A highly important factor in enhancing quality of patient care and job satisfaction of health care staff is inter-professional communication. Due to the critical nature of the work environment, the large number of staff and units, and complexity of professional tasks and interventions, inter-professional communication in an emergency department is particularly and exceptionally important. Despite its importance, inter-professional communication in emergency department seems unfavorable. Thus, this study was designed to explain barriers to inter-professional communication in an emergency department.This was a qualitative study with content analysis approach, based on interviews conducted with 26 participants selected purposively, with diversity of occupation, position, age, gender, history, and place of work. Interviews were in-depth and semi-structured, and data were analyzed using the inductive content analysis approach.In total, 251 initial codes were extracted from 30 interviews (some of the participants re-interviewed) and in the reducing trend of final results, 5 categories were extracted including overcrowded emergency, stressful emergency environment, not discerning emergency conditions, ineffective management, and inefficient communication channels. Tumultuous atmosphere  was the common theme between categories, and was decided to be the main barrier to effective inter-professional communication.Tumultuous atmosphere  was found to be the most important barrier to inter-professional communication. This study provided a better understanding of these barriers in emergency department, often neglected in most studies. It is held that by reducing environmental turmoil , inter-professional communication can be improved, thereby improving patient care outcomes and personnel job satisfaction. An important factor that has long been recognized as the basis of quality of health care is effective communication. Effective inter-professional communication (EIC) is vital to enhancing quality and safety of care and as such a patient’s health  is particularly important, and should especially be considered . ED is aFor better and deeper understanding of barriers to inter-professional communication in ED, qualitative inductive content analysis approach of Granheim and Focusing on 30 in depth interviews, this qualitative study relied on a content analysis approach. To obtain different experiences, we selected participants from different medical sections and also, with maximum diversity in terms of age, gender, and work history .Accordingly, purposive sampling was used by visiting various EDs in Zanjan City between August 2012 and July 2013.Data were analyzed according to stages suggested by To ensure trustworthiness of data, researchers maintained long-term engagement with the data, ensuring depth and familiarity needed to extract core themes. To ensure the codes matched experiences of participants a member check was used. Interviews, initial codes and themes were reviewed through peer debriefing, as well as external checking.This study was approved by the Ethics Committee of Tehran University of Social Welfare and Rehabilitation Sciences. Both verbal and written consent were obtained from participants. Ethical principles of anonymity, confidentiality, and right to withdraw were also observed.During analysis, 251 initial codes were extracted from a total of 30 interviews, and in the decreasing trend of final findings, 5 categories were extracted, including overcrowded emergency, stressful emergency environment, not discerning conditions in ED, ineffective management, and inefficient communication channels. From these 5 categories, tumultuous atmosphere  was identified as the main barrier to effective inter-professional communication. The results obtained from data analysis are presented in Busy times tire everybody and cause inappropriate communication.” . Another participant said: “Because of contacts in a crowded emergency, too many patients, and workload, I cannot take in what the doctor says.” .It seemed evident according to the participants that overcrowded was exacerbated by presence of large numbers of patients and their family members. It is considered a very important factor in the inability to establish appropriate communication, stress, and friction between personnel. Large numbers of patients with complicated care needs create heavy workloads and fatigue for personnel, thereby reducing their tolerance and causing unintentional and inappropriate reactions, resulting in unfavorable communication, which was cited by most participants. In this respect, a participant stated: “In the crowd, I cannot find a chance to explain and transfer information.” , or “…Staff don’t get a chance to visit their patient, and in such circumstances, no information can be exchanged between doctors and nurses.” .Furthermore, overcrowded emergency prevents exchange of scientific data between doctors and nurses, and thus acts as an information barrier. “…Colleagues don’t tend to help new ones, as they get really tired.” .Another consequence of large number of patients was lack of cooperation between personnel, especially between experienced and new nurses, resulting in ineffective professional relationships. In this respect, a participant argued, “Nurses don’t pay attention, and drop their needle-heads on the floor, even used needles. Such cases increase at busy times.” .Also furthermore due to overcrowded emergency and workload, principles of hygiene were not fully observed, which created difficult affects such as irritation nursing assistant. For instance: “The only ward that transfers patients without a nurse is ED and patient information is not exchanged.” .Moreover, due to busy emergency ward, when transferring patients to different wards and handing over the patient, the presence of relevant nurse was not compulsory, which led to lack of exchange of information between emergency personnel and the wards. A participant stated: “Busy times tire everybody and cause inappropriate communication.” Or “…Large number of family members impedes our work, and in such situations, even in team work, communication is lost.” .On the other hand, numerous agitated patients’ family members disrupt personnel by going to nurses and asking questions frequently exerting further pressure on personnel, contributing to display of ineffective communication on the nurses’ part. In this respect, a participant stated: “Due to huge workload, nurses angrily utter ‘why don’t you transfer the patient, don’t you know how?’ This happens when work is heavy.” .On many occasions, overcrowded emergency not only prevents establishment of inter-professional communication, but also acts as a cause of friction. In this respect, a participant said: “3.2 Stressful Emergency EnvironmentBecause of unstable conditions of patients, we are constantly worried; some of us may even shout” .It seemed evident according to the participants that stressful environment acted as a barrier to establishment of appropriate inter-professional communication, and presented as unstable patient conditions, Knowledge deficiency of some doctors, and unavailability of doctors. Unstable patient condition was a source of stress that was frequently referred to in participants’ statements. A participant stated: “Pressure of work is huge in emergency, both mental and physical, and it is really stressful, which affects our communication.” .Many participants cited stressful atmosphere of ED, and its impact on establishing appropriate communication: ““… Emergency staffs are stressed, and fear not being able to do their work on time; everybody is busy doing her own thing, and less communicates with others.” .Also, stress probably causes nurses not to carry out tasks on time, which leads to less communication with other personnel. I have a patient that has been here three days, and they cannot diagnose what’s wrong with him, and only order consultation. This causes more stress, and communication fails.” Knowledge deficiency of some doctors was another theme that could contribute incorrect or belated diagnosis and treatment, thereby imposing further stress onto personnel, and acted as a barrier. “…There is no attending professor, and residents don’t ring him to make a decision, they’re afraid he says what the hell they are doing here.” .Non-continuous presence of doctor was another factor in intensifying stress in ED and ineffective communication between professions in many ways, leading to lack of decision about patients and exacerbated overcrowding in ED. A participant described the latter as follows gave these words: “Some doctors’ handwriting is so illegible that creates more stress for us.” . Moreover, since doctors were not continually present, and alternately did their rounds, they were not closely involved in clinical duties of nurses or their care procedures, which led to ineffective communication and stress for personnel. In this respect, a participant argued: “[The doctor] comes to visit writes such and so x-ray order, and an hour later comes in screaming the order has not been done; he is not here to see we are doing the best we can. This causes further stress.” Sometimes, unavailability of doctors, and their illegible handwriting causes further stress for personnel; “As they occasionally come and give orders, and leave in a hurry, they look down on us.” , or “We see some attending professors very little, and we shy away from them.” (Intern 2)Also, short presence of doctors in ED, prevented close communication between them and personnel. A nurse stated: “The supervisor is not aware that this is ED and beds should be vacant. She doesn’t cooperate with me, it gets busier all the while, and staffs are increasingly agitated.” . Other wards did not understand circumstances in ED frequently, and it displayed itself as reluctance to admit emergency patients into other wards. Often heads of other wards refused to admit emergency patients, which led to further overcrowding and agitated atmosphere in ED. “…When I admit emergency patients, head-nurse argues with me why I don’t consider staff in that ward. She hasn’t understood emergency beds should be kept vacant.” (Deputy Head of a ward with 13-year experience). This was also witnessed by the current researcher. Even some ED personnel did not discern emergency conditions of patients, and did not make the effort to quickly carry out procedures, which troubled other staff and led to ineffective communication. “…You see the nurse is not bothered to carry out procedures faster for patients in bad conditions. It’s so irritating and causes friction.” .One of the reasons for ambience turmoil and subsequent ineffective communication was lack of discerning conditions in ED, which was evident at different levels throughout the hospital. “…Some doctors insist that patients from ED should be on their assigned beds in wards, and this causes patients to be left in ED. When according to orders from nursing office, we transfer patients to wards and onto other beds; they would come in and make a fuss.” .Some doctors did not understand emergency conditions either, and refused to transfer patients to wards for their own benefits, which resulted in overcrowding emergency yet again. “…Staff are continually working, with no days off, they get tired, and communication problems occur between them.”. Shortage of facilities and equipment comprised another communication barrier. A participant stated: “There are a lot of stressors in ED; one is unavailability of tools, which creates conflict between nurses and doctors” . Inconsistent supervision by managers led to reduced occupational motivation, resulting in lack of proper communication between personnel. In this respect, a participant stated: “Training supervisor doesn’t come to see trainees, to see how they perform, to show what relationship they should have with a resident.” . Lack of proper feedback was another barrier, “…Whether you do or don’t do your job doesn’t make any difference.” .This was another sub-theme in ambience turmoil, which included barriers associated with inadequate resources, inconsistent supervision, and lack of proper feedback. One of the barriers associated with resources was nursing staff shortage. In this regard, a participant stated: “Some have such a bad handwriting, and it gets worse when they are busy, causing hassle and time-wasting.” , or “When attending professor came in the morning to read patient’s notes, resident’s handwriting was so bad, he couldn’t read it.” .A sub-theme of ambience turmoil was inefficient communication channels, which included deficiency in written and electronic communication. Inefficient written communication was frequently cited by participants. Doctors’ illegible handwriting caused lack of understanding doctor’s orders, waste of time for nurses, and stress. “…It is a new system and we have difficulty working with it.” , or, deficiency in electronic system; “We had a lot of problems in ED, … it wouldn’t connect.” (Intern 2). Sometimes, an ill patient needed quick action to receive medication to start treatment and it was necessary to approve it electronically. In fact, having to use electronic systems occasionally caused delays in treatment, and in vital situations, it meant excessive stress for personnel. “…You see the patient is in a critical condition, by the time H.I.S request is sent and approval has come back, vital time is wasted, which means stress and agitation.” .Inefficient electronic communication was another case cited by participants. This issue was sometimes as inadequate training, for instance: “It was busy. They called from emergency and asked me to tick a patient’s medication [on computer] as he was being transferred to a ward. Now, I have to fill the prescription I have on the monitor first and then exit this page and do this patient’s order. Meanwhile, they ring me again, and agitate me” , or “On the one hand they say, do these tests quickly, it is an emergency, and then you find H.I.S has not been done, and we don’t know what we are supposed to do.” , or “There is no one in charge of H.I.S. Nurses do this, but they can’t when they’re busy.” .Despite personnel’s knowing drug and para-clinical request procedures, sometimes, due to huge workload, this is practically impossible. “…This study described that overcrowding in ED was an important barrier to inter-professional communication. The descriptions are very similar to other studies have also recognized it seemed evident according to the participants that overcrowded as a barrier to effective communication  considered critical conditions in ED the reason for closer cooperation of medical team and better communication. It seems if personnel are suitably trained to deal with crisis in emergency, the atmosphere is generally unemotional. During busy times, since medical team members mutually need cooperation with one another, the atmosphere is maintained, and may even get effective partnering. However, when the atmosphere is emotional, close communication cannot take shape, and busy ED intensifies interrupted communication, as was seen in the present study.In the present study, stressful atmosphere in ED acted as a barrier to establishing proper inter-professional communication. Instability in ED, patients’ conditions, over-admission of patients beyond ED capacity added to already stressful atmosphere in this department. This finding is similar to that found in a study, where workplace stress was proposed as a barrier to inter-professional communication  and In the present study, inefficient communication channel, in written and electronic forms was an issue. In this study, principle barriers to establishing inter-professional communication in ED were identified. However, distinguishing barriers in practice is not easily possible. In fact, it can be argued that barriers associated with tumultuous atmosphere in emergency department create a chain of major limitations in establishing desirable inter-professional communication, and identifying main inhibiting factors can be effective in removal of other barriers. Accordingly, reduction of stress and factors that exacerbate stress in ED for establishing appropriate communication is essential. Emergency nurses can increase their knowledge and skills for promoting inter-professional communication. Because the present study results were obtained through real experiences and perceptions of participants in the field, they can be used in designing appropriate interventions to enhance inter-professional communication. The present qualitative study is indicative of experiences and perspectives of different medical professions within Iranian context and culture. Therefore, the transferability of findings should be considered with caution and critiqued and compared with those of similar studies conducted in other contexts.


Public health officials, parents, school leaders, community leaders, and regulators need and deserve valid evidence free from spin on which they can base decisions.Childhood obesity remains a substantial health concern for our population and thoughtful attempts to develop and evaluate the utility of programs to reduce childhood obesity levels are needed. Unfortunately, we believe the conclusion by Burke et al. that the HealthMPowers program produces positive change in body composition is incorrect because the results obtained are likely due to regression to the mean (RTM), a well-known threat to the validity of studies that is often overlooked. Using empirical data, we demonstrate that RTM is likely to be the cause for the changes reported. A more reasonable conclusion than the one of effectiveness the authors offered would be that the results did  Childhood obesity remains a substantial health concern for our population and thoughtful attempts to develop and evaluate the utility of programs to reduce childhood obesity levels are needed. For such efforts to be valuable, a sound evidential base is needed. As Casazza and Allison  wrote, wRegarding statements of causal inference, single group research designs have well-established threats to the internal validity summarized in the classic works of Cook and Campbell . Two sucFirst formally recognized by Galton over a century ago , regressUnfortunately, RTM is often neglected in reasoning about effects . For exaUnderstanding the potential impact of RTM in this situation requires evidence of the expected changes among children not involved in an intervention . We do not have data for children in similar schools across time, but other longitudinal surveys can provide some evidence of what we would expect.http://www.bls.gov/nls/nlsy97.htm). This longitudinal survey examines a nationally-representative group of children at two year intervals. We included children who had measured values of height and weight at both age 9 and age 11 (approximating the fourth grade), and examined the change in BMI z-score. For these children, the mean change in BMI z-score for girls was 0.21 for healthy weight, −0.12 for overweight, and −0.22 for girls with obesity; for boys the change was 0.15 for healthy weight, −0.10 for overweight, and −0.21 for boys with obesity. This empirical evidence raises doubt regarding all studies showing declines in z-scores among children with obesity that do not include an appropriate control group.We used the National Longitudinal Survey of Youth, 1997 cohort , while we would expect a decline of −0.22 over two years with no intervention. Similarly, they show a decline of −0.12 for boys, while we expect a decline of −0.21. Given the known changes among children with obesity, it is not only plausible, but in fact probable, that the changes seen by Burke were simple RTM effects.Before Burke et al. conducted their research, it was plausible that the particular intervention used involving promotion of “healthy eating and physical activity in schools” might reduce obesity levels in participating children. However, after this research finding of no significant reduction in BMI z-scores in the total sample and no greater reduction in BMI z-scores among the higher BMI children than one would expect by RTM, a more reasonable conclusion would have been “Our results did not support the effectiveness of our intervention and, though it remains possible that it is effective, perhaps alternative approaches should be tried.” Burke et al.  state “T


Observed breast, cervical and colon cancer screening rates are below provincial targets for the province of Ontario, Canada. The populations who are under- or never-screened for these cancers have not been described at the Ontario provincial level. Our objective was to use qualitative methods of inquiry to explore who are the never- or under-screened populations of Ontario.Qualitative data were collected from two rounds of focus group discussions conducted in four communities selected using maps of screening rates by dissemination area. The communities selected were archetypical of the Ontario context: urban, suburban, small city and rural. The first phase of focus groups was with health service providers. The second phase of focus groups was with community members from the under- and never- screened population. Guided by a grounded theory methodology, data were collected and analyzed simultaneously to enable the core and related concepts about the under- and never-screened to emerge.The core concept that emerged from the data is that the under- and never-screened populations of Ontario are characterized by diversity. Group level characteristics of the under- and never- screened included: 1) the uninsured ; 2) sexual abuse survivors; 3) people in crisis; 4) immigrants; 5) men; and 6) individuals accessing traditional, alternative and complementary medicine for health and wellness. Under- and never-screened could have one or multiple group characteristics.The under- and never-screened in Ontario comprise a diversity of groups. Heterogeneity within and intersectionality among under- and never-screened groups adds complexity to cancer screening participation and program planning. Cancer screening rates are below targeted rates for breast, cervical and colon cancer for the province of Ontario in Canada , despiteMost screening studies intended to increase cancer screening rates focus on specific vulnerable and marginalized populations known to have low cancer screening rates -10, such2) and capturing two time zones). Our intention is to use the results to inform cancer screening programs, intervention activities, policy and practice at the provincial level, and begin to validate the generalizability of other studies findings to the Ontario context.Our objective was to explore who the perceived under- and never- screened populations are for Ontario, the second largest province in Canada  using maps  of breasWe learned who the perceived under-screened and never-screened populations were for each area using an iterative qualitative process involving two rounds of focus group discussions ,33. The The second round of focus group discussions was with community members from each of the under- and never- screened populations identified by health service providers in each of four low screening rate communities.Recruitment of community members varied by community, because each under- or never- screened population identified had its own socio-cultural norms and processes around connecting with research, modes of communication, and methods of participant recruitment. We relied on local health service providers and key community informants to guide us through the appropriate process. For example, for the urban and suburban communities, community outreach workers who participated in the health service providers focus group recruited community members using a relationship based approach  and co-fThe University of Toronto research ethics board reviewed and approved this project. The purpose of the study and focus group discussion was reviewed with participants, as was confidentiality of the discussion. Potential participants were invited to ask questions and verbal consent to participate was sought.Cancer screening rates and maps were shared with consenting participants, followed by a group discussion about who participants believed were the under- and never- screened, and the perceived barriers and facilitators to screening. Barriers and facilitators to cancer screening will be presented in depth elsewhere. The focus group discussion guide was the same for health care providers and community members, with the language around questions modified slightly to fit the context of the group. For example, health care providers were asked about who they do not see coming in for cancer screening, while community members were asked who they thought did not seek cancer screening. Different team members led different focus groups  but all were trained in the spirit of what information was being sought from the discussions so there was consistency across groups. Focus group discussions lasted approximately one and a half to two hours each and were voice recorded and transcribed. Field notes were also taken during each discussion and used to provide context, inform the analysis, and assist interpretations of results. Focus group discussions were held between June 2011 and May 2012.A classic grounded theory approach was taken in the analysis of the data, where transcripts were read and re-read for familiarity and open coded ,38 by sith focus group with community members. We continued to 16 focus groups both to confirm saturation and to honour the under- and never-screened community groups that had already been organized to share their perceptions and recommendations.We conducted four focus groups with health service providers and 16 focus groups with community members from communities with low screening rates for all three cancers . Unexpectedly, health service providers in urban, suburban and rural areas identified the uninsured, or individuals who do not access OHIP coverage, as under- or never- screened in their community:Yes, it has been a taboo issue, even among service providers who acknowledge that part of their clients are uninsured.” “In the urban setting, the uninsured are often immigrants who had a claim for refugee status denied but never left Canada. Community members confirmed that some people were in Canada illegally and therefore not insured, and consequently under- or never- screened for cancer. They indicated that the cost of health care and cancer treatment was so high for this group, that they could not afford to be screened:“if the person isn’t legal here, even the eye on the face costs them… if one is not here legally, you have to pay for everything that presents itself.” (Urban community member)In the rural setting, health service providers identified Old Order Mennonites as uninsured:“…we have two to three thousand people who are Mennonite… they pay taxes… they don’t have OHIP.” Rural community members reviewing maps of cancer screening rates confirmed:“That is the Mennonite population and they pay cash when they go to the doctor and the hospital.” Rural community members further explained that seeking health care for health problems was rare for Old Order Amish and Old Order Mennonites:“There’s a lot of Mennonites in this area and I’m not sure that isn’t affecting your [map] …The Mennonites are more forward but even them, I’m not sure. But I’m sure the Amish wouldn’t see you unless they were dying. They just don’t do that.” Old Order Amish and Old Order Mennonites are sometimes called horse and buggy people, or plain people. Traveling to town by horse and buggy for preventative care was unlikely:“It’s a half hour drive - if you have a car or somebody can take you there. What about people who don’t have a car or transportation? What about Mennonite women? People who don’t have insurance? Those are barriers.” Sexual abuse survivors were identified as an under- or never- screened group, which makes sense since breast, cervical, and colon cancer screening involve our most intimate sexual body sites. As one health service provider explained:“I’ve been a psychotherapist for 17 years in the community and a large group of female clients who were recovering from childhood sexual abuse and sexual trauma, would never go for a pap test. And part of my working in several cases was to help them consider the possibility of doing it. Even women in their fifties and sixties who never had that test done….if they’re hurt may be one thing, but to be screened. No.” Many sexual abuse survivors do not want physical contact with those areas of their body where screening is focused. Some sexual abuse survivors have psychologically dissociated with these areas as a way to cope with their trauma:“And there is a phenomenon that goes along with sexual abuse, particularly with childhood sexual abuse where you psychologically … remove those body parts from your body. Like they don’t exist and you ignore that they are there because they’re the source of your trauma and it’s a division. Like I have a body, it does not include those parts.” Health service providers also observed that people in crisis are usually focused on meeting their basic needs of food, shelter, and safety, and therefore, are unlikely to be screened for cancer:“The folks at our centre, they’re mostly in crisis. So, they’re leading … marginalized lives, so cancer screening is really at the bottom of the list. That’s because there’s serious mental health stuff going on; there’s absolutely no money; there’s no food. How do you think about going for a Pap when you can’t feed your kids, for example?” This observation was later validated by several women in a small city:Respondent 1: Bus transportation is expensive. You, for a bus pass if you’re not on disability,Respondent 2: You can’t afford it.Respondent 3: You’re taking that from somewhere needed.And most succinctly put by one single mother in a small city when she stated:“I can’t afford to fall down and go boom”The implications of a positive screening test can be a barrier to screening for people living in crisis or poverty.As expected, health service providers identified several immigrant groups as having low cancer screening rates:“…among the Indian population, cervical cancer rate is usually very high for a number of reasons. And they’re the ones who are least screened.” Immigrant community members explained that the health paradigms, attitudes, and health care seeking practices that existed in their country of origin, coupled with a lack of knowledge of the Canadian health system or the Ontario Health Insurance Program (OHIP) contributed to under-screening, or not getting screened at all:…as a newcomer when you come, you don’t know what your OHIP covers. You don’t know you get a full body check and even so issues like breast cancer, cervical cancer, it’s not something that people like the government in [many] countries would talk about…” ““…if you look at the male West Indian, particularly, or the male Asian particularly, or the Afro man, in developing countries, you know, you are taught to do certain things and so when you look at a mature adult, who has come to this country, you know, that mentality carries on.” (Suburban community member)Stigma and cultural taboos were also identified as important factors that kept immigrants, particularly men, from seeking screening:Respondent 1: “The stigma that is attached to, you know, going to the doctor’s office for things that are considered to be taboo from a testing perspective…”Respondent 2: “Especially for a male, yeah.”Respondent 1: “We don’t want to deal with it…even if that word gets out on the street, well, there are so many different ways you’re going to get rubbed about this. It doesn’t sit very well with the ethnic community, in a developing country.” (Suburban community members)Immigrant community members also explained that literacy and other communication barriers, including English as a second language, prevented some immigrants from learning about screening:“The reminder comes in English, and many people cannot read English. What do they do? Their husband or children look at the envelope, see it’s from some hospital and put it aside. They don’t even bother to open it and see what it is about, let us know what its saying, and tell us to go.” (Urban community member)Both health service providers and community members identified men as an under-screened population:“You have to threaten the men to the point where you push them in the door, right?” “Most men around here are afraid to go to doctors, you know. Unless somebody’s dying you know. Actually dying. And if they don’t have somebody to push him to get him to the doctor, maybe he’ll die. They don’t like to go to the doctor .” (Urban community member)Though many men, if not most men, limit their interaction with the medical system, there is some contact. Rural health service providers described using these moments of contact to address multiple health checks:“See that’s the problem, the men don’t tend to come as much for their health care, it’s hard to catch them for those things. We try and catch them at any visit that they come for…” Rural health service providers also described the conditions under which men will come in to the clinic to seek health care:Interviewer: “And when do they finally come in?”Respondent 1: “When they can’t actually walk anymore.”Respondent 2: “Their wife called and made the appointment cause she couldn’t stand listening to them anymore.”Respondent 1: “Or they’re bleeding from an orifice somewhere.”Respondent 3: “Or if it’s impacting their work.”Respondent 4: “After a long time. They’ll put up with a lot before they’ll finally breakdown.”Men had a generalized reputation of not accessing health care, and therefore, being under-screened or never- screened for cancer. Women were perceived as having more, even regular contact with the medical system and hence, were perceived as being up-to-date with screening. However, similar to Grunfeld’s finding with cancer survivors , we founAdditionally, suburban and rural men indicated that we would find a difference in health care seeking behaviours between working men and retired men, with retired men being more likely to interact regularly with the medical system, including for screening.Health service providers indicated that many individuals and groups living in Ontario seek traditional and alternative forms of healthcare before, instead of, or in addition to seeking health care services from mainstream contemporary health care providers and systems:“But I also think it’s not only the uninsured that subscribe to the use of alternative medicine. It’s others. I mean we have so many cultural groups. I know of many as well, you know the African community, the Caribbean community who, they believe in traditional medicine, you know not the mainstream medicine, and they will be diagnosed and they will choose not to…they will go back home to drink something, or eat something, but that’s their belief and we have to respect that.” Urban, suburban and rural community members indicated that many community members, especially men, do not want to seek medical care from a physician, preferring to rely on themselves, and described the use of traditional and alternative medicine to facilitate self-healing:“…one of my best friends lost his life this very last year, we went to the funeral. He had prostate cancer for years and years and not even his wife know, and he hide it from the doctor. And when he buy all this herb they tell him about and he boil it and he hide it from his wife. When he died his wife found a whole thing of herb. A whole thing of herb, he’s been drinking herbs for years and years and don’t check on his health, he’s scared of doctor.” (Urban community member)“We have a majority of farmers here and the farmers take care of themselves. I’ve seen it where they’ll inject themselves with whatever they give their cows and stuff like that. … Antibiotics and stuff. … No seriously. And they will not go to the doctors. Their philosophy is … Self-healing” The populations perceived by health service providers and community members to have low cancer screening participation in Ontario were similar to other studies and included: the uninsured ,18,20, sTraditional, complementary and alternative medicine (TCAM) users were perceived as being less likely to participate in breast, cervical or colon cancer screening programs. This group has not been identified previously. In 2006, 74% of Canadians surveyed had used alternative therapies in their lifetime and 54% had used alternative therapies in the past year . This grThe uninsured are a well-recognized group of under/never screeners in the United States -55. HoweIn Ontario, the uninsured population is relatively small, making cancer screening program decisions around prioritizing cancer screening efforts and resources to the uninsured challenging. There are also ethical considerations to balance regarding the cost of out-of-pocket cancer screening and the frequent refusal of cases to follow-up with cancer treatment. Additionally, cervical cancer risk appears to be very low to negligible for the Old Order Mennonites whose religious and cultural practices are highly protective when it comes to sexually transmitted diseases.The sexual abuse survivor population is large  with estSo far, we have presented the under- and never-screened as discrete groups. However, the under- and never-screened can also exist at the intersection of any of these group combinations; for example, abuse survivors living in crisis, or immigrant men relying on folk medicine for health and wellness. Empirical data may be used to identify the individual groups; however, it is unlikely that cancer screening programs will routinely collect data that enable the overlap to be identified. Intersectionality has its roots at the experiential intersection of gender and race ,61 and, We do not know which participants were under- or never-screened for breast, cervical or colon cancer. We only know that we specified under- and never-screened during recruitment. Participants did not differentiate between under- and never-screened characteristics, barriers, or facilitators during group or individual discussions, suggesting there may not be a difference between these groups beyond frequency of screening.We also do not know what proportion of the Ontario population the different under- or never-screened groups represent, with the exception of “men”. Although we know the population of men in Ontario, many men are screened and do get screened regularly for colon cancer, so the characteristics of men who are under- or never-screened is still unknown.We did reach saturation with the groups we talked to about who is under and never screened for cancer. However, our initial seed groups were health care providers and so all focus groups were connected with mainstream western medicine, in some way. Thus the communities identified will have a history of interaction with mainstream western medicine and so be more likely to be screened for cancer. It is possible that we missed those groups who have limited or no contact with mainstream western medicine. For instance, indigenous communities were not mentioned even though indigenous people are known to have lower cancer screening rates than the general population . AdditioOne of the lessons learned conducting these focus groups is that many under- and never-screened groups are hard-to-reach. It takes time to identify and reach those communities, and then to connect and build relationships with them. Once a relationship has been established and the community is ready to collaborate, the collaboration must be followed through with because collaborations themselves are an intervention bringing under- and never-screened to a forum where ideas and concerns can be heard, misinformation corrected, knowledge exchanged and mutual understanding developed. Stopping collaboration early can trivialize the relationship, and therefore the group, potentially causing irreparable damage and further marginalizing a population that is already hard to reach.One question emerging from our research is: which, if any, of the under- or never- screened are open to, or willing to consider, regular screening, and which are not? It may be easier to return the under-screened to regular screening than the never-screened because the under-screened have participated in screening in the past. However, it is also possible that the under-screened had experiences, or made decisions, that will stop them from ever getting screened again. Along these lines, understanding the reasons for stopping or delaying screening for the under-screened will lend insight into how to prevent individuals from stopping screening in the first place. This will also help distinguish between under-screened individuals who have made a vow, or permanent commitment, not to get screened in the future, compared to under-screened individuals who are still of two-minds about screening.It is also likely that there are never-screened populations who will never be screened for cancer, no matter how much effort is expended. If this is true, a public health ethics question emerges around cancer screening and informed freedom of choice, with respect to what might constitute too much external pressure to comply, or unfair manipulation or persuasion. For these individuals, it may be more important to maintain open communication without an emphasis on change.Prioritizing cancer prevention activities is difficult for cancer screening programs and the under- or never-screened groups identified. Add the complexity of being at the intersection of two or more under- or never-screened groups and cancer screening  quickly becomes for “one of the lucky ones”  for the under- and never-screened.Women 50 years old and older are eligible for breast cancer screening with the Ontario Breast Screening Program (OBSP) and may refer themselves to the OBSP for a mammography. Women between the ages of 30 to 49 who are at high risk for breast cancer are also eligible but need a referral from their doctor or nurse practitioner to be screened through the OBSP. Women are recommended to have a mammogram every 2-3 years, however, yearly mammograms are recommended for women at high risk for breast cancer.Women 21 year old and older, who have been sexually active, are eligible for cervical cancer screening every three years, unless their health care provider recommends more frequent screening. Women must make an appointment with their clinician for pap testing, which is the only cervical cancer screening test covered by health insurance currently.Women and men 50 years old and older, and individuals at increased risk for colon cancer  are eligible for colon cancer screening. Colon cancer is screened using the fecal occult blood test, which looks for blood in stool, as the first pre-screening test. Colonoscopy, which looks for cancer, is recommended for people with unexplained blood in their stool or at increased risk for colon cancer because of family history. Some doctors prefer to send their patients straight to colonoscopy. The fecal occult blood test (recommended every two years) can be provided by doctors, nurse practitioners, or Telehealth Ontario. Colonoscopy (recommended every 10 years) is only available through a physician.Relevance of study question:1. Research Question explicitly stated – yes2. Research question justified and linked to existing knowledge base - yesAppropriateness of qualitative method1. Study design described and justified – yes  experience and observation, non-sensitive topic)Transparency of procedures1. Criteria for selecting study sample justified and explained – yes, purposive for diversity of opinion, volunteer because hard to reach2. Details of how recruitment was conducted and by whom - yes3. Details of who chose not to participate and why – not available4. Methods outlined and examples given (interview questions) - yes5. Study group and setting clearly described - yes6. End of data collection justified and described - yes7. Role of Researcher- influence on formulation of research question, data collection, interpretation?8. Informed consent process explicitly and clearly detailed - yes9. Anonymity and confidentiality discussed - yes10. Ethics approval cited - yesSoundness of interpretive approach1. Analytic approach described in depth and justified - yes2. Indicators of quality: description of how themes derived from data (inductive or deductive)3. Evidence of alternative explanations sought4. Analysis and presentation of negative or deviant cases - yes5. Description of the basis on which quotes chosen - yes6. Semi-quantification when appropriate - yes7. Illumination of context and/or meaning, richly detailed - yes8. Method of reliability check described and justified - yesa. Six independent analysts reviewed data and contest themes; anda. Resolution of disagreements9. Findings presented with reference to existing theoretical and empirical literature and how they contribute -yes10. Strengths and limitations explicitly described and discussed - yes11. Evidence of following guidelines - yes12. Detail of methods or additional quotes contained in appendix13. Written for health sciences audience - yes14. Grounded theory – not a simple content analysis but complex sociological theory generating approach.OHIP: Ontario Health Insurance Program.The authors declare that they have no competing interests.DG, AM, SR, BF, JA, PR and DFP have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; TN, FA and NK made substantial contributions to acquisition of data. DG drafted the manuscript. All authors have been involved in revising the manuscript critically for important intellectual content, given final approval of the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.DG is an Associate Professor with the Dalla Lana School of Public Health at the University of Toronto; AM and SR are doctoral candidates with the Dalla Lana School of Public Health at the University of Toronto; BF and JA are Research Associates with Cancer Care Ontario; PR and NK are Senior Scientists with Cancer Care Ontario; PR and FA are Associate Professors at York University; and DFP is a doctoral student at York University.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/14/495/prepub


Here we review other measures based on signal detection theory and receiver operating characteristics (ROC) analysis that are “bias free,” and relate these quantities to the calibration and discrimination measures developed in the probability estimation literature. We go on to distinguish between the related concepts of metacognitive bias (a difference in subjective confidence despite basic task performance remaining constant), metacognitive sensitivity (how good one is at distinguishing between one's own correct and incorrect judgments) and metacognitive efficiency (a subject's level of metacognitive sensitivity given a certain level of task performance). Finally, we discuss how these three concepts pose interesting questions for the study of metacognition and conscious awareness.The ability to recognize one's own successful cognitive processing, in e.g., perceptual or memory tasks, is often referred to as metacognition. How should we quantitatively measure such ability? Here we focus on a class of measures that assess the correspondence between trial-by-trial accuracy and one's own confidence. In general, for healthy subjects endowed with metacognitive sensitivity, when one is confident, one is more likely to be correct. Thus, the degree of association between accuracy and confidence can be taken as a quantitative measure of metacognition. However, many studies use a statistical correlation coefficient (e.g., Pearson's  Early cognitive psychologists were interested in how well people could assess or monitor their own knowledge, and asking for confidence ratings was one of the mainstays of psychophysical analysis  across different domains that have been discussed at length elsewhere Keren, . Our focP—parameters of this distribution such as d′ are concerned with how effectively an organism can discriminate objective states of the world. In contrast, Table P . The Pearson r correlation between these two vectors defines the “phi” coefficient. A related and very common measure of metacognitive sensitivity, at least in the memory literature, is the Goodman–Kruskall gamma coefficient, G , and that this may lead to erroneous conclusions, such as interpreting a difference in G between groups as reflecting a true underlying difference in metacognitive sensitivity despite possible differences in bias.d′ based on the hit rate and false alarm rate, which  is mathematically independent of bias. That is, given a constant underlying sensitivity to detect the signal, estimated d′ will be constant given different biases.A standard way to remove the influence of bias in an estimation of sensitivity is to apply SDT  − z(FA2), where z is the inverse of the cumulative normal distribution functiond′ is argued to be independent from metacognitive bias .There have been several evaluations of this approach to characterize metacognitive sensitivity , it is highly problematic for type 2 analysis. Galvin et al.  analysis, in which data are obtained from multiple response criteria. For example, if the payoffs for making a hit and false alarm are systematically altered, it is possible to systematically induce more conservative or liberal criteria. For each criterion, hit rate and false alarm rate can be calculated. These are plotted as individual points on the ROC plot—hit rate is plotted on the vertical axis and false alarm rate on the horizontal axis. With multiple criteria we have multiple points, and the curve that passes through these different points is the ROC curve. If the area under the ROC is 0.5, performance is at chance. Higher area under ROC (AUROC) indicates higher sensitivity.d′ does not make parametric assumptions that are known to be false.Because this method is non-parametric, it does not depend on rigid assumptions about the nature of the underlying distributions and can similarly be applied to type 2 data. Recall that type 2 hit rate is simply the proportion of high confidence trials when the subject is correct, and type 2 false alarm rate is the proportion of high confidence trials when the subject is incorrect Table . For twod′ and type 1 criterion placement, a conclusion supported by experimental manipulation  d′, the two can be directly compared. Therefore, for a metacognitively ideal observer (a person who is rating confidence using the maximum possible metacognitive sensitivity), meta-d′ should equal d′. If meta-d′ < d′, metacognitive sensitivity is suboptimal within the SDT framework. We can therefore define metacognitive efficiency as the value of meta-d′ relative to d′, or meta-d′/d′. A meta-d′/d′ value of 1 indicates a theoretically ideal value of metacognitive efficiency. A value of 0.7 would indicate 70% metacognitive efficiency (30% of the sensory evidence available for the decision is lost when making metacognitive judgments), and so on. A closely related measure is the difference between meta-d′ and d′, i.e., meta-d′ − d′  is small, meta-d′/d′ can give rather extreme values which may undermine power in a group statistical analysis. However, this problem can also be addressed by taking log of meta- d′/d′, as is often done to correct for the non-normality of ratio measures  introduced by Jang et al. . The SDRMetacognitive bias is the tendency to give high confidence ratings, all else being equal. The simplest of such measures is the percentage of high confidence trials  and a decreased use of the middle of the scale (3 and 4).d′ in standard psychophysics. If a continuous range of stimulus difficulties are available, such as when a full psychometric function is estimated, it is of course possible to apply the same methods to each level of stimulus strength independently. An alternative approach is to compute an aggregate measure of metacognitive sensitivity as the difference in slope between psychometric functions constructed from high and low confidence trials  ends up matching the frequency of rainy days in the long run we can say that the forecaster is well calibrated. In this framework metacognition has a normative interpretation as the accuracy of a probability judgment about one's own performance. We do not aim to cover the literature on probability judgments here; instead we refer the reader to several comprehensive reviews .There are two general classes of probability judgment problem. Discrete cases refer to probabilities assigned to particular statements, such as “the correct answer is A” or “it will rain tomorrow.” Continuous cases are where the assessor provides a confidence interval or some other indication of their uncertainty in a quantity such as the distance from London to Manchester. While the accuracy of continuous judgments is also of interest, our focus here is on discrete judgments, as they provide the clearest connection to the metacognition measures reviewed above. For example, in a 2AFC task with stimulus class An advantage of couching metacognitive judgments in a probability framework is that a meaningful measure of bias can be elicited. In other words, while a confidence rating of “4” does not mean much outside of the context of the experiment, a probability rating of 0.7 can be checked against the objective likelihood of occurrence of the event in the environment; i.e., the probability of being correct for a given confidence level. Moreover, probability judgments can be compared against quantities derived from probabilistic models of confidence :The judgment and decision-making literature has independently developed indices of probability accuracy similar to g Harvey , a “probPS is better. The Brier score is analogous to the phi coefficient discussed above.The mean value of the PS averaged across estimates is known as the Brier score Brier, . As the The decomposition of the Brier score into its component parts may be of particular interest to metacognition researchers. Particularly, one can decompose the Brier score into the following components Murphy, :O is the “outcome index” and reflects the variance of the outcome event c: O = c(1 − c); C is “calibration,” the goodness of fit between probability assessments and the corresponding proportion of correct responses; and R is “resolution,” the variance of the probability assessments. Note that in studies of metacognitive confidence in decision-making, memory, etc., the outcome event is simply the performance of the subject. In other words, when performance is near chance, the variance of the outcomes—corrects and errors—is maximal, and O will be high. In contrast, when performance is near ceiling, O is low. This decomposition therefore echoes the SDT-based analysis discussed above, and accordingly both reach the same conclusion: simple correlation measures between probabilities/confidence and outcomes/performance are themselves influenced by task performance. Just as efforts have been made to correct measures of metacognitive sensitivity for differences in performance and bias, similar concerns led to the development of bias-free measures of discrimination. In particular, Yaniv et al.  is defined as:Calibration  and its associated rating , with a lower discrepancy giving a better PS. A calibration curve is constructed by plotting the relative frequency of correct answers in each probability judgment category  against the mean probability rating for the category   Figure . A typic) Figure —probabilResolution is a measure of the variance of the probability assessments, measuring the extent to which correct and incorrect answers are assigned to different probability categories:R is subtracted from the other terms in the PS, a larger variance is better, reflecting the observer's ability to place correct and incorrect judgments in distinct probability categories.As Both calibration and resolution contribute to the overall “accuracy” of probability judgments. To illustrate this, consider the following contrived example. In a general knowledge task, a subject rates each correct judgment as 90% likely to be correct, and each error as 80% likely to be correct. Her objective mean performance level is 60%. She is poorly calibrated, in the sense that the mean subjective probability of being correct outstrips her actual performance. But she displays good resolution for discriminating correct from incorrect trials using distinct levels of the probability scale . This example raises important questions as to the psychological processes that permit metacognitive discrimination of internal states  and the mapping of these discriminations onto a probability or confidence scale  show better sensitivity when the delay between initial learning and JOL is increased  if worse performing subjects didn't make noisier ratings. On the other hand, it is possible that skill in a domain and metacognitive efficiency share resources (Dunning and Kruger's preferred interpretation), leading to a non-linear relationship between d′ and metacognitive sensitivity. As discussed above, one-shot ratings are unable to disentangle bias, sensitivity and efficiency. Instead, by collecting trial-by-trial metacognitive judgments and calculating efficiency, it may be possible to ask whether efficiency itself is reduced in subjects with poorer skill.Finally, the influence of performance, or skill, on efficiency itself is of interest. In a highly cited paper, Kruger and Dunning  report aThere has been a recent interest in interpreting metacognitive measures as reflecting conscious awareness or subjective  phenomenological experience, and in this final section we discuss some caveats associated with these thorny issues. As early as Peirce and Jastrow  it has bd′)—indeed, this is the essence of metacognitive sensitivity. It has been argued that type 1 d′ itself should not be taken as a measure of awareness because unconscious processing may also drive type 1 d′ , but near-zero metacognitive sensitivity. Although this finding has proven difficult to replicate , not the subject's experience, which is unknown to the experimenter. Thus, while low metacognitive sensitivity could be due to an absence of conscious experience, it could also be due to hallucinations, such that the subject vividly sees a false target and thus generates an incorrect type 1 response. Because of the vividness of the hallucination, the subject may reasonably express high confidence . In the case of hallucinations, the conscious experience does not correspond to objects in the real world, but it is a conscious experience all the same. Thus, low metacognitive sensitivity cannot be taken unequivocally to mean lack of conscious experience.That said, we acknowledge the close relationship between metacognitive sensitivity and awareness in standard laboratory experiments in the absence of psychosis. Intuitively, metacognitive sensitivity is what gives confidence ratings their meaning. Confidence or bias fluctuates across individual trials , whereas metacognitive sensitivity is a property of the individual, or at least a particular condition in the experiment. High confidence is only meaningfully interpretable as successful recognition of one's own effective processing when it can be shown that there is some reasonable level of metacognitive sensitivity; i.e., that confidence ratings were not given randomly. For instance, Schwiedrzik et al.  used thid′ is not a confound, and that the confidence level expressed is solely due to introspection of the conscious experience in question. Thus, the strongest argument for preferring metacognitive bias rather than metacognitive sensitivity as a measure of awareness is a conceptual one. Metacognitive sensitivity measures the ability of the subject to introspect, not what or how much conscious experience is being introspected upon on any given trial. For instance, in what is sometimes called type 2 blindsight, patients may develop a “hunch” that the stimulus is presented, without acknowledging the existence of a corresponding visual conscious experience. Such a hunch may drive above-chance metacognitive sensitivity , metacognitive sensitivity (how good one is at distinguishing between one's own correct and incorrect judgments) and metacognitive efficiency . Finally, we discussed how these three concepts pose interesting questions for future studies of metacognition, and provide some cautionary warnings for directly equating metacognitive sensitivity with awareness. Instead, we advocate a more traditional approach that takes metacognitive bias as reflecting levels of awareness and metacognitive sensitivity as a background against which other measures should be referenced.The Editor Dr. Harriet Brown declares that despite having previously collaborated with the author Dr. Klaas Stephan the review process was handled objectively. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Ugo Foscolo, was an Italian poet whose works rank among the masterpieces of Italian literature. Talented and well educated in philosophy, classics, and Italian literature, Foscolo gave literary expression to his ideological aspirations and to the numerous amorous experiences in odes, sonnets, plays, poems and an epistolary novel. Concurrent with his rich literary output, Foscolo’s correspondence represents a unique perspective from which to monitor his literary and political views and investigate aspects of his everyday life. Among other interesting information, one can find elements of Foscolo’s medical history which is generally unknown. Based on his testimonies we suggest that he suffered of longstanding bladder outlet obstruction presumably due to urethral stricture. In the present article we investigate the possibility that chronic bladder outlet obstruction and the consequent renal insufficiency was attributed to the death of Ugo Foscolo. Tieste. In due course he was promoted to captain in the Italian division of the Napoleonic army and was sent to serve in northern Italy and western France (1804–06). During that period he translated some classical works of the ancient Greek literature as well as the Sentimental Journey of Laurence Sterne into Italian. He also wrote some odes sonnets, plays and the epistolary novel The Last Letters of Jacopo Ortis. In 1807 Foscolo returned to Milan where he composed the poem On Tombs. One year later he won the chair of Italian rhetoric at the University of Pavia. As soon as the chair was abolished by Napoleon (1808), Foscolo started composing the tragedies Aiace and Ricciarda, and the unfinished poem, Le grazie. In 1814 Napoleon fell, the Austrians returned to Italy and Foscolo, refusing to take the oath of allegiance, was self-exiled first in Switzerland and then in England. There he wrote commentaries on Dante, Boccaccio, and Petrarch for The Edinburgh Review and The Quarterly Review for livelihood , the letter no 1230 to Sigismondo Trechi , the letter no 1236 to Isabella Teotochi Albrizzi , the letter no 1253 to Francesco Aglietti (November 1812), the letter 1315 to Isabella Teotochi Albrizzi (Bellosguardo 8 June 1813), the letter 1316 to Sigismondo Trechi (Bellosguardo 10 June 1813), the letter 1371 to his mother  and the letter No. 2291 to his friend John Cam Hobhouse (1 September 1818). According to the information retrieved from the above letters, in September 1812, Foscolo was infected by urethritis. Symptoms gradually disappeared and 8 days later he experienced acute urinary retention which was treated by passing a sound. Dysuria, local pain and mucus overflow occurred since after. Following an episode of gross hematuria the above symptoms were relieved. In the same letter, he reported that he had similar but less painful symptoms 1 year before the onset of “gonorea” (November 1811). This previous infection is also mentioned in the letter nr. 1236. Accordingly to his testimony, the progress of this situation was accompanied by nocturnal bleeding (hematuria). He was practiced dilatation of the urethra using rods of increasing thickness and of variable materials for an unspecified time period. He was also suffering of local pain and fever that were treated with baths and hydrotherapy, bloodletting and Chinese Quinine as well. Foscolo wasn’t able to determine the nature and the precise onset of the disease, however; through his correspondence with Antonietta Fagnani Arese (between 1801 and 1803), became clear that he experienced the above condition many years before. In fact, among almost 200 letters that Foscolo wrote to her there are many mentioning hydrotherapies for pain relief, some reporting febrile flare ups and few presenting Foscolo and Arese to suffer in common from an infectious disease whose nature was not clarified. Correspondence from 1819 to 1826 provides no specific information regarding the above health matter.According to the information retrieved from the literature the cause of his death is actually unspecified. Most Foscolo’s biographers report that he died on Sept/10/1827 of a long standing liver disease while, Pecchio mention an inflammatory malady of the liver. However among numerous febrile episodes reported by Foscolo there are two characterized as bilious fever (febbre biliosa) [letter no 650 (Aug/12/1826) and letter no 652 (Sept/5/1826)] and one characterized as inflammatory fever (febbre infiammatoria) [letter no 632 (Sept/12/1824)]. Some months before, on 17th April 1824 he reported to Lord Dacre [letter no 627] that he suffered from fever that lasted for several weeks. In the letter no 637 to Mr Walker (Oct. 1824) he mentioned that he had just recovered from a disease. In the letter no 637 to Hudson Gurney (Aug/12/1826) he was seeking of a more effective remedy against the bile, since nor the pills, nor the rhubarb (which he took in high doses) were able to straining the stomach. He also states that he would prefer of any other disease since bilious attacks rendered him oppressively sleepy. In the letter no 652 to Mr Edgardo Taylor (Sept/5/1826), he reported: “when I walked up to my last hovel, I began to suffer of a bilious fever” and “fever turns in what we call cholera morbus. Now I feel better, but I feel very tired, yet, the worst in this disease is a lethargic slumber”. Four months later he writes to Mr Reinaud di Zante [letter no 666 (Jan/9/1827)]: “I was staying for long in bad or mediocre (situation) and never in good health”. Finally, after a short recovery period [letter no 670 (Mar/28/1827)], a febrile (?) disease described as lasting for more than 3 months was reappeared. Accordingly to Antona-Traversi’s notes, Foscolo’s health was getting worst: He wrote to Bossi (Mar/1827) that his fever comes every afternoon and it is associated with bilious irritation. Two months later (Jul/1827) he wrote to Mami that his illness lasts 8 months and was gradually aggravated: Despite frequent bloodletting sessions the fever comes twice daily being slight in the morning and rages during the evening. He also noted that the true nature of this disease was finally revealed as it is a chronic liver and intestinal inflammation. Accordingly to Pecchio’s observations it was not before August 1827 that his health status was irreversibly deteriorated and indeed, towards the end of this month, Foscolo’s disease made life very hard for him. He was losing weight day by day and manifested a predisposition to dropsy as a consequence of a disease of the liver that has long afflicted him. In fact, in the letter no 674, to Canonico Riego (Aug/5/1827), Foscolo notes that the dropsy was growing rapidly however; the surgeon didn’t consider it mature enough for an operation. According to Antona-Traversi, Foscolo finally underwent surgery (paracentesis), which was repeated few days later, however they offered little help. In fact, Foscolo wrote to Bossi (Aug/21/1827) that weakness, insomnia and dyspepsia continued while dropsy relapsed as well. In Sep/7/1827 he went into a coma and died on Sep/10/1827.The term dropsy  describes the edematous accumulation of fluid in the interstitium. The amount of interstitial fluid is determined by the balance of fluid homeostasis. When the last is disrupted—either by the increased secretion or the impaired removal of the fluid into and from the interstitium—can cause edema. The typical clinical manifestation is whole-body swelling. Situations that alter the balance of fluids are cardiac, kidney and liver failure . Of note, the term gonorea (gonorrhoeae) used by him merely describes the usual symptoms of STDs such as burning with urination and penile discharge than refers to infection by Neisseria gonorrhoeae (unknown at that time since it was first discovered in 1879). Ιnfection was followed by inflammation and urinary retention. Gradually pain and lower urinary tract symptoms (both storage and voiding) were established. The exact disease from which Foscolo suffered is not mentioned in his correspondence however many common diseases and conditions were practically unknown from medicine of that time.Today, it is well known that an important number of patients with gonococcal urethritis develop urethral stricture. Especially those with posterior strictures are in higher risk to develop acute urinary retention Mundy . In factThe fact that, between 1813 and 1818, Foscolo’s correspondence includes information regarding urethral strictures treatment indicates a longstanding bladder outlet obstruction. In fact, if instrumentation is required more frequently or is complicated, then chronic retention and inflammation are established. The expanding inflammation may result in inflammatory-mediated pain and fever and is usually characterized by flare-ups and remissions Mundy . WhetherOf note, numerous febrile episodes are mentioned in the correspondence of Foscolo since the presumed onset of the disease. The term bilious fever (febbre biliosa) used by him is not necessarily associated with a disease of the liver. Actually, “bilious” means the condition was thought to arise from disorders of bile, the two types of which were two of the four humours of traditional Galenic medicine in 200 A.D., and bilious fever was a medical diagnosis often used for any fever that exhibited the symptom of nausea or vomiting in addition to an increase in internal body temperature. The term is no longer used, but was used by medical practitioners in the eighteenth and nineteenth centuries. Among various definitions for the term bilious fever that have emerged over the past centuries is that of Buchan : “continModern diagnoses for the same symptoms would include a wide range of conditions and infections including obstructive uropathy. Interestingly, consequences of urine retention were known at that time: “When the urine is too long retained, it is not only resorbed, or taken up again into the mass of fluids, but by stagnating in the bladder it becomes thicker, the more watery parts flying off first, and the more gross and earthly remaining behind. By the constant tendency which these have to concrete, the formation of stones and gravel in the bladder is promoted […] Many persons have lost their lives, and others have brought on very tedious, and even incurable disorders, by retaining their urine too long, from a false delicacy. When the bladder has been over-distended, it often loses its power of action altogether, or becomes paralytic, by which means it is rendered unable either to retain the urine, or expel it properly. The calls of Nature ought never to be postponed. Delicacy is doubtless a virtue; but that can never be reckoned true delicacy, which induces any one to risk his health, or hazard his life” Buchan .It therefore remains unclear how Foscolo, his doctors and his biographers missed this point. Given the long-stand- ness of the urethral structure treatment it is less likely that obstruction was spontaneously resolved. The fact that references to urological problems do not appear in Foscolo’s correspondence from 1819 onward could be associated to an improvement of his lower urinary tract symptoms. It should be noticed that the management of urinary tract infections at that time included hospitalization, bed rest, attention to diet, plasters, narcotics, herbal enemas and douches and judicious bleeding . Most of the above mentioned treatments are practically ineffective. Foscolo was treated with baths and hydrotherapy, bloodletting and Chinese Quinine as well. Quinine is an alkaloid derived from the bark of the cinchona tree. It has been used as an antimalarial drug since before 1633. It has also antipyretic, analgesic, and anti-inflammatory properties and at that time it has been used in common cold preparations for that purpose. It reduce the sensitivity of muscle cells to stimuli that cause them to contract, and prolong the time it takes for the muscle to contract. The above properties of Quinine suggest effectiveness in the treatment of prostatitis related pain and storage lower urinary tract symptoms, however reduced contraction rate may progress to chronic urinary retention . Moreover, Foscolo used to eat excessive quantities of rhubarb and drink its extract in order to treat his illness. The leaves of this vegetable contain high levels of oxalic acid, which causes serious problems in the liver and kidney and even a small amount is sufficient for someone to get sick.In conclusion, the medical history of Ugo Foscolo is poorly investigated. While most authors report that he died of a long standing liver disease, its nature and beginning are not clear. Evidence from his correspondence suggests that he suffered of chronic bladder outlet obstruction and he may gradually developed chronic renal insufficiency that probably attributed to his death.vescica”, “prostata”, “uretra”, “medico”, “chirurgo” combined with “malatia”, “infermita”, “irritazione”, “terapia, “salute”, “infiammazione”. The text was studied in original language , from: Ugo Foscolo, Epistolario, Edizione Nazionale delle Opere di Ugo Foscolo, Le Monnier, Firenze 1954.We conducted a research on Ugo Foscolo’s correspondence -included in the Epistolario- in order to identify information regarding his medical history focusing mainly on urological diseases and relative conditions. Initial search terms were “Information regarding his death were retrieved from his correspondence (Epistolario) and the journals “The Gentleman’s Magazine”, , “The New Monthly Magazine and Literary Journal” , “The Museum of Foreign Literature, Science and Art” , and the books “Divagazioni letterarie” , “Ugo Foscolo: An Italian in Regency England”  and “Vita di Ugo Foscolo” . Information related to dropsy was investigated in medical textbooks of that time such as: “Bilious Inflammatory Fever” , “The Causes, Treatment, and Cure of Fever and Ague, and Other Diseases of Bilious Climates” , “Collection Of Papers On The Subject Of Bilious Fever” , “A Text-Book with Particular Reference to Physiology and Pathological Anatomy” .


For over 100 years, endosymbiotic theories have figured in thoughts about the differences between prokaryotic and eukaryotic cells. More than 20 different versions of endosymbiotic theory have been presented in the literature to explain the origin of eukaryotes and their mitochondria. Very few of those models account for eukaryotic anaerobes. The role of energy and the energetic constraints that prokaryotic cell organization placed on evolutionary innovation in cell history has recently come to bear on endosymbiotic theory. Only cells that possessed mitochondria had the bioenergetic means to attain eukaryotic cell complexity, which is why there are no true intermediates in the prokaryote-to-eukaryote transition. Current versions of endosymbiotic theory have it that the host was an archaeon (an archaebacterium), not a eukaryote. Hence the evolutionary history and biology of archaea increasingly comes to bear on eukaryotic origins, more than ever before. Here, we have compiled a survey of endosymbiotic theories for the origin of eukaryotes and mitochondria, and for the origin of the eukaryotic nucleus, summarizing the essentials of each and contrasting some of their predictions to the observations. A new aspect of endosymbiosis in eukaryote evolution comes into focus from these considerations: the host for the origin of plastids was a facultative anaerobe. There are various perspectives from which eukaryote origins can be viewed, including palaeontological evidence , energetdie kleinste morphologische Einheit der organisirten Materie’) [One can occasionally read (though we will politely provide no examples) that Altmann  is to beaterie’) , p. 258.Symbiose’ to designate this type of coexistence [The concept of symbiosis , that two different organisms can stably coexist and even give rise to a new type of organism, traces to Simon Schwendener , a Swissxistence . Schimpexistence  is sometxistence , p. 113.in toto, from cyanobacteria [Schimper ,12 did, bacteria .Mereschkowsky's scheme was more fully elaborated but basically unchanged in his 1910 series : there wMany biologists still have a problem with the notion of endosymbiosis and hence prefer to envisage the origin of eukaryotes as the product of gene duplication, point mutation and micromutational processes . A 2007 why the origin of eukaryotes corresponds to the origin of mitochondria [There is one alternative to classical endosymbiotic theory that took anaerobic mitochondria and hydrogenosomes into account, the hydrogen hypothesis ; it predchondria ,34. But chondria , and thechondria ), but he2.To get a fuller picture of eukaryote origins, we have to incorporate lateral gene transfer (LGT) among prokaryotes, endosymbiosis and gene transfer from organelles to the nucleus into the picture. That is not as simple as it might seem, because it has become apparent that individual genes have individual and differing histories. Thus, in order to get the big picture, we would have to integrate all individual gene trees into one summary diagram in such a way as to take the evolutionary affinities of the plastid (a cyanobacterium), the mitochondrion (a proteobacterium) and the host (an archaeon) into account. Nobody has done that yet, although there are some attempts in that direction . In 2015But because of the role of endosymbiosis in eukaryote cell evolution, eukaryotes tend to have two evolutionarily distinct sets of ribosomes , or sometimes three  and in An early study looking at the phylogeny of the core gene set, which largely but not entirely corresponds to the ribosomal protein superoperon of prokaryotes, came to the conclusion that the information contained within the alignment is problematic because of the low amount of sequence conservation involved across many of the sites . ConcernAlways critical of the branches in trees that phylogenetic methods produce , Embley Now is a good time to have a look at endosymbiotic theories and related ideas for the origin of eukaryotes, their nucleus and their mitochondria. In doing so, we pick up on our own earlier reviews of the topic ,53, the 3.a; [The nucleus is a defining feature of eukaryotes . Theoriefigure 1a; ).Figureb; [c; [figure 1d; [Gemmata obscuriglobus (a member of the Planctomyces-Pirella group) appears to be surrounded by a folded membrane, the organization of which was thought to resemble the nucleus . He b;  presenteb; –58. Hb; [c; ). In thegure 1d; ,61). Fuegure 1d;  observedgure 1e; ). Later gure 1e; ; subsequmembrane , as had membrane . Searcy membrane  interpregure 1f; ).g). A vesicular model for the origin of the nucleus in a cell that had a mitochondrial endosymbiont was proposed  for the origin of the nucleus. They postulated a fusion of plasma membranes in an agglomeration of δ-proteobacteria entrapping a methanogenic archaebacterium, which evolved to the nucleus , leading to both the eukaryotic flagellum and the nucleus , which was engulfed by a γ-proteobacterium . It posgure 1h;  it positgure 1h; ,68 modifgure 1i; ,68). Thegure 1i; ,68 envisgure 1i; . Lynn Magure 1j; ,70). A vgure 1k; ). Horiikgure 1l; ). An ori 1l; [m; –75). Pen 1l; [m;  sometimen; [More recently, the community of scientists interested in cytoskeletal evolution have—in unaltered form—rekindled Cavalier-Smith's hypothesis of an autogenous (non-symbiotic) origin of a phagocytosing amitochondriate eukaryote (an archezoon) via point mutational changes leading to a host that does not need a mitochondrion at all to enjoy its phagocytotic lifestyle, but acquires one nonetheless .o; [Forterre  departedfigure 1o; ).A problem with all models that envisage a role for planctomycetes in eukaryote origin is that there is no molecular phylogenetic evidence that would link any lineage of planctomycetes with eukaryotes . The proThe recent focus both on the evolution of cytoskeletal components  and on a4.a; [Endosymbiotic theory for the origin of chloroplasts and mitochondria started again with Mereschkowsky  and his figure 2a; ). Compara; –82—he wab; [Mereschkowsky failed, however, to recognize the endosymbiotic origin of mitochondria, although the physiological properties of cells that he explained with the endosymbiotic origin of the nucleus are, from today's perspective, properties of mitochondria . As veryfigure 2b; ). Like Pb; , p. 144.Irrwege der Symbioseforschung’ (translation: Symbiosis research gone astray) and (iii) from Lederberg [In print, cell biologists rejected endosymbiotic theory during the 1920s and through into the 1970s. A few prominent trouncings were (i) from Wilson  who wrotederberg , who surc; [Endosymbiotic theory was repopularized in 1967 by Lynn Sagan (later Margulis)  and alsofigure 2c; ). The DNc; . GoksøyrMycoplasma), in whose cytoplasm an aerobic prokaryotic microbe (the proto-mitochondrion) was ingested, resulting in the evolution of an aerobic amoeboid organism, which later acquired a spirochaete, resulting in the eukaryotic flagellum .e; [figure 2f; [Countering Margulis, de Duve  outlinedfigure 2e; ). Staniee;  and placgure 2f; ).g; [figure 2h; [figure 2i; [et al. [In the early 1970s, there was considerable resistance to the concept of symbiosis in cell evolution. Raff & Mahler  presentefigure 2g; ). Bogorag;  describegure 2h; ). Cavaligure 2h;  explainegure 2i; ). Though [et al.  in their [et al. , p. 464.Paracoccus denitrificans), giving rise to the mitochondria where again the host's origin is not addressed. Woese [During the 1970s and 1980s, some other models for the origin of eukaryotes were developed, which are not presented in d. Woese  recognizd. Woese .j; [In 1980, both van Valen & Maiorana  and Dooj;  put archj;  adjustedk; [2-producing) fermentations, thus it directly accounts for the common ancestry of mitochondria and hydrogenosomes as well as for intermediate forms between the two, the anaerobic mitochondria [l), as does the sulfur cycling theory of Searcy . It entchondria . The modchondria  operatesk; . It egure 2m; ), but neα-proteobacterium) was then surrounded by the syntrophic couple, which led to an obligatory (endo)symbiotic stage with metabolic compartmentation as selective force to avoid interference of opposite anabolic and catabolic pathways. After the mitochondrion was stabilized, a loss of methanogenesis occurred generating the proto-eukaryote stage, in which the archaeal endosymbiont became the nucleus .o; [Rickettsia-like α-proteobacterial endosymbiont . This mo;  in that o; . Gray [1o;  recentlyo; ,19, oxyggure 2p; ). The prq; [The perhaps latest model for the origin of the eukaryotic cell and mitochondria is the inside-out theory by David & Buzz Baum . They arfigure 2q; ).Bdellovibrio-like penetration mechanisms, an ability that has evolved in many independent lineages of bacteria, including Micavibrio, and that has been suggested to have possibly played a role in mitochondrial origin [This section has shown that much thought has been invested on the topic of how the mitochondrial endosymbiont could have entered its host. Many theories place a premium on phagocytosis and predation upon bacteria as the essential step for allowing the symbiont to enter its host. Predation is actually very widespread among bacteria , but it l origin ,111. But5.Endosymbiotic theory is traditionally founded in comparative physiology (core carbon and energy metabolism). That is true for Mereschkowsky ,15, for Entamoeba, Giardia and microsporidia, which harbour neither respiring mitochondria nor fermenting hydrogenosomes and were later found to harbour relict organelles that came to be known as mitosomes [Entamoeba and Giardia are derived, via reduction, from organisms that possessed the same endosymbiont as gave rise to mitochondria and hydrogenosomes. It also clearly predicted the chimaeric nature of eukaryotic genomes [The theories in the foregoing have different strengths and weaknesses; they are also designed to explain different aspects of eukaryotic cells too numerous to outline here. It is not our aim to defend them all or criticize them all. Instead we wish to focus on one of them, the one that accounts for the anaerobes. Theories are supposed to make testable predictions; in that respect the hydrogen hypothesis  has doneitosomes ,112–114. genomes , which w genomes .2-dependent archaeon, the symbiont being a facultative anaerobe that was able to respire in the presence of O2, or to perform H2-producing fermentations under anaerobic conditions. This is sketched in figure 3a for the example of methanogenesis, the metabolic model upon which the hypothesis was based, but, clearly, there are many H2-dependent archaea, and it was clearly stated that any strictly H2-dependent host would fit the bill [The nature of host–symbiont interactions at the onset of mitochondrial symbiosis in the hydrogen hypothesis was posited to be anaerobic syntrophy, the host being a Hthe bill . This isthe bill ,68,118, 2-transfer) is thus the metabolic context of host–symbiont association, leading to hosts that tend to interact tightly with and adhere to their symbionts (b), similar to the symbiotic associations between methanogens in hydrogenosomes in the cytosol of anaerobic ciliates [Anaerobic syntrophy , but the host is a strict autotroph and cannot supply them in excess of its own needs because H2-dependent autotrophs live from gases and do not import reduced organic compounds. This phase of the symbiosis is thus unstable because the symbiont will eventually consume the host's cytosol. In order for the symbiosis to persist, either the host needs to invent importers for organics, or the symbiont's preexisting genes for importers are transferred to the host's chromosomes and can be expressed there, and the bacterial importers need to be functional in the archaeal membrane, which is true in haloarchaea [figure 3d).The Hoarchaea . Gene troarchaea , except Expression of carbon importers in the host's membrane does not completely solve the problem though, because the hydrogen hypothesis posits that the host was an autotroph, hence its carbon metabolism was specialized to anabolic pathways. A good example of such enzymatic specialization is the bifunctional fructose 1,6 bisphosphate aldolase/bisphosphatase that is characteristic of archaeal autotrophs  but is a2 via fermentation to satisfy the host. Second, it confers heterotrophy upon the host compartment (the cytosol), but only if transfer of the symbiont's entire glycolytic pathway is successful , because the first net gain of ATP in glycolysis is at the pyruvate kinase step. Third, if that occurs, it directly accounts for the bacterial origin of eukaryotic glycolytic enzymes . No oth2 to run its carbon and energy metabolism. But the expression of genes for heterotrophic carbon flux in the host compartment supply it with reduced carbon species and ATP and there is no longer any selective pressure to maintain the host's autotrophic lifestyle, which will necessarily have involved membrane bioenergetics because all autotrophs are dependent upon chemiosmotic coupling. As a result, the host can relinquish its autotrophy; it has become a heterotroph with chimaeric chromosomes harbouring archaeal and bacterial genes, and archaeal ribosomes and glycolysis in the cytosol. In addition, the cytosol harbours a facultatively anaerobic bacterial endosymbiont with a respiratory chain and H2-producing fermentations (d) that can donate a full genome's worth of bacterial genes over and over again, replacing many indigenous archaeal pathways with bacterial counterparts, and thus transforming the archaeon from within. Part of this transformation involves the establishment of bacterial lipid synthesis , where they subsequently spread to many sites in the host's chromosomes (figure 3e). Evidence for this is the observation that about half of introns in eukaryotic genes are ancient, being present at positions that are conserved across divergent eukaryotic lineages, indicating their presence in the eukaryote common ancestor [figure 3f). That is not a problem for group II introns, which use their maturase from one ribosome passage to block the mRNA 5′ end until the intron is removed. But with the origin of fully fledged spliceosomes (symbolized as purple dumbbells in figure 3g) transitioning to spliceosomal splicing, nascent transcripts are translated before they can be spliced. This means that introns are translated, leading to defective gene expression at hundreds of loci simultaneously, a surely lethal condition for the host unless immediately remedied. There are a finite number of solutions to this problem, in addition to precipitating the origin of nonsense-mediated decay (nmd), a eukaryote-specific machinery that recognizes and inactivates intron-containing mRNAs [The crux of the splicing hypothesis for nuclear origins  is this:figure 3ancestor . Once thancestor , while tng mRNAs .h), allowing the slow process of splicing to go to completion around the chromosomes, and thereby initially allowing distal diffusion, later specific export of processed mRNAs to the cytosol for translation [One solution would be to simply remove all the introns in the chromosomes. That did not happen, because many intron positions are ancient ,139. Anofigure 3nslation . The nucnslation ,141.In that view, the origin of the nucleus marks the origin of a genuinely new cell compartment—not the nucleus itself, but the eukaryotic cytosol—that is free of active chromatin, where protein–protein interactions, rather than protein–DNA interactions, move to the fore in signalling and regulation, and where proteins can spontaneously aggregate and interact in such a way as to generate new structures and functions, including the true cytoskeleton and membrane traffic processes that distinguish eukaryotes from prokaryotes. A curious property of this model for the origin of the nucleus is that it only requires eukaryotes to possess a nuclear membrane when they are expressing genes, which directly points to another very curious (and vastly underappreciated) character that separates eukaryotes from prokaryotes: prokaryotes express their genes continuously during cell division, while eukaryotes shut down the expression all of their genes before chromosome partitioning and cell division. To us, this suggests an evolutionary link between splicing the splicing-dependent origin of the nucleus, the origin of genome-wide gene silencing mechanisms , which gh) (i) that requires a nucleus in order to express genes, (ii) that has retained archaeal ribosomes in the cytosol as a vestige of the host, (iii) that has bacterial energy metabolism both in the cytosol and in the mitochondrion, (iv) that has lost all electron-transfer phosphorylation functions in the plasma membrane, (v) that has nonetheless retained the archaeal ATPase, which however now operates backwards to acidify the vacuole, and (vi) that has typical eukaryotic features. It is true that many theories for eukaryote origin surveyed here address many of the same aspects, but what everyone has overlooked for the now nearly 50 years since Margulis revived endosymbiotic theory [This set of events leads to a bipartite cell h (i) thac theory  is that c theory . The intc theory . That pu6.Euglena [Chlamydomonas [Chlamydomonas [Trichomonas and Giardia use to survive under anaerobic conditions, not to mention their conservation in Cyanophora [Of course, there was one additional and crucial prokaryotic endosymbiont in eukaryotic history: a cyanobacterium that became the plastid. This is outlined in Euglena ,145,146 ydomonas –149. Theydomonas , and in anophora , lead toe); possible metabolic contexts [figure 4f). The origin of protein import machineries of organelles played an important role, both in the case of mitochondria [figure 4g–i). At least two secondary endosymbioses involving green algae occurred [The origin of plastids has been the subject of several recent papers ,82,151. figure 4contexts  for thatcontexts , nitrogecontexts  or a comcontexts . Similarcontexts , which ichondria  and in tchondria , becauseoccurred –159, andet al. [Since the inception of endosymbiotic theory by Mereschkowsky ,15, the et al. . Both paet al. , and it et al.  surveyed7.An important component of endosymbiotic theory is the circumstance that organelles have retained genomes. The observation that organelles had DNA at all was one of the key observations that supported endosymbiotic theory in the first place . Indeed,Why have organelles retained DNA? The answer to that question is satisfactorily explained by only one theory: John F. Allen's CoRR hypothesis (co-location for redox regulation) ,165. It 2, generating the superoxide radical (O2−), which is the starting point for reactive oxygen species (ROS) [One of the burgeoning strengths of Allen's CoRR hypothesis for the evolutionary persistence of organelle genomes concerns its predictions with regard to hydrogenosomes. Hydrogenosomes have more or less everything that mitochondria have, but they have lost the respiratory chain in their inner membrane. CoRR posits the selective pressure to maintain organelle DNA to be the necessity to maintain redox balance. Some readers might ask: What is redox balance? Redox balance refers to the smooth flow of electrons through the electron transport chain. The concept of redox balance applies both to mitochondria and to chloroplasts, because both have electron transport chains that generate proton gradients to drive their respective ATPase. In both electron transport chains, quinols and quinones are an essential component. These membrane soluble electron carriers can transfer electrons non-enzymatically to Oes (ROS) . If the es (ROS) . Other tes (ROS) , do not 8.There is currently much buzz about the possibility that a group of crenarchaeotes, the TACK superphylum  might harbour the closest ancestors of the host that acquired the mitochondrion. Several different trees that address the issue have appeared recently  methane production occurs spontaneously at serpentinizing hydrothermal vents –176 (for2-dependent chemolithoautotroph to facultatively anaerobic heterotroph) as the hydrogen hypothesis posits for the origin of eukaryotes [Indeed, recent findings have it that many archaeal lineages stem from methanogenic ancestors via gene transfers . In partkaryotes , and thekaryotes . It is pkaryotes .2-dependent state seems to be a recurring theme within the archaea, with gene transfers from bacteria providing the physiological capabilities to access electron and energy sources other than H2. Early archaeal evolution and the origin of eukaryotes are ancient events, so ancient that they push phylogenetic methods to their limits, and possibly beyond. The book of early evolution holds many exciting chapters, and the origin of eukaryotes is clearly one of the most crucial, because eukaryotes—and only eukaryotes, the cells that have mitochondria—brought forth genuinely complex life.Thus, as the position of eukaryotes starts to come into focus within the archaeal tree, so does the position of the root among archaea, and multiple evolutionary transitions from an ancestrally H