poverty and socio-demographic factors is complex. The reviewed studies indicate that food insecurity in children in both Greenland and Canada is connected to a higher consumption of traditional foods, but also to a higher consumption of soda and junk food, as well as having less variation in the diet , 21. ThiAt the population level, socio-economic differences in having a healthy diet are found , and lowWithout doubt, food insecurity in children exists in Greenland too. However, it has been sparsely investigated, and only data on more severe food insecurity measured as hunger were found –6, 17. TIn fact, children are often better reporters than their parents of their own experiences of internal state. Greenlandic children in poor homes expressed many of the same coping strategies on food insecurity as expressed by, for example, U.S. children , 48. TheThe HBSC study in Ireland found the relative odds of hunger somewhat connected to family management. Similarly, in Greenland an association between food insecurity and the home environment has been speculated . These iThe prevalence of food insecurity seems to vary widely around the Arctic Circle. The different measures on food security used in Greenland, Canada and the United States indeed make direct comparisons difficult. Only one study with Greenlanders has used the modified USDA scale and thereby can be compared to Canadian data . It founBecause of the complex, multidimensional nature of food insecurity and the strong subjective element of the construct, it is difficult to identify a simple “gold standard” against which food insecurity scales can be validated . Using oIn conclusion, the study revealed face and content validity of the HBSC item on food insecurity. It found that the proportion of people reporting food insecurity is valid, and the findings of same associations between food insecurity and negative outcomes to key items on same dimensions as revealed in the literature from western and Arctic indigenous populations give indirect support to the validity of the measure in the Greenlandic setting. Although further research on explanatory and mediating factors is needed, the study indicates that the HBSC measure is a reliable indicator of food insecurity in Greenlandic schoolchildren.


Contemporary neuroscience seems to be undergoing an intriguing pragmatist turn Engel, . Clark’spotentiating. A relevant affordance can generate bodily “action readiness” (Frijda, An animal’s eco-niche is made up of affordances Gibson,  or possi Frijda, , 2007, t Frijda, . Just asAction-oriented predictive processing as described by Clark is, we are sure, an important part of the answer to these hard questions (Kiverstein, The phenomenology of skillful unreflective action in everyday life provides us with a clue here. In a skilled individual’s responsiveness to a field of relevant affordances (Rietveld et al., No doubt this can partly be explained in terms of action-oriented predictive processing and the cascades of generative models that are able to successfully predict how to bring about the sensory consequences the agent anticipates. However we would argue that a challenge for Clark remains to integrate this neural level explanation with what the phenomenology of everyday agency tells us. More precisely, we must account for how neural processing is always taking place within a particular situation in which specific possibilities of action stand out from a larger landscape of affordances as soliciting or motivating for the agent.


Mammalian brains span about four orders of magnitude in cortical volume and have to operate in different environments that require diverse behavioral skills. Despite these geometric and behavioral diversities, the examination of cerebral cortex across species reveals that it contains a substantial number of conserved characteristics that are associated with neuroanatomy and metabolism, i.e., with neuronal connectivity and function. Some of these cortical constants or invariants have been known for a long time but not sufficiently appreciated, and others were only recently discovered. The focus of this review is to present the cortical invariants and discuss their role in the efficient information processing. Global conservation in neuroanatomy and metabolism, as well as their correlated regional and developmental variability suggest that these two parallel systems are mutually coupled. It is argued that energetic constraint on cortical organization can be strong if cerebral blood supplied is either below or above a certain level, and it is rather soft otherwise. Moreover, because maximization or minimization of parameters associated with cortical connectivity, function and cost often leads to conflicts in design, it is argued that the architecture of the cerebral cortex is a result of structural and functional compromises. Bigger mammals tend to have bigger brains Jerison, . There eCerebral cortex, which is responsible for processing sensory, behavioral, and cognitive informations  is approximately independent of brain size . Data for adult mammals of different sizes show that this ratio is conserved, and excitatory synapses comprise about 80–90% of all synapses in the cerebral cortex . This conclusion agrees well with the data in Table Apart from neurons the cortical tissue contains non-neuronal cells called glia. There are different types of glia, each with a specific role in the nervous system. The most numerous are astrocytes  in capillaries provides two critically important metabolic substrates, oxygen and glucose, to neurons, synapses, and astrocytes Figure . ATP mol+, K+, Cl−, and Ca++; Ames, The energy released from hydrolysis of ATP is used to maintain the brain in a state that is far from thermodynamic equilibrium, which is mainly characterized by differences in intra- and extra-cellular concentrations of various ions  at postsynaptic terminals of glutamatergic synapses. Na+ influx and corresponding K+ efflux counteract the ionic gradients and pull the whole system closer to a thermodynamic equilibrium . A single action potential has only a marginal influence on the neural gradients, yet, a cumulative effect of many action potentials in a short period of time may significantly alter the gradients because the pump kinetics are slow  diminish with increasing brain size in a similar allometric pattern across brains of different species. From this, it follows that 1 mm3 of human visual cortex uses about four times less energy than 1 mm3 of mouse visual cortex, and similarly for other cortical areas. These facts may suggest a common mechanism of energy utilization in different brain regions that is evolutionary conserved from small to large mammals.Given the above scaling for total brain metabolism, it is easy to notice that brain metabolism per volume, i.e., CMR  decreases with brain volume, with an exponent about −0.15 or close to −1/6  and microvascular parameters such as CMR, CBF, and capillary length density scale with cortical volume Values of parameters used in allometric scalings are always mean values averaged over different cortical areas. However, usually there is some small local variability in all parameters. Regional coupling between metabolism and neuroanatomy means that regional and laminar variabilities in metabolic/microvascular and structural parameters should be correlated. Data for visual cortex in adult primates (human and macaque monkey) indicate that capillary length density is the largest in the middle layers 4 and 2/3, and the smallest in boundary layers 1 and 5/6  cause neuron death in the process known as neurodegeneration  leading to neuron damage Ingvar, . AlthougGiven a possible brain damage associated with epilepsy, one can ask how much energy can be supplied to the cortex? Is there any upper limit? Theoretical arguments indicate that indeed capillary dimensions (capillary length density) set such a limit  = ρs/(ρ2nV). Neuron density ρn decreases with cortical volume V as ρn ~ V−α, where the scaling exponent α is generally different for different mammalian orders, and takes values: α = 0.37 for rodents and α = 0.12 for primates (Herculano-Houzel, s is scale invariant, we obtain that neural connectivity p scales with cortical volume as p ~ V2α − 1. In particular, for rodents we get p ~ V−0.26, while for primates we obtain p ~ V−0.76. These results imply that cortical networks at a microscopic level become sparser as they increase in size. The effect is more pronounced for very large primate brains. For example, for human cortex with N ~ 2· 1010 (Pakkenberg and Gundersen, M ~ 3· 104 (DeFelipe et al., p ~ 10−6, whereas for mouse with N ~ 107 and M ~ 7· 103 (Braitenberg and Schüz, p ~ 7· 10−4. Thus, the average microscopic connectivity in the human cortex is about 1000 times smaller than that in the mouse cortex.Let us start with the microscopic connectivity between neurons. We define an average probability of connection between two neurons as V−1/3, whereas the density of capillary length decreases slightly weaker, as V−1/6 (Karbowski, Interestingly, the number of capillaries per cortical volume and capillary length density also decline allometrically with brain size across mammals, although not that dramatically (Karbowski, On a macroscopic level the cerebral cortex is composed of functional areas, each containing many micro modules known as columns. The functional cortical areas have to be somehow connected for an efficient exchange and integration of information (Tononi and Edelman, A related quantity to cortical connectivity is the so-called path length or a degree of cortical separation, which is associated more directly with the efficiency of communication in a network (Karbowski, The pattern of cortical connectivity, especially that on the macroscopic level is probably very important for proper cortical functioning. There are many experimental studies suggesting that some mental disorders such as schizophrenia or autism are caused by altered long-range neural connectivity (McGlashan and Hoffman, One of the main consequences of the cortical conservation, which is not fully realized and appreciated, is the existence of trade-offs between structural design of the cortex, its cost, and a way the cortex can effectively process and store information. These trade-offs are present on micro-scale in axonal and dendritic arbors design (Wen et al., + ions that have to be pumped out, which costs additional energy. As a result, there exists some compromise between enhancing neural connectivity and reducing the consumption of metabolic energy, which is visible in microscopic and macroscopic patterns of wiring (Bassett et al., The analysis above shows that the connectivity between neurons decays quickly with brain size, which generally may not be beneficial for cortical communication because this decaying trend enhances neuronal isolation in bigger brains. To prevent a complete isolation, one would have to increase the length of axons and dendrites to place more synapses on them. However, such an enlargement of neural wiring leads to its larger surface area and volume. This, in turn, is associated with higher influx of NaCortical path length is a measures of neuronal separation. If that separation is large, then the path length is large and interneuronal signal does not reach its target on time. That situation cannot be beneficial for an animal, which often has to respond fast to environmental inputs. Therefore it seems that evolution should keep the cortical path length as small as possible (Karbowski, In a similar fashion, if we want to increase the speed of electric signals traveling along unmyelinated axons in gray matter, we need to increase axon thickness. This is because the conduction velocity of unmyelinated axons is proportional to the square root of axonal diameter Hursh, .Energy available for neurophysiological processes in the cortex is not freely given, but instead it is restricted by the capillary size and glia number. In particular, cerebral metabolic rate is proportional to the fraction of cortical volume occupied by capillary length (Boero et al., f declines with increasing brain size, with an allometric relationship f ~ V−0.15, where V is the cortical volume (Karbowski, How neural spiking activity depends on brain size? Estimates based on cerebral metabolic data show that the average neural firing rate Moreover, larger brains have neurons with longer fibers (Braitenberg and Schüz, The scaling approach across species taken in this review, as every approach, has its limitations. First, the available empirical data is limited. Therefore, the number of mammalian species used in the scaling plots, and thus the number of data points, is not large. This fact can potentially alter precise bounds of statistical confidence intervals used in describing the scaling trends. Second, each data point represents an average value for a given species. It is good to keep in mind that there is always some degree of variability among individuals of the same species or even across cortical regions of the same individual. Error bars in Table One has to realize that the two above limitations, i.e., small number of species and variability in parameters of interest, may in some cases preclude a clear-cut interpretation of the data. This is the case with surface density of neurons in the cortex, which initially was claimed to be invariant with respect to brain size (Rockel et al., One of the consequences of metabolic processes in neurons is heat generated in the cerebral tissue (Erecinska et al., Despite a huge literature concerning cortical neuroanatomy and metabolism, these two subjects have been treated mostly separately in the neuroscience community. A few exceptions in evolutionary and developmental neuroscience dealt with a question of energetic limitations on brain size Martin, , and witIt is possible that constancy of some of the cortical parameters could be a result of an evolutionary optimization of metabolic, vascular and functional characteristics. However, as was shown above on several examples, any optimization procedure, i.e., maximization and/or minimization of one group of parameters, can lead to a suboptimal performance of another group. Therefore, it is argued that the observed cortical architecture is a result of structural, functional, and energetic compromises, which had to appear during a long evolutionary process.The importance of metabolic and hemodynamic invariants discussed in this review may go well beyond traditional evolutionary and developmental neurobiology. For example, they can be used in mathematical models of brain activity, which practically neglect any conservation rules (Dayan and Abbott, The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The anatomy of the clitoris is described in human anatomy textbooks. Some researchers have proposal and divulged a new anatomical terminology for the clitoris. This paper is a revision of the anatomical terms proposed by Helen O'Connell, Emmanuele Jannini, and Odile Buisson. Gynecologists, sexual medicine experts, and sexologists should spread certainties for all women, not hypotheses or personal opinions, they should use scientific terminology: clitoral/vaginal/uterine orgasm, G/A/C/U spot orgasm, and female ejaculation, are terms that should not be used by sexologists, women, and mass media. Clitoral bulbs, clitoral or clitoris-urethrovaginal complex, urethrovaginal space, periurethral glans, Halban's fascia erogenous zone, vaginal anterior fornix erogenous zone, genitosensory component of the vagus nerve, and G-spot, are terms used by some sexologists, but they are not accepted or shared by experts in human anatomy. Sexologists should define have sex, make love, the situation in which the orgasm happens in both partners with or without a vaginal intercourse. Findings from the disciplines of embryology, anatomy, and physiology of the clitoris should form the basis of the discourse about the biological basis of the female orgasm. The anatomy of the clitoris is described in human anatomy textbooks, but often it is neglected by sexological textbooks, for this reason some researchers have proposal and divulged a new anatomical terminology for the clitoris. This review is a revision of the anatomical terms proposed by Helen O'Connell, Emmanuele Jannini, and Odile Buisson.This is a revision of the Helen O'Connell and Emmanuele Jannini articles published by Journal of Sexual Medicine and of Odile Buisson's article published by Gynécologie Obstétrique Fertilité.O'Connell et al. in The Anatomy of the Distal Vagina: Towards Unity  wrote: “The aim of this presentation is to provide a comprehensive overview of anatomy of the distal vagina.” “This would aid communication between clinicians, researchers, and the nonclinician regarding this anatomy.” “The other components are the walls of the vagina and its associated exocrine glands,” “which will focus instead on the distal vagina, the site of the female sexual response and the area where confusion in terminology most exists” .O'Connell et al. fail to describe the “anatomy of the distal vagina”: for instance in her article nothing is written about the size of the “distal vagina” and of its gross and microscopic anatomical structure. Moreover, the term “distal vagina” is not used in human anatomy and there are no exocrine glands in the walls of the vagina; the focus of the female sexual response is not the “distal vagina,” but the clitoris . There is general consensus about female sexual anatomy and the standard terminology employed in this respect, such as the anatomical terms used to describe the components of the vulva in all human anatomy textbooks –7.O'Connell et al. wrote: “There is no uniformity to the vagina, the distal vagina having distinctly different properties to the proximal vagina, reflecting their different developmental origins from the urogenital sinus and Mullerian duct ” 1]..1].Fliegner, quoted by O'Connell et al. , in 1994The vagina and cervix develop without the involvement of the Müllerians ducts; only just the body of the uterus and uterine tubas are formed by the Müllerian ducts, and in males the prostatic utricle is the homologue of the female vagina , 6, 10.“There is also substantial variation in the structure of the walls. For example, the lateral walls are very different from the posterior vaginal wall” .For this statement, in O'Connell et al.'s article, there are no references and the authors do not clarify if they relate to the gross or microscopic anatomy and they do not write the differences between lateral and posterior walls of the vagina.“The distal vagina is a structure that is so interrelated with the clitoris that it is a matter of some debate whether the two are truly separate structures.” “Deep to the vaginal wall mucosa laterally lies only the clitoris.” .The vagina has no anatomical relation with the clitoris  2–7].–7.2–7].“The urethra is separated from the distal vagina by a discrete white layer referred to as the periurethral fascia” .The anterior vaginal wall is separated from the posterior urethral wall by the urethrovaginal septum (its thickness is 10–12 mm) .“Although the literature written for lay readers implies that the urethra is erectile in nature or is surrounded as a tube by vessels, this idea is not supported by anatomical studies” .The corpus spongiosum of the female urethra is reported in anatomy textbooks –7 and in“The labiae, like the clitoris, are derived embryologically from the undifferentiated phallus” .Only the corpora cavernosa of the clitoris and the glans are formed from the phallus. Labia minora, vestibule of the vagina, and vestibular bulbs are formed from the pelvic and phallic parts of the urogenital sinus and from the urogenital folds , 13–15.O'Connell et al. wrote “Clitoral bulbs” . Clitora“The urethral orifice and distal urethra are surrounded by the erectile tissue of the clitoral bulbs.” “The urethra is encircled by the clitoris to a variable degree” .The external urethral orifice is situated on the vaginal tubercle  and it is not surrounded by the erectile tissue of the vestibular bulbs; the female urethra is not encircled by the clitoris, and it is not in related with the crura and body of the clitoris –7, 13–15“The clitoris is composed of the glans, which is its only external manifestation.” “the clitoris itself, in turn, being covered by the vulva” .The clitoris is not “covered by the vulva”: it is a part of the vulva. The whole clitoris  is an external genital organ: the glans and body are visible while the roots are hidden, therefore they are not “internal” –7, 13–15“The tiny glans clitoris, a component of the clitoris composed primarily of large nerve trunks and sensory receptors, is often referred to as the clitoris.” .In O'Connell et al.'s article there are no references for this assertion, and in the pictures of the vulva in anatomy textbooks always there is the body of the clitoris –7.“This area was emphasized in the descriptions of Kobelt, and more recently by Arien, Sevely, and Douglas.” .The author “Arien” cited by O'Connell et al. does not exist, and Reference 29 is not correct, the authors are not “Arjen A, Turnhout V, Hage J, Diest P.”, but Van Turnhout AA, Hage JJ, van Diest PJ . Also in“The interrelationship between the clitoris, urethra, and vagina has been studied by various modalities including ultrasound [34], MRI [35]” .The authors quoted in Reference 35 by O'Connell et al. are Georgiadis et al. , also th“The clitoral complex, composed of the distal vagina, urethra, and clitoris, is the location of female sexual activity, analogous to the penis in men” .This definition has no embryological, anatomical, and physiological support and in the male penis there is no vagina –16, 19. In Measurement of the Thickness of the Urethrovaginal Space in Women With or Without Vaginal Orgasm: A Response from the Study Authors , answering to “Rebuttal” of Professor Vicentini , JanniniGravina and Jannini et al. wrote: “Gräfenberg described an erogenous zone located in the anterior vaginal wall and subsequent studies have correlated the focus of female sensitivity with the external urethral sphincter” .G-spot of Ladas, Whipple, and Perry does not correspond to the external urethral sphincter but to the intraurethral glands: Komisaruk et al., in 2006 write “Stimulation of the pelvic nerve may also occur with stimulation of the area of the G-spot  and may also account for the reports of orgasm and female ejaculation from the urethra experienced by some women” (and why in this book “the science of orgasm” nothing is written about the clitoris?) .Furthermore the authors also write: “between the thickness of urethrovaginal space, or G-spot,” “clitoris-urethrovaginal complex, also known as the G-spot” : therefoGravina and Jannini et al. write that they made an echography of the G-Spot , but in “Female genital anatomy and the physiology of female sexual function have been scientifically neglected in the past” .The female genital anatomy has been described in Human Anatomy textbooks and the female genital physiology has been described for the first time in Dickinson's textbooks in 1949 and subsequently by Masters and Johnson , 19, 25.“The urethrovaginal space  seems critical, being constituted of fibroconnective tissue and large numbers of blood vessels, glands, muscular fibers, and nerve endings” .Urethrovaginal space is an incorrect term from a scientific point of view, the anterior vaginal wall is separated from the posterior urethral wall by the urethrovaginal septum –6. In ad“The most interesting finding of our study is the evidence that women who experience vaginal orgasm have an urethrovaginal space thicker than those who do not … The self-reported nature of presence or absence of vaginal orgasm is another strong limitation of our findings … By vaginal orgasm we mean the orgasm experienced after direct stimulation of the anterior vaginal wall by penetration” .One vaginal orgasm “at least once in the past month,” in women that “reported at least two acts of sexual intercourse per week” , is not “As there is now evidence that the clitoris is related to the distal third of the urethra in the perivaginal space … The close physical proximity of the urethra and the clitoris to the anterior vaginal wall suggests an association between these anatomical structures and sexual function … The presence of pseudocavernous tissue  in the anterior vaginal mucosa is a frequent but not universal finding (86%)” .The vagina has not anatomical relation with the clitoris and in the anterior vaginal mucosa there is no “clitoral bulb” –7!“In fact, the anterior vaginal wall is an active organ, transmitting, during intercourse, the effect of penile thrusting in the vagina to the clitoris, by stretching the two ligaments that insert around its base” .Gravina and Jannini et al. have quoted a “Current Opinion” of 200 words : this st“However, our data cannot directly demonstrate that the thickness of an anatomical space may generate a mechanism that can be related to the creation of an orgasm … But, in conclusion, the results here presented allow us to speculate that there may be a functional correlation between the thickness of urethrovaginal space, or G-spot, and the ability to experience the vaginal orgasm” .Sexual medicine experts should spread scientific notions and not speculations!G-spot is not a term used in human anatomy: Grafenberg, in 1950, describes some cases of female and male urethral masturbation and the corpus spongiosum of the female urethra. Grafenberg wrote that the intraurethral glands could only release fluids that are not urine during the orgasm: but he did not report an orgasm of intraurethral glands. There are no ultrasonographic images or anatomical pictures of the G-spot, and the female prostate has no anatomical structure that can cause an orgasm: G-spot does not exist and the hypothetical area named G-spot should not be defined with Grafenberg's name , 13, 28.In The G-spot and Lack of Female Sexual Medicine (Gynécologie Obstétrique Fertilité 2010), Odile Buisson writes: “G-spot was popularized by sexologist Beverly Whipple in 1980 in honor of the gynecologist Ernst Grafenberg”, “the exact anatomy of the clitoris only recently has been recognized”, “the dynamic study of the clitoris urethra-vaginal complex,” “the vaginal penetration causes a close contact between the inner clitoris and the distal anterior vaginal wall” .G-spot is a hypothesis, and there is no anatomical evidence of the vaginal orgasm which was invented by Freud in 1905, without any scientific basis , 28, 30.Clitoris is localized under the urogenital diaphragm, in front the pubic symphysis and in the anterior perineal region and the roots of the clitoris are located in contact with the ischiopubic ramus, covered by the ischiocavernosus muscles: they cannot come into contact with the anterior vaginal wall and the “inner clitoris” does not exist , 13, 30.The female perineal urethra, which is located in front of the anterior vaginal wall, is about one centimeter in length and the G-spot is located in the pelvic wall of the urethra, 2-3 cm into the vagina. The male penis cannot come in contact with the venous plexus of Kobelt (situated until the angle of the clitoris) or with the roots of the clitoris (which do not have sensory receptors or erogenous sensitivity) during vaginal intercourse  2–7, 1313, 30.Buisson stated that the clitoris is composed of two arcs, the first consisting of two corpora cavernosa along the right and left ischiopubic ramus, with a length of 12–15 cm; they join on the summit of the vulva to form a bend 90 degrees forward: the raphe; the raphe ends in the glans clitoris, the visible part of the clitoris. The second arc consists of two bulbs that surround the lateral walls of the vagina . This BuIn the article by O. Buisson there are only hypotheses to explain others that are conclusions without scientific basis (and she does not write how many women would have the G-spot): the clitoral stimulation is important to have an orgasm and the clitoris exists in all women , why not simply stimulate, during intercourse with penetration of the penis, the clitoris with a finger ?The meaning of words is important in science, but particularly in the female sexuality: gynecologists, sexual medicine experts, and sexologists should spread certainties for all women not hypotheses or personal opinions, they should use correct scientific terminology: clitoral/vaginal/uterine orgasm, G/A/C/U spot orgasm, female ejaculation, are terms that should not be used by sexologists, women, and mass media; clitoral bulbs, clitoral or clitoris-urethrovaginal complex, urethrovaginal space, periurethral glans, Halban's fascia erogenous zone, vaginal anterior fornix erogenous zone, genitosensory component of the vagus nerve, and G-spot, are terms used by some sexologists but they are not accepted or shared by experts in human anatomy .Women have the right to feel sexual pleasure : in all I hope that this review article will give rise to some fruitful discussions on the topic of female sexuality.


Most evolutionary processes occur in a spatial context and several spatial analysis techniques have been employed in an exploratory context. However, the existence of autocorrelation can also perturb significance tests when data is analyzed using standard correlation and regression techniques on modeling genetic data as a function of explanatory variables. In this case, more complex models incorporating the effects of autocorrelation must be used. Here we review those models and compared their relative performances in a simple simulation, in which spatial patterns in allele frequencies were generated by a balance between random variation within populations and spatially-structured gene flow. Notwithstanding the somewhat idiosyncratic behavior of the techniques evaluated, it is clear that spatial autocorrelation affects Type I errors and that standard linear regression does not provide minimum variance estimators. Due to its flexibility, we stress that principal coordinate of neighbor matrices (PCNM) and related eigenvector mapping techniques seem to be the best approaches to spatial regression. In general, we hope that our review of commonly used spatial regression techniques in biology and ecology may aid population geneticists towards providing better explanations for population structures dealing with more complex regression problems throughout geographic space. Most evolutionary processes occur in a spatial context. The genetic variation originated by random mutations and drifting within local populations will disperse through geographically-mediated gene flow, whereas selection gradients will appear, since environmental factors will also be geographically arranged. Consequently, since the late 1970's, several techniques in spatial analysis started to be used to investigate these processes by analyzing spatial patterns of genetic variation among populations . Inferences on micro-evolutionary processes have been reached based on parameters extracted from autocorrelation analysis, through a descriptive and exploratory analysis of the spatial structure underlying genetic variation. However, recognition that isolation among populations caused by exogenous effects (including anthropic disturbances)  or intensity of anthropogenic effects that, for example, could create patterns through increasing isolation. The standard approach to analyze this kind of data is to perform a linear regression of allele frequencies (Y) against the explanatory variable (X), so that the observed frequency in each a and b are the linear (intercept) and angular (slope) coefficients and εi is the residual term, given by the difference between observed and expected frequency of the population i. In a matrix form, the equation above can be written  by:where k explanatory variables (plus the intercept term β0 or a). Thus, the R2 of this regression model, given by the ratio between predicted and observed sum of squares, will provide the amount of variation in allele frequency that is “explained” by the explanatory variables. It is assumed that the ε term is normally distributed with constant variance, and is independently distributed among observations, so that covariance matrix C among residuals is equal to:where β is the vector with coefficients associated with 2 is the variance of the residuals, which is constant throughout the diagonal of C, and I is an identity matrix. Under these assumptions, the coefficients in the vector β can be obtained by:where σi.e., which are linked by higher levels of gene flow) show similar deviations from expected allele frequency by effects of X. This problem can be formally evaluated by checking whether the residuals E of the model for local populations closer in geographic space are more similar than expected by chance alone. In other words, this can be evaluated by estimating spatial autocorrelation in model residuals ε.These coefficients are usually estimated by using least-square techniques, and this simple non-spatial regression model will be called here Ordinary, or non-spatial, Least-Squares (OLS) . However, a higher dispersal or migration will link populations closer in geographical space, so that any single stochastic variation will be shared among adjacent populations, and their similarity will be explained by these stochastic processes and not by their common response to X. Thus, close populations in geographic space , yi and yj are the values of the allele frequencies (or any quantitative trait) measured in the populations i and j, y is the average of y and wij is an element of the W matrix. In this W matrix, the elements are equal to 1 if the pair i, j of local populations is within a given distance class interval (indicating populations that are “connected” in this class), and otherwise wij = 0. S indicates the number of entries (connections) in the W matrix. The value expected under the null hypothesis of the absence of spatial autocorrelation is -1/(n - 1).where I is usually calculated by using different distance classes, connecting, in the W matrix, pairs of local populations situated at increasing geographic distances. Thereby, a sequence of coefficients is obtained and a spatial correlogram appears when they are plotted against geographic distance classes. This correlogram better describes the complexity of spatial patterns, both in original variable and model residuals. Most evolutionary inferences using autocorrelation in population genetics and phylogenetic comparative analyses have been performed based on correlograms, although these were not obtained from model residuals, but instead from original allele frequencies or phenotypes  can be performed taking this into account, both in order to improve understanding of genetic variation, as well as to better estimate and test model parameters. In general, we will refer to these subsequent models, as reviewed below, as “spatial regression models”. These can be grouped into two classes, based on the idea of incorporating autocorrelation either into a model structure or into model residuals. Since the problem of modeling spatially-structured genetic data appears when autocorrelation exists in model residuals, as described above, the solution to the problem is exactly to eliminate this autocorrelation. This can be statistically achieved by two different approaches see : 1) it iThere are many ways of incorporating spatial variables into the model structure to eliminate residual autocorrelation. This can be expressed by a general model of the form:X, β and ε are as defined for Eq. (2) and G is a vector or matrix  expressing geographic space or, more appropriately, the geographically-structured genetic variation among local populations. Thus, this class of spatial regression tries to “filter” or eliminate autocorrelation in model residuals by capturing it in the G term of Eq. (6). Therefore, the problem is how to define “space” in Eq. (6) and express it in G terms.where i.e., latitude and longitude) that can be added as spatial predictors, so that:The first and simplest way of defining space is by directly using the spatial coordinates of populations  is actually doing is to express part of genetic variation, such as a north-south cline, as a plane in geographic space. The spatial component in Eq. (7) can be changed by adding polynomial expansions, thereby adjusting to quadratic or cubic functions of spatial coordinates. This technique is known as “trend surface analysis”  or by the inverse of geographic distances dij among local populations (wij = 1/dij). It is also possible to use another term to increase the complexity of the relationship between weights and distances, so that wij= 1/dij, where α is a coefficient that controls curvilinearity in the relationship between geographic distances and weights. Thus, the above term ρWY is the estimated value of Y in a given local population if its genetic variation is a function of nearby local populations weighted by their geographic distances (expressed as weights). Thus, the term G in the above equation can be expressed as the vector ρWY, so that:where ρ is an autoregressive coefficient and This model is usually called the “lagged-response autoregressive model”. Alternatively, it is possible to incorporate autoregressive terms, as defined above, for both Y and X variables, so that the overall Eq. (6) becomes:where γ are the spatial autoregressive coefficients ρ for each explanatory variable. This model is usually called the “lagged-predictor or mixed autoregressive model”.G of Eq. (6). This approach have been called eigenvector-based spatial filtering, the principal coordinate of neighbor matrices (PCNM), or, and in general, spatial eigenvector mapping (SEVM)  see . The basi.e., those associated with large eigenvalues) tend to express broad-scale structures, whereas eigenvectors with small eigenvalues tend to express local patterns. Thus, the advantage of eigenvector mapping is the flexibility in dealing with patterns at multiple scales, and the possibility of iteractively improving modeling process by adding or removing these eigenvectors. However, this may also pose a problem, since a very large number of eigenvectors  exists, so there must be a certain criterion for establishing which are to be used in the model. This is the same as the “stopping-rule problem” in multivariate analysis for deciding which eigenvectors are meaningful  the way coefficients in β and their variances are to be estimated. The basic idea is actually based on Eq. (4) above. Actually, Eq. (4) is a simplification of a more general equation of the form:C is a covariance matrix expressing the relationships between local populations, quite similar  to W. Notice that, if there is no autocorrelation in residuals, and variances are homocedastic, the C matrix becomes a single number (σ2), so that Eq. (10) is reduced to Eq. (4).where C. W matrix , can be obtained by defining C as:Equations (8) to (10) are also forms of simultaneous autoregressive models, but since they are based on the “filter” approach, they are called lagged-models, whereas the simultaneous form presented in Eq. (11) is sometimes referred to the SAR error model . The allele frequencies were then modeled by using spatial regression techniques as a function of the main directions of spatial variation in human occupation throughout the biome, these being derived from a factor analysis of 23 socio-economic variables, surrogates of modernization in farming, cattle breeding and human demography , and for PCNM the eigenvectors used in the model were those with significant spatial patterns (Moran I in the first distance class > 0.1), with truncation distance equal to 250 km. In general, spatial regression models performed better than OLS, both in terms of frequency of models and frequency of coefficients, the two best models being LagRES and PCNM, with a frequency of significant coefficients equal to 13% and 18%, respectively. However, some spatial regression methods, such as CAR, performed even worse than OLS.Repeating these analyses, using the 7 different spatial regression models, gave mixed results, when counting the number of significant models and coefficients. For autoregressive models, elements in the A “distance” from null expectation can also be obtained for each method, by the sum of squares of standardized slopes or each explanatory variable, assuming that expected slopes are zero. According to this metric, SAR, MA, LagRES and PCNM gave lower distances than OLS, thus being less affected by autocorrelation and furnishing results closer to the expected under the null hypothesis (a null vector of slopes).Finally, an ordination using a non-metric multidimensional scaling of distances among methods, and based on their standardized slopes, supports the above patterns. LagRES, PCNM and TSA are the most diverse methods, at extreme positions in ordination space , whereasOur analyses agree with the recent comparative evaluation by Because of the relatively great number of significantly large coefficients and models found in our analyses (a minimum of 13% for LagRES), one could argue that spatial regression models, although tending to perform better than OLS, are not entirely effective in decoupling the endogenous and exogenous processes driving allele frequencies. This is true, although it is not necessarily due to statistical problems with methods, but instead to conceptual problems underlying correlation and causation . It is ii.e., zero slopes for the predictors). Also, Type I error of OLS increases to 40%, whereas Type I errors of spatial regression models are reduced to much more acceptable levels, equal to 7.5% for LagRES  and human demography. Indeed, if this last explanatory variable is not included in the analyses and the frequency of significant models and coefficients are recalculated , it is pgRES see . Notice Despite the somewhat idiosyncratic results of comparing spatial regression models in the literature . Due to


Mental health disorders, depression in particular, have been described as a global epidemic. Research suggests that a variety of lifestyle and environmental changes may be driving at least some portion of the increased prevalence. One area of flourishing research involves the relationship between the intestinal microbiota  and mental health. In order to appreciate the recent scientific gains in this area, and its potential future directions, it is critical to review the history of the topic. Probiotic administration (e.g. Lactobacillus) and fecal microbiota transfer for conditions associated with depression and anxiety is not a new concept. Here, in the first of a 3-part series, we begin by reviewing the origins of the contemporary research, providing a critical appraisal of what has become a revisionist history of the controversial term ‘autointoxication’. We argue that legitimate interests in the gut-brain-microbiota connection were obscured for decades by its association with a narrow historical legacy. Historical perspectives provide a very meaningful context to the current state of the contemporary research as outlined in parts II and III. The global mental health crisis and prevalence of depression is increasingly being viewed, at least to some degree, as a consequence of modernization. There are numerous suspect candidates to explain what has been described as an epidemic increase in mental health disorders. These include, but are not limited to, socio-economic changes, urbanicity, alterations in dietary habits, sedentary behavior, excessive screen-based information consumption, lack of adequate sunlight, erosion of real-world (off-line) social support, and an overall disconnect from nature -3. Reseath century, to a time when some within medicine had veered off a rational course in a relatively short-lived obsession with so-called ‘autointoxication’ and ‘intestinal toxemia’  at Rainhill Asylum and many other places, though there was a good one at Wakefield. Dr Wiglesworth, who was the speaker’s chief, was greatly interested in the subject, and he gave many of the patients plenty of sour milk. But when subjected to what might be called the “acid test” they did not, after some months of treatment, show any difference mentally.”“British Journal of Psychiatry, 1930 [W.F. Menzies, M.D. - ry, 1930 British Journal of Medicine (1912), famed pediatric surgeon Hastings Gilford stated that ‘autointoxication, the term as we commonly use it is significant of nothing but a sort of mental flatulency on the part of the user as a substitute for thought’ [Since autointoxication was a catch-all classification, connected to virtually every acute and chronic medical condition imaginable, even at its zenith it was still viewed with a degree of skepticism. Even those who supported the notion of intestinal microbial involvement in systemic disease conceded that the term made no rational scientific sense, at least not in the context in which it was used. There was little ‘auto’  in intestinal toxemia - autointoxication was a more apt descriptive for the spontaneous generation of toxins by human cells – not a descriptive for the activities and consequences of microbial inhabitants. Writing in the thought’ . The voithought’ .L. acidophilus in the stool of 187 patients with a variety of mental health disorders vs. controls  [Despite the enthusiasm related to a theoretical clinical value of lactic acid bacteria potions and milk products in those with mental health disorders, the actual benefits of administration were not realized. In three small published case series, acidophilus milk was reported to improve constipation and diarrhea, but not behavioral or mental status of patients, at least not in those with more serious forms of mental illness such as schizophrenia -104. Mor at all) .L. acidophilus or L. bulgaricus preparations had correct labeling and sufficient viability [New York Medical Journal wherein the company (Berlin Labs) sought physician alliance – the advertisement header stated “We are telling the layman about Intest-Fermin…may we count on your assistance in spreading this message to everyone?” In the emerging world of evidence-based practice, the short answer was no, Berlin Labs could not count on physicians to spread the word about an agent lacking scientific support. Put simply, bacterial supplements were increasingly being viewed in the same category as pseudo-scientific patent medicine and nostrum cures. By the mid-1930s even the dairy industry was distancing acidophilus milk from medicinal properties. In a 1938 article [merchandise acidophilus milk as a superior fermented milk beverage – not as a medicine’. Whether it was in heed to Dr Butterworth’s advice or not, the mainstream advertizing of acidophilus and autointoxication in tandem largely disappeared.There was also a growing discontent among physicians concerning the marketing of bacterial products within medical journals and beyond. Autointoxication, by being both scientifically vague and broad in its potential application, became a Petri dish for the growth of quackery and charlatanism - so-called colon-cleaning products, dubious “colonic” contraptions and unsafe, lay-administered protocols stood side-by-side with largely unregulated bacteriotherapy products. Purveyors of what would later become known as probiotics were often part of fantastical claims built upon questionable products. Even prior to the 1927 study by Lawrence H. James in JAMA showing that only 13 of 107 commercial iability , there w article  entitledalternate constipation and diarrhea is a far more diagnostic symptom’ and that this was, in turn, tied to greater frequency of functional nervous symptoms [cloak of ignorance’ for mental illness or legitimate underlying organic disease states. Alvarez challenged the experimental studies showing the harmful effects of indole (and most of the other putrefactive substances) in animals, stating that they were of little relevance to humans. He presented research challenging the notion that putrefactive substances could be absorbed from the intestinal tract in anything other than trace amounts, and he also criticized the microbial culture techniques as used in studies supportive of Metchnikoff [any scientifically trained man who would read Metchnikoff’s book on the Prolongation of Life will probably stop to wonder how a man in his position could have written so positively on the basis of so little exact proof’ [nervous, worn-out women’. Even more specifically, he stated that ‘some of the most striking manifestations of reverse peristalsis are observed in the hysterical’ [et them free’. It is, of course, debatable whether or not informing a so-called nervous, worn-out woman that she is responsible for colonic material appearing on her tongue, would indeed, set her free. There were many who rallied to support Alvarez; the response by Edward Goodman, a University of Pennsylvania gastroenterologist, clearly highlights the chasm and lack of middle ground related to intestinal toxemia – ‘The suggestion that symptoms are due to mechanical distention and irritation may not meet with the approbation of the army of toxemiaphils but will certainly be a welcome suggestion for us in the anti-toxemia squad’ [all human ailments, including baldness. These vocal armies and squads were in opposition; there were few considering the possibility of mechanical distention, psychological inputs, and, for example, intestinal permeability and gut-derived endotoxins working in concert and in a bi-directional fashion.Walter C. Alvarez, an internal medicine physician at the University of California, San Francisco, was one of the most vehement critics of the autointoxication theory, at least as it pertained to chronic functional constipation. Although modern historians also equate autointoxication exclusively with constipation, there are multiple physician reports during the autointoxication era claiming that diarrhea and/or alternating constipation and diarrhea was equally, if not more often, a key symptom of neurasthenia/melancholia due to autointoxication. New York physician William H. King is an example among many; he wrote in 1913 that among 300 of his reported cases, ‘symptoms . Alvarezchnikoff ,111. Alvt proof’ . This baterical’ . It was a squad’ . Among ta squad’ ; he alsoone does not sober a drunken man immediately by taking his flask of whiskey away from him’ [In 1922, Arthur N. Donaldson used petroleum-soaked and barium-coated cotton pledgets packed into the rectum of four otherwise healthy volunteers, reporting that after three hours the procedure could provoke the classic mental symptoms of intestinal toxemia. Since the rectal plugging for three hours subsequently brought about neuromuscular fatigue and prolonged mental reaction time, it was presumed that the symptoms of autointoxication could be explained by mechanical distention. Donaldson also had 5 adults in the same case series volunteer in refraining from any bowel movements for 90 hours. This process induced mental symptoms of depression, irritability, loss of attention and headache. One hour after the first permitted bowel movements (most used an enema), Donaldson queried the subjects and they reported the mental symptoms to be alleviated  . Donaldsrom him’ . As we wrom him’ . Howeverrom him’ . Low levrom him’ ,120. Alvhealthy adults suppressing a normal urge to defecate; they were not adults with chronic illness (e.g. major depressive disorder) and co-morbid functional constipation. The extent to which holding back bowel movements for 90 hours was itself a psychological stressor, one capable of provoking symptoms in these 5 healthy adults, was never discussed by Donaldson or Alvarez. What we know from contemporary evidence is that in much larger studies of functional constipation, the fecal concentrations of Lactobacillus and Bifidobacterium are significantly lower and intestinal permeability is significantly higher vs. healthy adults without constipation. Furthermore, in functional constipation there is an enhanced systemic immune response, almost certainly due to larger molecules gaining access across the intestinal barrier [Despite this, modern medical historians, at least through the late 1990s, consistently point to Alvarez and Donaldson as providing the clear evidence that debunked autointoxication as nonsense -11. It s barrier . How doe barrier , and the barrier ? Undoubt barrier . However barrier ? IntestiRecto-gastric and recto-colonic reflexes, manifest through mechanical distention, are now active areas of research in IBS and functional intestinal disorders. Indeed, recent studies involving experimental rectal distention have shown the induction of postprandial nausea and upper gut symptoms along with delayed gastric emptying and altered colonic transit in humans -128. Alvin the worst of these cases of “autointoxication” the sufferers are undoubtedly psychopathic. I have learned to recognize the type at the first interview, and I no longer waste much time with them, as it is practically impossible to change their habits of thought. They are generally of neurotic or insane ancestry and often give a history of “nervous breakdowns” in the past’[In 95 percent of the hundreds of my women patients, I found social attractiveness, a better-than-average intelligence, and a decided quickness of thought and bodily movement. Three out of four of the women had a small, trim feminine body with well-formed breasts’ [is either not intelligent enough or not sane enough to work, even in a labor battalion. Unfortunately, too, these people breed their kind day after day’. Going on to state that ‘It is important to face the fact that today antibiotics are keeping alive hundreds of thousands of persons who are a drain on the community’, and concluding that ‘modern medicine is keeping alive those who will never pull their weight in the boat’ [Whenever I have been constipated, and these symptoms have distressed me, they have stopped the instant the constipation was overcome. Eventually, I gathered and wrote up so much evidence against the idea of “autointoxication” that most doctors stopped making this diagnosis’ [As for Alvarez, he was not a man to shy away from opinion. He wrote that ‘the past’. Alvarezbreasts’ . He wenthe boat’ . Callingagnosis’ . Moreoveagnosis’ .go-getter” type – ‘he is often a keen, wide-awake, sensitive type of man who drives himself all day and part of the night, who responds too much to things that break into his routine, and does not know how to relax’ [to take a little vacation now and then when the stomach gets to hurting” [commonly, the biggest factor in the production of an ulcer is a psychic one’ [Helicobacter pylori at work, a microbe that appears to be mostly, if not completely, unimpressed if the patient takes a little vacation or not [H. pylori infection has recently been linked with extragastric diseases including dementia, depression, cardiovascular disease and type II diabetes [H. pylori subsequently display delayed gastric emptying and visceral hypersensitivity [H. pylori with migraine, and eradication with improvement in symptoms [He had little confidence in the infectious theory of peptic ulcers, and described the individuals with them as the “o relax’ . If therhurting” . For dechic one’ . In the n or not . This, tdiabetes -144. Recsitivity  - alterasymptoms ,147; thiL. acidophilus can help reduce the systemic ammonia load related to the symptoms of hepatic encephalopathy, there were some renewed and fleeting references to intestinal autointoxication [L. acidophilus milk reduced seizure frequency among 12 patients during a 3-month administration period [a self-evident case of hypochondriasis with an undoubted ano-erotic hysterical element’ [In the mid-1960s, with the recognition that antibiotics and xication . Earliern period . Howevern period , where celement’ ,152; we essentially unhappy individuals…any suggested panacea and therapeutic straw is grasped. No regime is too severe, and no program too forbidding. With the tenacity of the faithful they grope their way from one physician to the next in a relentless search for a permanently successful remedy’[Journal of Clinical Gastroenterology (JCN) argued that lingering notions of concern related to intestinal autointoxication among patients  are simply explained by Freudian psychology [advances invalidated the medical credibility of intestinal autointoxication’. Of course, many of the suppositions of intestinal autointoxication were never scientifically invalidated; they were simply never thoroughly examined at all. The core theoretical tenet bears repeating – i.e. that intestinal microbes, directly and/or indirectly, could influence systemic health, including that in the mental realm. This was certainly not proven, but it was not even remotely invalidated. Still, there were no letters to the editor of the JCN in 1989 to challenge a Freudian explanation, peer-reviewers evidently found the premise acceptable enough to publish. And so it was that legacy of autointoxication was deemed to be that of complete nonsense; a by-gone era of medical malpractice (high-risk surgery based on theory) and the commercial spin of shysters who co-opted and diminished the legitimacy of fledgling discoveries.As intestinal toxemia faded away, and Freudian psycho-neuroses and top-down psychosomatic theories became popularized as a means to explain so-called ‘functional’ disorders, Alvarez’s view would linger for decades. Indeed as late as 1976 one of the leading gastroenterology textbooks would state that patients with reported carbohydrate intolerance and symptoms in line with autointoxication were ‘l remedy’. To fullychology . SpecifiLogan and Katzman first proposed the use of probiotics as adjunct therapy in the management of depression. Since then there has been an accumulation of data from both clinical and preclinical studies supporting the view that probiotics may have a role in the treatment of depression’ [for mental health, one banished for over 70 years, insinuate itself back into to mainstream psychiatric thinking in just under a decade? The rapid advances that justify some bridled enthusiasm and further outside-the-box thinking, in the context of translational medicine, will be discussed in Parts II and III.Ultimately, these forces, along with absolute lack of human evidence, would block rational lines of potential investigation  and allow for Freudian theory – toilet training conflicts - to provide a default answer that could only be described as extravagant, convenient, and scientifically unverifiable. Only a few in primary medicine dared raise the spectre of Freud as pseudo-scientist . No one,ression’ . Settingression’ , the larACB and EMS have no competing interests. ACL has received consulting fees from Genuine Health, Toronto, Canada.ACB, ACL and EMS contributed equal time and effort in the investigation, research and drafting of this manuscript. All authors read and approved the final manuscript.