With a growing trend for those with advanced cancer to die at home, there is a corresponding increase in need for primary medical care in that setting. Yet those with lower incomes and in rural regions are often challenged to have their health care needs met. This study examined the association between patient income and residence and the receipt of Family Physician (FP) home visits during the end-of-life among patients with cancer.Data Sources/Study Setting. Secondary analysis of linked population-based data. Information pertaining to all patients who died due to lung, colorectal, breast or prostate cancer between 1992 and 1997  in the Canadian province of Nova Scotia (NS) was extracted from three administrative health databases and from Statistics Canada census records. Study Design. An ecological measure of income ('neighbourhood' median household income) was developed using census information. Multivariate logistic regression was then used to assess the association of income with the receipt of at least one home visit from a FP among all subjects and by region of residency during the end-of-life. Covariates in the initial multivariate model included patient demographics and alternative health services information such as total days spent as a hospital inpatient. Data Extraction Methods. Encrypted patient health card numbers were used to link all administrative health databases whereas the postal code was the link to Statistics Canada census information.Over 45% of all subjects received at least one home visit (n = 3265). Compared to those from low income areas, the log odds of receiving at least one home visit was significantly greater among subjects who reside in middle to high income neighbourhoods . This association was found to be primarily associated with residency outside of the largest metropolitan region of the province.The likelihood of receiving a FP home visit during the end-of-life is associated with neighbourhood income particularly among patients living outside of a major metropolitan region. In the last ten years, more and more of those dying of cancer in Canada are doing so out of hospital. In NovaAs this trend has developed, it has become even more important for patients and families to have access to medical care in the community. Such first line medical care, in Canada, is generally provided by a family physician, usually previously known to the patient. Initially those with terminal illness will obtain their medical care in the office or out patient setting. As they become sicker, however, there will come a time when getting from the home to the clinic office will be too difficult. At such a time, access to home visiting by a physician becomes very important -11. ReseThere is evidence that those better off financially live longer and are in better health than poorer individuals,16. ReasWe wondered if access to terminal care home visiting by family physicians is better for those with higher incomes even in our publicly-funded health system. Therefore, the purpose of this study was to examine the association between income and the likelihood of receiving home visits by family physicians during the end-of-life among those with cancer. In addition, we examined the effect of regional residency, specifically residency in a major urban centre versus all other regions of NS .Data for this retrospective, population-based study were obtained through the linkage of individual-level information extracted from four administrative health databases: (1) the Nova Scotia Cancer Centre Oncology Information System (OPIS) which includes the Nova Scotia Cancer Registry (NSCR) and provincial vital statistics information, (2) the Nova Scotia Medical Services Insurance Physician Services (MSIPS), (3) the Nova Scotia Hospital Admissions / Separations (HAS) file, and (4) the Queen Elizabeth II Health Sciences Center Palliative Care Program (PCP). The MSIPS provides a record of all services provided by physicians to residents of Nova Scotia whereas the HAS contains information relating to all hospital inpatient and outpatient stays and procedures. Because individual-level income information is not available from these sources, the Postal Code Conversion File (PCCF) and 1996 Statistics Canada census data were used to develop an 'ecologic-level' proxy for household income, enumeration area median (EAM) income quintiles or 'neighbourhood income'. These aggregate measures are derived from census information grouped by provincial enumeration areas or 'neighbourhoods'. The resulting quintiles are based on the median income value of each enumeration area. Evidence suggests the use of such proxies in population-based studies is a valid alternative in situations where household level information in not available. It is, Encrypted patient health care numbers were used to link all four administrative health databases whereas the postal code was the link to the PCCF and Statistics Canada census information. Ethics approval for this project was provided by the Queen Elizabeth II Health Sciences Centre research ethics committee.th revision [ICD9-CM]) from 1992 to 1997 were included as subjects. These four cancers represent the most common causes of cancer death in Nova Scotia.All adults identified on death certificates in the NSCR database as having died due to lung, colorectal, breast or prostate cancer death , date of initial cancer diagnosis, year of death (1992–1997) cancer cause of death , and neighbourhood income categorized as provincial quintiles . Almost 40% (39.5%) of Nova Scotia's population resides in the HRM which spans a primarily urban geographical region. Within HRM's boundaries are all of Nova Scotia's major tertiary health care centres, several community hospitals and many specialized care programs. Although regions outside of HRM also encompass many towns with regional and community health care facilities, they span a much larger, diverse, geographical area and may be considered to be relatively more rural than HRM.Health services information was limited to each subject's 'survival time'. In our end-of-life research we have defined 'end-of-life' as the last 180 days of life, or if of shorter duration, from the date of initial cancer diagnosis to death. This six month time period is commonly used in end-of-life studies -24.Total family physician home visits received during this survival time were counted and, due to the highly skewed distribution evidenced, also dichotomized to represent at least one home visit received or none. Additional health services of interest and potential covariates included the total number of ambulatory visits made to a family physicians by each subject, the total number of visits made by the subject to a specialist, the total number of days spent as a hospital inpatient, receipt of palliative radiotherapy, and whether or not the patient had been admitted to the PCP, a comprehensive palliative care program which has been operating since 1992. As an indirect measure of whether the patient was a resident of a long term care (LTC) facility during the end-of-life, a flag was created indicating whether a patient had received at least one family physician within a LTC centre.Following descriptive statistics and the application of nonparametric tests to assess median differences and cross-tabulations with chi-square analyses for association, regression techniques were employed to estimate the effect of neighbourhood income (EAM income quintile) on the receipt of family physician home visits. Our initial regression analysis retained the total number of home visits as a continuous dependent variable and involved negative binomial regression where differences in survival time were accounted for as an offset variable. This was followed by logistic regression techniques where the probability of receiving at least one FP home visit versus no home visits was assessed. For both forms of regression, unadjusted analyses were followed by multivariate where the initial model included neighbourhood income in addition to sex, year of death, age, cancer cause of death, region of residency, the number of visits made to a medical specialist, the receipt of palliative radiotherapy and admission to the PCP as covariates. To account for the possibility that the subject may not have been 'at home' during their 'survival time' and hence unable to receive a home visit, our LTC residency flag and the total days spent as a hospital inpatient were added to the model.To control for differences in 'survival time', the number of days from the initial cancer diagnosis date to death were categorized and added to the model. Subsequent modeling involved the sequential elimination of covariates and confounders found to no longer be significantly associated with the receipt of FP home visits in the multivariate model at the p = 0.05 level of significance.Since our administrative data do not provide the ability to make adjustments for regional differences such as the availability of alternative health services, physician density or community resources, as an alternative, we stratified each analysis by region of residency.All analyses were performed using SAS software.In total, 7212 adults were identified from death certificate information as having died from lung, colorectal, prostate or breast cancer between 1992 and 1997 in Nova Scotia. Over 94% of these advanced cancer patients had seen a family physician at least once during the end-of-life. In total, home visits accounted for 29% of all ambulatory visits provided by family physicians with 3265 (45.3%) patients receiving at least one FP home visit. The total number of FP home visits received varied widely, from 0 to 89 with an average number of 2 (standard deviation [SD] 4.2) and median of 0. Table Subject characteristics and health service utilization by receipt of at least one home visit are displayed in Table Regression results incorporating the total number of home visits using negative binomial regression and those derived from logistic techniques assessing the log odds of receiving at least one home visit compared to none proved similar. Therefore, for ease of presentation, we present the logistic regression results only.Displayed in Table Among all advanced cancer patients, additional factors predictive of receiving at least one FP home visit included a longer length of survival , admission to the QEII Palliative Care Program (PCP) , older age  and being female . Patients who were in LTC at some point during their survival period  and those who spent 32 or more days in hospital compared to none  tended to be less likely to receive at least one FP home visit. Over time, the likelihood of receiving a home visit tended to decline. However, after accounting for all other predictors in the model, year of death was not a major factor.Cancer cause of death, receipt of physician specialty visits and undergoing palliative radiation were not associated with home visit receipt in the final multivariate model.The neighbourhood income of those dying of cancer is associated with the likelihood of receiving a home visit during the end-of-life by a family physician in Nova Scotia. The association found, however, appears to be modified by region of residence for those who died of cancer. It appears that income plays less of a role in predicting home visits by a family physician for those who live in the larger, urban centre of Halifax Regional Municipality. Given the finding that patients followed by the QEII Palliative Care Program are also more likely to receive family physician home visits, we speculate that the urban centre may provide a collaborative 'team-care' advantage to cancer patients. The publicly-funded PCP may act to equalize the opportunity to stay at home and facilitate family physician home involvement in ways rural locations may not be able to. In previous work, income was not associated with location of death but region of residency was. We haveIn the United Kingdom, Aylin and colleagues found, fWe hypothesize that when it comes to routine home visits for brief, episodic illnesses, the home visiting trend may be as Aylin suggests. However, for those who are at home and looking to stay at home with advanced cancer, there are more substantial financial issues driving whether this is likely to happen or not. In Nova Scotia, as in many Canadian settings, there is access to home visiting nurses and some other health professionals through the publicly-funded health system. However, as disease progresses, the ability of a family to support death at home depends on many other factors. These include the presence of a family member who can stay at home, the ability of a family member to manage the medications and symptom assessment along with health professionals, the cost of drugs which are paid for in hospital but not in the home , the cost of equipment in the home, and possibly the cost of additional nursing or personal care workers in the home . All of the critically enabling feature. Thus, the home visit is essential but not sufficient and without the rest of the support required, the patient will not be able to stay at home, thereby resulting in fewer home visits.The home visits provided by family physicians may therefore be a direct response to the other capacities of patients and families to stay at home rather than being Another interpretation is that those with lower incomes may actually make different choices about how they wish to receive health care and where they would like to spend their last days. Depending on the study cited, up to 80% of those with advanced cancer wish to spend their last days at home,28-30. GHome visiting has long been an element of continuity of care across settings  provided by family physicians. Some would argue that home visits may be influenced by the geography in which the physician operates daily. As a result, physician travel patterns to and from the office (when home visiting often occurs) may not take them through low income neighbourhoods, thus reducing the likelihood of a visit. The work of Aylin and McNiNew initiatives are underway in Canada which may provide more opportunities for the enhanced presence of a range of health professionals in the homes of the dying. In response to the Romanow Commission, the fedOur study has limitations. As we are using routinely collected data used for administrative and billing purposes there may be biases operating. The data reflect those family physicians who bill for the services they provide. It should also reflect the "shadow-billing" of those on alternate payment mechanisms (estimated to be less than five per cent of family physicians at the time of the study) but in reality, these physicians may have less incentive to capture these fee codes and so may under-report home visiting slightly.The data file used in this study was originally created for an alternate project looking at health service utilization among patients who died due to lung, colorectal, breast or prostate cancer. We were therefore limited to examining home visits provided to these patients only and are not able to report whether the use of family physician home services among those who died due to all other cancer causes is similar or different.We are unable to adjust for homecare utilization (data did not exist for the study years), family member caregiving status (no data available) or account for additional insurance coverage  which may have covered additional costs associated with drugs, home nursing, home equipment, etc. Our attempt to account for service availability by region is crude. HRM is more homogeneous with respect to services than our combination all other regions outside of HRM; however, the effect evidenced may, therefore, be a conservative estimate.And so, in conclusion, it appears that even in death those with fewer financial resources may be less likely to achieve the same access to health services as those better off. What does this mean for our care of the dying? We must examine carefully which elements are the cause of this inequality. If there is less desire among those with more financial barriers, we need to examine the origins of these desires. Is it fear of caring for those at home? Is it an established culture of caring to move loved ones to hospital at the end-of-life? These issues need identification if we are to support such families. If there truly are financial barriers to such things as drugs, equipment and personnel then we must redefine health policy to make these more accessible to those with fewer financial resources. And finally, we should attempt to understand whether or not there is any bias operating on the part of health professionals. All of these need further research if we are to ensure patients receive the care where they wish to as they approach death.The author(s) declare that they have no competing interests.FB and BL participated in the conceptualization and design of the project, the analysis and interpretation of the data, first-drafted the majority of the article, and incorporated co-author comments into the final draft. GJ participated in the interpretation of the data and the drafting and revising of the manuscript. All authors gave approval to this final version.The pre-publication history for this paper can be accessed here:


Student attitudes to mental health consumers were measured pre and post the program. All tutorial evaluation data was analysed using univariate statistics. Both tutors and students evaluated the teaching program using a 4 point rating scale. The mean scores for teaching and content for both students and tutors were compared using an independent samples t-test.Consumer tutors were successfully trained and accredited as tutors and able to sustain delivery of tutorials over a 4 year period. The study found that whilst the medical students started with positive attitudes towards consumers prior to the program, there was a general trend towards improved attitude across all measures. Other outcomes for tutors and students (both positive and negative) are described.Consumer tutors along with professional tutors have a place in the education of medical students, are an untapped resource and deliver largely positive outcomes for students and themselves. Further possible developments are described. Interview skills, while important in all areas of medicine, are a prime focus of educational endeavour in the teaching of psychiatry. The interview is the cornerstone of psychiatric investigation and the scene for the establishment of rapport and therapeutic engagement. The importance of effective skills training in interviewing for medical students was highlighted in the core curriculum in psychiatry published by The World Psychiatric Association and the World Federation for Medical Education . An addith year medical students in psychiatry. The idea is based on the belief that consumers have a legitimate experience to share and a rich skill base on which to draw. The purpose of this ongoing project is to contribute to the ultimate development of a workforce of medical practitioners with clinical assessment skills that are better tailored to the needs of mental health consumers. More immediate potential benefits are the promotion of an engaging curriculum in psychiatry for students, offering direct meaningful contact with mental health consumers.Moving beyond the traditional teaching of interview skills by psychiatrists in the "see one, do one, teach one" mode, we report the development of an innovative approach to the teaching of psychiatric interview skills. This approach began four years ago as a partnership between mental health consumers and academic psychiatry to examine the ongoing feasibility of training mental health consumers as tutors for 4Consumers and patients are not new to medical education, offering a unique perspective on their experiences with the health system. There are 3 levels of consumer participation in education. Consumers may be the subject of teaching tutorials (a demonstration), a visitor to a tutorial (sharing their experiences with few guidelines) or a paid trained tutor delivering an agreed curriculum (a 'consumer tutor'). Consumer tutors are distinct from 'professional tutors' (those with a career obligation to teach) a distinction that does not imply a lack of professionalism regarding the consumer tutor. The issue of language is not trivial: the local user support network was committed to the term 'consumer' rather than other common labels like client or patient. The language used was chosen for the perception of action and autonomy and to reflect respect for the role and to make it clear to students and staff that these people were a committed part of the teaching workforce, not visitors only present to tell of their (often negative) experiences.This work drew on the Partners in Arthritis project  that demth year medical students in effective approaches to interviewing. There was commitment to evaluate the effectiveness of the teaching in terms of (i) changing student attitudes towards consumers, (ii) preparing students for a common examination in psychiatry, (iii) monitoring consumer tutor involvement and feedback.In summary this project set out to train and support mental health consumers as consumer tutors for the delivery of a jointly developed curriculum for 4The project was set in a medical school (University of Sydney) undergoing transition to graduate entry, with adult self-directed and problem based learning models providing an opportunity to students keen to explore new ways of learning. This environment of educational change added to student and staff enthusiasm to trial new ideas. There was recognition that carers and consumers required the same respect and courtesy as professional tutors, and inequities such as only being paid travel expenses were unsatisfactory . ConsumeThe Academic Unit of Psychological Medicine approached consumers from the local mental health consumer network seeking expressions of interest to join a steering committee to oversee the project. Consumers were involved at all stages including planning, development, implementation and evaluation. The steering committee met weekly to determine an approach to consumer tutor recruitment and training, and to author the student curriculum for delivery.Consumer tutors were recruited, trained in small group methods and assessed. The assessment task was a nine-item quiz. Typical questions included "List three strengths of working in small groups" and "List three strategies to get a discussion going amongst students". Those who wished to teach were then allocated in pairs to a consistent student group of six to eight students for weekly tutorials over seven weeks. Consumer tutors conducted the planned curriculum, provided feedback on each tutorial and contributed to curriculum review.Evaluation of the content of the curriculum, the quality of the teaching and handouts was measured using a 4-point Likert scale  followed by an open comment item. After each tutorial consumer tutors were debriefed by academic staff and arrangements for the following tutorials confirmed. An expedient payment method was established. Over time, consumer tutors and academic staff periodically reviewed tutor and student feedback and decided on tutorial modification.The steering committee comprised six consumers, three with previous teaching experience at secondary or tertiary level. Professional approaches were adopted for recruitment, training, assessment, graduation and payment. Academic staff drafted a structure for consumer tutor training completed by the committee. The committee determined the priorities for the student curriculum and each oversaw the writing of a tutorial in conjunction with academic staff. Consumer input was central and meaningful rather than at the level of editing academic staff work. The committee were paid regular sitting rates for committee attendance. The steering committee met during the first trial to review progress, an overseeing role replaced later by the consumer tutors themselves.Expressions of interest from potential consumer tutors were sought through the consumer network against selection criteria. These included the essential criteria of being a current consumer of mental health services and having an interest in the development of medical student interviewing skills. Desirable criteria included previous experience in teaching. Applications were reviewed by the steering committee and all applications for training were accepted. Payment for training and tutoring was set at the current university casual tutor rates appropriate to qualifications.Recruitment resulted in a cross section of consumers including several 'marginalised consumers' who are usually under represented in such activities Three training cycles have occurred with 20 consumers  commencing training and 18 consumers graduating from training. Fifteen consumer tutors have taught over the four years, whilst three decided after graduation that they did not wish to teach. Drop out occurred because of illness, disinterest or realising that tutoring was more difficult than first imagined.The tutor training program comprised six weekly, one and a half hour tutorials delivered by academic staff encouraging discussion, controversy and practice in a supportive environment. See Table Students in one of four teaching centres of the University of Sydney participated in the consumer tutor-led tutorials. Students were oriented by academic staff and completed a pre-participation measure. This measured student attitudes to mental health consumers adapted from work on the 'hated patient' . Five stStudents were then introduced to their consumer tutors and participated in an 'ice breaker' session involving an interactive board game designed to sensitise medical students to the experience of being a mental health consumer. This was followed by six tutorials which both consumer tutors and medical students evaluated using the same measure. Students repeated the attitude measure at the end of the program and completed assessment tasks as per the university requirements. Students also participated in a seminar series (including didactic teaching on interview content) with professional tutors similar to that delivered in the other teaching centres. All tutorial evaluation data was analysed using univariate statistics. The pre and post attitude measure was compared using term group means (as completion was anonymous) using an independent samples t-test. The mean scores for teaching and content for both students and tutors were compared using an independent samples t-test.The student curriculum was developed as six one-hour tutorials . The curriculum and written materials underwent several revisions in response to feedback aimed at improving interactivity and clarity. Consumer tutors used the ground rules set out in training for dealing with absences. Reserve tutors were introduced at the start of the term so they were familiar to students if required. Tutor pairs were able to support each other and compensate for ebbs and flows in performance.The consumer tutors debriefed following each tutorial with academic staff. These meetings were an important opportunity for tutors to give positive and constructive feedback to each other as well as addressing ways to improve their delivery of the tutorials. They discussed problems and obstacles and brainstormed effective solutions. The larger consumer tutor group contributed to successfully resolving most conflict. Discussions were frank. Formal mediation was used to resolve a conflict between two tutors, in dispute over matters beyond teaching. Mediation was successful in terms of allowing ongoing involvement in teaching for both people. Academic staff informally debriefed the students during other tutorials. While a few students complained about the whole experience of being taught by a consumer, most students were positive. Indeed many reported they used the consumer tutors as a sounding board for other interview-related experiences during the week, seeking advice about alternative styles and approaches.Like all tutors, the consumer tutors required support, stimulation and refreshment. This happened in the tutorial debriefs outlined and in occasional workshops to review feedback, revise curriculum and refresh skills. Consumer tutors were encouraged to present reports of their experiences at appropriate meetings and received a national award for consumer research. Consumer tutors' motivation particularly increased when clinical mental health staff asked them about their teaching experiences and recognised that the individual had made many gains since the last episode of acute care.Consumer and professional tutors were commonly concerned about intervening illness and the impact on teaching. Some consumer tutors became acutely unwell during the term and required care. As a result they developed an agreement to postpone their involvement in the tutoring whilst they received necessary treatment. Consumer tutors and students were understanding of this and students had a rare experience of the longitudinal patterns of an illness and the person.Out of a total cohort of 104 medical students, students completed the pre (n = 72) and post (n = 68) attitudes questionnaire using a 5 point scale . A comparison of mean scores on 3 items reflecting student attitudes towards consumers was conducted using an independent samples t-test. Results showed that prior to the program the medical students began with positive attitudes towards learning from consumers  and working with mental health clients . Whilst there was a general trend towards further improvement in their attitudes, their mean scores pre and post the program were not significantly different. However, the medical students did show a significant improvement in their belief that "clients in psychiatric units give reliable histories"   were returned on 452 occasions. Analysis of the mean scores of students on the quality of the 'teaching' and 'content' of the program revealed favourable ratings . Whereas, tutors tended to rate the program even higher . A comparison of the mean scores of students and tutors using an independent samples t-test showed that this difference was statistically significant (p < 0.001), see Table All medical students who participated in the consumers as tutors program passed the university wide assessment of an observed psychiatric interview rated against defined criteria.th year medical students in effective approaches to interviewing. Training and delivery has continued requiring modest maintenance, perhaps in keeping with sustaining professional tutors. Consumer tutors have shown themselves to be reliable, professional in approach and amenable to feedback. Benefits for students  included the extended experience of working with a consumer of health services, the development of a clearer perspective regarding consumer views and an opportunity to see people with mental illness in recovery. Students were at least as well prepared as their peers for a structured assessment in interviewing . Students largely reported positive experiences, found the curriculum and delivery acceptable and saw tutor experience and knowledge as legitimate and valuable. Ideally it would have been useful to follow up medical students over a longer term to assess their psychiatric interviewing skill, however, this was not practically possible within this study.This project established the feasibility of training and supporting mental health consumers as tutors for delivery of a jointly developed curriculum for 4The attempt to measure attitudes deserves discussion. Attitudes are recognised as an important component of curriculum development yet remain the personal business of each of us. It would be reasonable to see education as a means of working past one's own attitudes rather than seeking to refine or replace student attitudes. Guidelines for working with consumers in health care assume that "for consumer participation to be effective, all participants in the process need to respect the different skills and expertise of the other participants" . In thisBenefits for consumer tutors  included enhanced self esteem and financial reward for work done. Consumer tutor curriculum development was novel such as utilising an art therapy vehicle to experience a non-pharmaceutical therapeutic device. Most consumer tutors have continued to teach, with appropriate breaks, and have mentored new tutors. Some have used this experience to step further into paid employment and to rehabilitate previous work skills. Consumer tutors have remained resilient and episodes of relapse appear to be multifactorial in origin (with teaching perhaps one of the factors). This robustness was also found in a study of psychological impact on consumers working in a peer support role in an acute care setting . ConsumeBenefits for the health system included the placement of consumers in a 'professional' light. Consumer tutors shared the staff tearoom, were paid as other casual tutors and were seen as well contributors rather than being in the sick role. Professional tutors were aware of the consumer tutor teaching and perhaps viewed it as 'politically correct' rather than educationally effective. Dissemination of findings via service and conference presentations has helped address this common view.Tutoring medical students is a skilful and potentially stressful role, and is not suitable for all mental health consumers. Following the training program some trained tutors realised that teaching was not their interest or strength . This was anticipated and should be factored into training plans. Some consumer tutors realised their tolerance level was insufficient to manage student junior skill level and found it hard to resist retelling their 'war stories' of difficult clinical encounters. This was a common theme in debriefing and required active refocusing on the curriculum of effective and ineffective interview techniques. The occasional protesting student required gentle persuasion to see that ongoing participation was a way of exploring contact with consumers. Like most education programs this approach did not run itself. Tutors required sustenance; feedback needed action and materials needed review. New tutors needed to be trained to add to the growing pool of available people. Despite these issues, our experience was that this was manageable and in keeping with maintenance of quality teaching by professional tutors.We believe this model is another valuable option in a range of consumer involvement programs and could be replicated in health, emergency services and support agency education. Discussions have occurred with carers about possible involvement. At this stage it was decided to invite carers to speak about specific topics in the mainstream program as consumers see their expertise as fundamentally different to that of a carer. Despite the potential for use with other groups, our attempt to use this experience in refreshing interview skills in general practitioners was unsuccessful. Notwithstanding the diligent work by all parties, local general practitioners held fast to the view that consumer tutors would lack the emotional robustness to survive teaching. They were welcome to come and talk of their experience but were not seen as competent to deliver a curriculum. This may well have been shorthand for more complex issues of concerns about confidentiality, power and autonomy. This example reminds us, however, that health education is in change and that new strategies are required to engage today's students in experiences that will produce clinicians skilled to support effective consumer participation in healthcare.We have detailed a feasibility study which demonstrates a new level of consumer participation in the design, implementation and evaluation of a medical student training program. The effort has been sustained over four years with appropriate maintenance. Largely positive outcomes were seen for students, consumer tutors and the health care system. These included raising the profile of consumers as 'legitimate teachers' in medical education and contributing to an improvement in the attitude of medical students towards mental health consumers. Together the joint partners in the program were able to manage obstacles, such as, pessimistic attitudes towards the involvement of consumers and difficulties adhering to the curriculum. Adopting a continuous review of the feedback from both medical students and consumer tutors has helped to further refine our ability to deliver the curriculum and better support the participants. Lastly, our experience has been that consumer tutors are an untapped resource offering a richness of experience and a professional approach to teaching that deserves closer examination in other health settings.Pfizer funded the initial pilot in the first year of the study.CO conceived of the study, participated in the design of both the consumer tutor curriculum and medical student curriculum and performed the data analysis. CO and RR participated in the training of consumers, monitored the implementation and evaluation phases and coordinated the program. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The manifestation of primary hyperparathyroidism with acute pancreatitis is a rare event. Ectopic paraesophageal parathyroid adenomas account for about 5%–10% of primary hyperparathyroidism and surgical resection results in cure of the disease.99mTc sestamibi scintigraphy. The tumor was resected via a cervical collar incision and calcium and parathormone tumor levels returned to normal within 48 hours.A 71-year-old woman was presented with acute pancreatitis and hypercalcaemia. During the investigation of hypercalcemia, a paraesophageal ectopic parathyroid mass was detected by computerized tomography (CT) scan and 99mTc sestamibi scintigraphy and CT scan of the neck and chest allows successful surgical treatment.Acute pancreatitis associated with hypercalcaemia should pose the suspicion of primary hyperparathyroidism. Accurate preoperative localization of an ectopic parathyroid adenoma, by using the combination of  Acute pancreatitis occurring secondary to hypercalcemia is rare. Most of the time adenomas are located in the neck. However, in 10–20% cases the parathyroid adenomas are found to be located within the mediastinum . ParaesoWe present a case of paraesophageal parathyroid adenoma clinically presenting as acute pancreatitis and successfully managed surgically by the collaboration of thoracic and general surgeons, via a cervical incision.3), increased serum levels of amylase , LDH (550 IU/L) and calcium (14.8 mg/dl). On ultrasonography of the upper abdomen a non homogeneous appearance of the head of the pancreas was noted with a common bile duct diameter of 8.5 mm. CT scan of the abdomen confirmed the diagnosis of acute exudative pancreatitis. Acute pancreatitis subsided within 72 hours after conservative treatment. Further laboratory investigation of the hypercalcaemia revealed increased 24-hours urine calcium (465 mg), decreased serum phosphorus levels at 1.3 mg/dl, increased serum parathyroid hormone levels (771 pg/ml), normal levels of serum free T3 (FT3), free T4 (FT4), thyroid stimulating hormone (TSH), calcitonine, carcino embryonic antigen (CEA), carcinoma antigen (CA) 15-9, CA 125, alpha feto protein (AFP). Ultrasonography of the thyroid gland and the neck showed a suspicious prevertebral mass. CT scan of the thorax and neck detected a paraesophageal mediastinal mass close to the thoracic inlet.  which failed to show bile duct lithiasis. With a diagnosis of parathyroid adenoma, resection of the parathyroid adenoma via a collar cervical incision was carried out. The tumor was easily separated from the surrounded structures  by blunt dissection and the feeding vessels were found and ligated anteriorly. Figure  The patiet al found significantly elevated serum calcium levels to be of major importance in the development of pancreatitis in patients with primary hyperparathyroidism [Recurrent episodes of acute pancreatitis secondary to hypercalcemia are an uncommon presentation of primary hyperparathyroidism -7. AcuteIncreased levels of serum calcium at the first episode of acute pancreatitis should pose the suspicion of primary hyperparathyroidism. In patients with a history of cholecystectomy (as in the presented case), where the main cause of an episode of acute pancreatitis is bile duct lithiasis, the diagnosis could be missed if serum calcium levels ranged within normal values. The main causes of primary hyperparathyroidism are single or double parathyroid adenoma (80%), hyperplasia of all four or more existing parathyroid glands 15–20%) and rarely cancer of the parathyroid gland (2%) 5–20% and.et al reported 5%–10% of the parathyroid glands to be located in the posterior mediastinum, 20% are found substernally within the thymic tissue in the anterior mediastinum (1–2%) while 1% of the glands are located in the carotid sheath and 5% into the thyroid gland. [99mTc sestamibi scintigraphy). The frequency of this occurrence at the moment is uncertain [Richards d gland. . By revid gland. . Parathy99mTc sestamibi scintigraphy and CT scan of the chest and neck gives important information to proceed with surgery and to minimize the risk of re-operation for recurrent hyperparathyroidism in the future [99mTc scintigraphy includes eutopic parathyroid disease, ectopic parathyroid disease, solitary, double or multiple parathyroid adenoma, cystic adenoma, lipoadenoma, multiple endocrine neoplasia, entities with atypical washout and non-parathyroid entities that take up 99mTc sestamibi  [99mTc sestamibi scintigraphy gives more information to the surgeon, concerning the depth of the lesion in atypical sites [Many investigators advocate the need for the concordance of at least two diagnostic modalities before surgical excision. The combination of e future ,16,18,19d tumor) . The addal sites .et al for preoperative detection and localization of parathyroid adenomas; high cost and limited availability of the scanners restrict its use as first-line examination in primary hyperparathyroidism [CT scan with intravenously injected contrast material has a low overall sensitivity of 45%–55% in primary hyperparathyroidism, but it is helpful mainly in the detection of ectopic mediastinal parathyroid adenomas ,3. Magneyroidism .Paraesophageal mediastinal adenomas are resected via a cervical incision in the majority of cases ,2,16,26.An ectopic paraesophageal parathyroid adenoma may be manifested with an episode of acute pancreatitis. Preoperative investigation for exact localization of an adenoma should include two imaging studies, preferably Tc-99m sestamibi scintigraphy or sestamibi-SPECT scintigraphy of the neck and chest and CT scan of the neck and chest. Resection of an ectopic paraesophageal adenoma is easily accomplished via a cervical incision and blunt mobilization of the tumor.The author(s) declare that they have no competing interests.CNF has made contribution to the conception, design and drafting of the article, was involved in the critical revision of the article.S R has made contribution to the conception, design and drafting of the article.C L has made contribution to the conception and design of the article.D K has made contribution to the conception and design of the article.G K has made contribution to the conception and design of the article, was involved in the critical revision of the article.AL has made contribution to the conception and design of the article, was involved in the critical revision of the article.All the authors have read and approved the final version of the manuscript.


The Endocrine Disruptor Screening Program (EDSP), mandated by the United States Congress in the Food Quality Protection Act of 1996, attempts to protect public health from adverse endocrine effects of synthetic chemical compounds by establishing a new testing regime. But the complexities and uncertainties of endocrine disruption and its broader regulatory and social context all but ensure the failure of this policy. This article addresses the issues facing EDSP comprehensively and in detail, in order to move beyond the current regulatory paradigm and foster discourse on a positive role for scientists in support of EDSP's end goal: to protect public health. The United States Environmental Protection Agency (EPA) created the Endocrine Disruptor Screening Program (EDSP) to regulate endocrine-disrupting chemicals (EDCs) as mandated in the Food Quality Protection Act of 1996 (FQPA) and the Safe Drinking Water Amendments Act of 1996 (SDWAA). Unlike the more easily appreciated effects of toxic chemicals, EDCs interact with the human body indirectly by mimicking, blocking, or otherwise disrupting the normal function of hormones. The prolific study of endocrine disruption has since uncovered many unconventional and worrisome mechanisms, exposures, and effects [[D]evelop a screening program, using appropriate validated test systems and other scientifically relevant  information, to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effects as the [EPA] Administrator may designate  Administrator shall, as appropriate, take action under such statutory authority as is available...as is necessary to ensure the protection of public health" .Unfortunately, due to four complicating factors, EDSP cannot protect public health. The first complication is practical considerations. EPA estimates the universe of potential EDCs numbers more than 87,000 items. Testing this many chemicals would take an unreasonable investment of time and resources, but even scientifically prioritizing among them is highly problematic. The second complication is hazard complexity. Establishing relationships between EDCs and health hazards proves very difficult if not impossible. Endocrine-disrupting action breaks all the rules and assumptions that have guided toxicology through the era of modern chemical regulation. Without these simplifying assumptions, science cannot establish causation efficiently or with sufficient certainty for regulation. The third complication is exposure complexity. Determining exposure levels becomes more important and more difficult because the low-dose effects of many EDCs means that low-dose and transient exposure can be just as or more dangerous than high-dose and prolonged exposure. Assessments typically discount these ill-defined exposures, but we can no longer assume them insignificant. The final complication is regulatory deficiencies. Although FQPA and SDWAA provided new authority to test for endocrine disruption, they provided no new authority for the regulation of EDCs. As a result, multiple government agencies must manage future test-positive EDCs under their jurisdiction using fragmentary and incomplete statutory authorities and different regulatory standards. This introduces significant confusion to the institutional and decision-making aspects of the EDSP regulatory framework.and legal standards, and an ethical position that prioritizes profit over human health by placing the burden of proof on public and environmental health advocates. These assumptions remain all but unchallenged in the U.S. context, and thus comprise a paradigm. While this paradigm has faced some critique in the context of carcinogenic pesticides and toxic industrial chemicals, questions of its efficacy remain unresolved. Because EDCs present new and fundamental difficulties for the science underlying the regulatory paradigm, a critical analysis of EDSP provides a more compelling case that the current chemical regulatory paradigm is in need of radical revision.The EDSP policy design represents revision at the margins of U.S. chemical regulatory policy, not a radical revision. EDSP employs the same basic strategy used to regulate carcinogenic pesticides or toxic industrial chemicals – scientifically proving harm prior to regulating a chemical. Two important aspects of this strategy include an epistemological assumption that science has the capacity to 'prove' harm under the relevant scientific This study investigates the policy design of EDSP and its broader context. The above four complications play varying roles in each stage of the EDSP policy design as discussed below. See figure The following discussion provides a comprehensive empirical basis for considering alternatives to the status quo. This study aims to integrate the many factors conditioning the failure of EDSP for the purpose of fostering constructive discussion on U.S. regulatory policy concerning EDCs and chemicals more generally. The author does not possess a unique answer to the many and complicated issues surrounding endocrine disruption and the U.S. chemical regulatory paradigm. Given that no simple, well-developed alternatives exist that merit immediate consideration by decision-makers, it stands to reason that more creative and open discussions of EDCs, the chemical regulatory paradigm, and possible roles for the scientific community may provide long-term payoffs in public and environmental health protection well worth our attentions today.The design of EDSP consists of three main stages: priority setting, screening and testing, and a risk analysis leading to potential regulation. The complications shown in figure Politics section below). Politics and policy design play significant roles in the modern chemical regulatory regime. Hence, a comprehensive analysis of EDC regulation must take politics and policy design as well as science into account. The appropriate standard by which to judge these disparate policy elements is Congress's mandated end goal: to protect public health. We will return to this issue.In other words, there is reason and precedent to doubt our ability to accomplish this feat. More importantly, despite our best efforts to mobilize science in support of this difficult task, policy mechanisms allow chemical use and abuse to go forward regardless of scientific results or lack thereof. "Pesticides are registered for use while important health and safety data are still being generated; they may continue to be used after evidence of their hazards is given to EPA; they may be registered through alternative processes that bypass important tests; and they may never be required to be tested for certain kinds of hazards"  and quantitative structure activity relationships (QSAR) both discussed below, have attracted attention and resources due to a general recognition of this problem. But more important than our current lack of data, EDCs operate with a high degree of complexity. Because of system complexity, some uncertainty about endocrine disruption probably cannot be resolved – resulting in some abiding doubt about the significance of a chemical as a potential endocrine disruptor. The scientific community and EPA seem quite cognizant of this complexity, but its relevance for policy and for the end goal of protecting public health deserves careful attention.EPA has not realized their ideal of priority setting based on hazard and exposure information because of the catch-22 mentioned above. As a result, "EPA's proposed approach focuses on human exposure-related factors rather than on a combination of exposure- and [hazard]-related factors" . While tScreening and testing section below) implies that exposure to some EDCs at extremely dilute doses may have a greater effect than massive exposure to that same chemical. Transient or low-concentration EDCs may also pose a greater risk than other high-exposure chemicals. Low-dose effects and other exposure complexities make exposure alone a poor proxy for setting priorities. Since different vulnerabilities and sometimes different health effects manifest at different developmental stages, any exposure-only judgment will run into significant difficulties defining spatial and temporal boundaries for exposure determinations. Some short-lived chemicals may have important endocrine- disrupting effects, but may not show up in EPA's most robust exposure data sources: biological sampling and environmental monitoring  to the point where people think it's real" . Non-monOther factors complicate a scientific determination of hazard. Two chemicals can interact in ways that alter their effects. Some chemicals together inhibit their individual effects, reducing or preventing an adverse effect where one is expected. Others simply add their effects together, and yet others interact synergistically, magnifying the effect either or both would normally have. "Synergistic interactions are the most problematic, because they indicate that the effects of multiple chemicals together can be significantly more powerful than might be predicted simply by adding up their effects one at a time. Regulatory science rarely incorporates any interactions; it is incapable, at present, of coping with synergies" . RegardlAnother serious complication involves the selection of testing endpoints, or dysfunctions possibly caused by EDCs. Some of the dysfunctions already identified through animal studies include cancer susceptibility and birth defects, but also more subtle endpoints like immunological dysfunction, suppression of secondary sex characteristics, decreased fertility, increased aggression, decreased mental capacity and focus, disrupted brain development, etc ,35. WhilA risk analysis concludes the EDSP policy design. EPA claims it will use its standard human health risk assessment process for EDCs . Simply Priority setting section and the hazard complexities treated in the Screening and testing section. These complexities include: HAZARD – low-dose effects, mixtures and synergies, and uncertain endpoints; and EXPOSURE – transient and low-concentration exposure to EDCs, maternal metabolism of bioaccumulated EDCs, varying vulnerability and response by developmental stage, poorly understood exposure sources, vulnerable subpopulations, and cultural, social, and economic patterns and spatial and temporal bounds of chemical release and exposure. More science cannot resolve all of these complexities and uncertainties.Because EPA's risk analysis demands an explicit integration of hazard and exposure data, the risk assessment itself is vulnerable to the exposure complexities treated in the in utero might easily be a chaotic or stochastic system. Ambiguity refers to a situation in which existing scientific data support equally valid but competing interpretations of risk , feedback loops, temporal delays between cause and effect, chaotic or stochastic system behavior, large numbers of intervening variables, and inter-individual variations. Uncertainty refers to limitations of the human analysis of a complex system. While science is often employed 'to reduce uncertainty,' the complexity of a system sets bounds on the prospective certainty of informed scientific judgment. For example, further science can never remove the chaos from a chaotic system or the randomness from a stochastic one. And to illustrate the point, exposure of a fetus to environmental EDC contamination isk , the Federal Food, Drug, and Cosmetic Act (FFDCA), the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), or the Safe Drinking Water Act (SDWA). The agencies with regulatory jurisdiction for EPA's list of 87,000 chemicals are: the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA) in the U.S. Department of Health and Human Services, and the Food Safety and Inspection Service (FSIS) in the U.S. Department of Agriculture. EDSTAC recommended and EPA adopted the following list of chemicals for endocrine disruptor testing: 75,500 commercial chemicals listed under TSCA, 900 pesticide active ingredients, 2,500 pesticide inert ingredients, 5,000 cosmetic ingredients, 3,000 food additives, an unspecified number of nutritional substances, and an unspecified number of natural hormonally active plant residues .Testing and enforcement authority for this universe of chemicals is fragmentary. For example, EPA has authority under FIFRA and FFDCA to set tolerances for pesticides on food, but enforcement authority falls to FSIS for meat and poultry products, and FDA for other food items. The authority is also incomplete. For example, FDA has authority over the estimated 5,000 cosmetic chemicals, but FDA has no authority to require any information from the manufacturer or to mandate product safety testing. FDA's regulatory authority over cosmetics begins only after a product (possibly without any safety information) enters the market. Additionally, the standards by which to regulate differ. Under TSCA and SDWA the economic costs of regulation must be balanced against the public health threat, but under FIFRA and FFDCA, economics can be considered in only narrowly crafted situations – the standard is largely health-only based. FFDCA and FIFRA as amended by FQPA use the "reasonable certainty of no harm" standard. This standard translates into a 95% certainty that fewer than one in a million additional cancer deaths will occur due to the expected exposure over a lifetime. No translation specific to EDCs of this standard is yet available. TSCA, on the other hand, must prevent "unreasonable risk" of injury to health or the environment. A risk is "unreasonable" if the risks exceed the benefits associated with that activity, including economic benefits. SDWA explicitly requires a consideration of the cost of compliance to state, local, and other water systems when setting safety standards.The estimated 2,500 pesticide inert ingredients may defy regulation due to trade secret norms, poor EPA data quality, and historic government neglect ,40. AddiThe complexity of the institutional and legal landscape (multiple interacting agencies with multiple overlapping mandates and authority) creates substantial regulatory confusion. In this situation, the powers and responsibilities of different government agencies might be interpreted differently by other agencies or by affected parties. Such confusion leaves room for interpretation that may require long delays and intensive court battles to resolve. The history of TSCA indicates that such confusion  as well as the menace of legal action can lead to crippling regulatory inaction . By requFinally, the role of politics in regulatory decision-making deserves note. The conventional ideal of regulation under the current paradigm is that good science leads to an informed decision-maker who can then remove or limit a proven hazardous chemical from commerce . The complexities of endocrine disruption science, practical considerations, and the regulatory deficiencies discussed above impose limitations on this conventional ideal. Neglecting the role of politics in regulatory decision-making, however, is perhaps this ideal's most significant omission. A variety of academic and government research as well as environmental and public interest group analysis points to the failure of testing regimes to produce significant regulation or protect public health . Hazard complexities, including low-dose effects, mixtures and synergies, and uncertain endpoints, contribute further obstacles to an unambiguous scientific determination of harm (see Screening and testing section). Under current policy mechanisms, these complications of endocrine-disruption science will prevent any meaningful regulatory action. Essentially, endocrine disruption is too complex and our science too uncertain; most scientific information regarding EDCs will remain ambiguous, with the available information supporting quite different judgments of risk.The internal validity of 'science leads to regulation' presumes the capacity of science to prove harm with sufficient certainty to regulate. Exposure complexities, including transient and low-concentration exposure to EDCs, maternal metabolism of bioaccumulated EDCs, varying vulnerability and response by developmental stage, poorly understood exposure sources, vulnerable subpopulations, and cultural, social, and economic patterns and spatial and temporal bounds of chemical release and exposure, place the ability of science to make solid exposure determinations in significant doubt  came to the conclusion that the failure of testing in the past means we need to test better in the future ,41. ThouThe relevance of science for regulatory decision-making lies predominantly outside the current trend of increasingly detailed mechanistic investigation of endocrine disruption. While endocrine disruption science can contribute much to a decision-maker, it cannot provide unambiguous information that 'objectively' determines the correct decision. But science could help guide decision-making under conditions of ambiguity; uncertainty does not entail 'anything goes.' On the contrary, the uncertainty itself might guide decision-making better than any other factual information. The 2001 Intergovernmental Panel on Climate Change reports provide a precedent in the explicit treatment of uncertainty – the reports indicate the relevance of scientific information for decision makers by ranking scientific conclusions by Bayesian confidence estimates  . This emA franker treatment of uncertainty can improve the relevance of science to decision-making and promote realistic expectations of science and the scientific community. Such progress might turn the spotlight on more significant impediments to regulatory decision-making under conditions of ambiguity, such as the difficulty of testing 87,000 chemicals and the role of politics and values in making regulatory decisions. Scientists can take action within their own communities to support the policy goal of protecting public health by exploiting and improving the role scientific information plays in chemical regulation. The possibility that scientists can empower decision makers and the public by developing community standards and norms explicitly addressing uncertainty is one creative idea, but more are needed. The key to progress is taking an active and creative role in support of the protection of public health. Waiting for a solution in the form of national legislation has failed to inspire significant change over the last several decades. But explicit action within the scientific community that discourages unrealistic expectations of science will support long-term progress on chemical regulatory policy and the protection of public health.DDT – dichlorodiphenyltrichloroethaneEDC(s) – endocrine disrupting chemical(s)EDSP – (U.S.) Endocrine Disruptor Screening ProgramEDSTAC – Endocrine Disruptor Screening and Testing Advisory CommitteeEPA – (U.S.) Environmental Protection AgencyFDA – (U.S.) Food and Drug AdministrationFFDCA – (U.S.) Federal Food, Drug, and Cosmetic ActFIFRA – (U.S.) Federal Insecticide, Fungicide, and Rodenticide ActFSIS – (U.S.) Food Safety and Inspection ServiceFQPA – (U.S.) Food Quality Protection ActHPV – high production volumeHTPS – high-throughput pre-screeningPCBs – polychlorinated biphenylsQSAR – quantitative structure activity relationshipsSDWA – (U.S.) Safe Drinking Water ActSDWAA – (U.S.) Safe Drinking Water Amendments ActTSCA – (U.S.) Toxic Substances Control ActThe author(s) declare that they have no competing interests.


Members of the EGF-CFC family play essential roles in embryonic development and have been implicated in tumorigenesis. The TGFβ signals Nodal and Vg1/GDF1, but not Activin, require EGF-CFC coreceptors to activate Activin receptors. We report that the TGFβ signaling antagonist Lefty also acts through an EGF-CFC-dependent mechanism. Lefty inhibits Nodal and Vg1 signaling, but not Activin signaling. Lefty genetically interacts with EGF-CFC proteins and competes with Nodal for binding to these coreceptors. Chimeras between Activin and Nodal or Vg1 identify a 14 amino acid region that confers independence from EGF-CFC coreceptors and resistance to Lefty. These results indicate that coreceptors are targets for both TGFβ agonists and antagonists and suggest that subtle sequence variations in TGFβ signals result in greater ligand diversity. TGFβ family members and their receptors are involved in setting up the left-right body axis early in development. This article clarifies the role of Lefty and elucidates the molecular basis for signaling diversity between the family members The analysis of whole-genome sequences has revealed that most signaling systems consist of multiple ligands that converge on a relatively small set of receptors and pathway-specific transcription factors. In the case of human transforming growth factor-β (TGFβ) signaling, 42 TGFβs converge on seven type I receptors, five type II receptors, and two classes of Smad signal transducers (reviewed in oep) lack all endoderm and most mesoderm, similar to the double mutants for the zebrafish Nodal-related genes cyclops and squint (sqt)  . Moreove mutants . During  mutants .The EGF-CFC protein Cripto is highly overexpressed in human epithelial cancers, such as breast and colon carcinomas , or zebrafish Vg1 (a chimeric molecule containing the Xenopus ActivinβB prodomain fused to the mature domain of zebrafish Vg1) in zebrafish embryos (goosecoid (gsc). ActivinβB, ActivinβA, Sqt, and Vg1-induced ectopic gsc expression in wild-type embryos  expression was only weakly induced , receptors (mouse ActRIIB[KR]/Myc and human Alk4[KR]/Flag), and a coreceptor (mouse Cripto/Flag) in  embryos . Similar embryos , Sqt for embryos A. In con embryos A. Since  embryos , Lefty s embryos B. Since  embryos , these t embryos C. To detep zebrafish embryos and analyzed the ectopic induction of the downstream genes ntl and gsc. Sqt, Vg1, and Activins induced these genes in wild-type embryos, allowing us to determine which chimeric ligands were active. Activins, but not Sqt or Vg1, were active in MZoep mutants, allowing us to test which sequences conferred EGF-CFC coreceptor dependence or independence.The finding that TGFβ ligands that activate Activin receptors can be grouped into a EGF-CFC coreceptor-dependent class that is susceptible to inhibition by Lefty  and a class that is independent of EGF-CFC proteins and resistant to Lefty (Activin) prompted us to examine which sequences underlie this ligand diversity. We therefore generated chimeras between Activins (EGF-CFC-independent) and Sqt or Vg1 (EGF-CFC-dependent) Figures  and 5. Aoep embryos  were sufficient to confer EGF-CFC independence. Further dissection of this region into loop alone (SqtActβB[loop]) or β8 alone (SqtActβB[β8]) yielded no or much weaker activity in MZoep mutants as compared with wild-type embryos  and Vg1ActβB[loopβ8] (Vg1 with an ActivinβB loop-β8 region) both induced gsc expression in MZoep mutants with similar efficiencies as in wild-type embryos  and Vg1. Sqt embryos D. These  embryos E and sugActβB[loopβ8] can signal in an EGF-CFC-independent manner in vivo, suggesting that this chimeric protein might bind to ActRIIB and Alk4 receptors in the absence of EGF-CFC coreceptors. To test this idea, we coexpressed and immunoprecipitated epitope-tagged ligands , receptors (ActRIIB[KR]/Myc and Alk4[KR]/Flag), and a coreceptor (Cripto/Flag) in Xenopus embryos  in Sqt did not enhance activity in MZoep mutants. These results suggest that multiple residues contribute to coreceptor independence, with the type II receptor-binding interface being an essential determinant.An alignment of the loop-β8 region of EGF-CFC-dependent and EGF-CFC-independent TGFβs A revealson assay . All conoep mutants. Chimeras containing the Sqt Finger 2 domain . The addition of Finger 1 in SAS or ActSqt[Finger1-loopβ8] relieved the inhibitory effect of the loop-β8 region of Sqt in wild-type embryos , previous studies have suggested that heterologous Nodal, Lefty, and EGF-CFC proteins have similar activities in zebrafish . For exaLefty1 and left-side specific Lefty2 (ΔASELefty2) mutants have been thought to be caused by inappropriate spread of Nodal signaling  fused to an HA-epitope/XhoI fragment (YPYDVPDYALE) and followed by the mature chimeric ligand into pcDNA3 vector. S denotes Sqt; A denotes ActivinβB. The boundaries for Sqt mature ligand domains are as indicated: Finger 1 (Asn263 to Cys325), Heel (Pro326 to Cys358), and Finger 2 . The boundaries for Xenopus ActivinβB mature ligand domains are as indicated: Finger 1 (Cys215 to Cys299), Heel (Pro300 to Cys335), and Finger 2 (Ile336 to Ala370). Full-length chimeras were generated by incorporating the indicated regions into Sqt, ActivinβB, or zebrafish Vg1, which were then subcloned into the pT7TS vector , loop (Phe348 to Ile354), β8 , and β9 (Met357 to Ala370). The Xenopus ActivinβA loop-β8 region sequence is FDRNNNVLKTDIAD . The zebrafish Vg1 loop-β8 region is from Try332 to Asp345. pcDNA3-zebrafish Vg1/HA, pcDNA3-Squint/HA, pCS2-Alk4(KR)/Flag (a kinase-defective mutant of human Alk4 with Lys234 to Arg234 substitution), pCS2-ActRIIB(KR)/Myc (a kinase-defective mutant of mouse ActRIIB with Lys217 to Arg217 substitution), and pCS2-Cripto/Flag have been described elsewhere  Sqt/ActivinβB chimeras were generated by subcloning the prodomain of S vector . The boulsewhere .Xenopus embryos at the one- to two-cell stage were used for injections into the animal pole.Plasmids were linearized and sense strand-capped mRNA was synthesized using the mMESSAGE mMACHINE system . Zebrafish embryos were dechorinated by pronase treatment and injected between the one- and four-cell stage. gsc and ntl  M2Bio dissecting microscope. In situ hybrization was performed as described previously , using R and ntl .LacZ mRNA. The A3-luc reporter DNA construct (25 pg)   was alsoXenopus embryos were harvested at stage 10. For chemical cross-linking of proteins, animal halves were incubated in PBS with 10 mM 3,3′-dithiobis(sulfo-succinimidyl propionate) (DTSSP)  and incubated for 2 h on ice. Coimmunoprecipitation was performed as described previously (eviously . Purifieeviously . Sampleshttp://www.ncbi.nlm.nih.gov/entrez/query.fc-gi?db=Nucleotide) accession numbers for the sequences discussed in this paper are ActivinβA (Q9W6I6), ActivinβB (Q91350), human ActRIIB (P08476), mouse ActRIIB (P27040), rat ActRIIB (P38445), Alk4 (Z22536), BMP7 (P23359), Cripto (P51865), Cryptic (P97766), cyclops (P87358), GDF1 (P20863), goosecoid (P53544), Lefty1 (Q9W6I6), Lefty2 (P57785), mLefty1 (Q64280), Nodal (P43021), no tail (Q07998), one-eyed pinhead (O57516), Pitx2 (P97474), squint (O13144), VEGF-D (P97946), and Vg1 (P09534).The GenBank (


Drosophila melanogaster for two consecutive years; susceptibility to three organophosphates tended to increase in the fall. To examine the hypothesis that variation in fitness among resistant and susceptible genotypes could trigger the change of genetic constitution within the fall population, we investigated density-independent population projection trajectories starting from single adult females with characteristics of chromosome-substituted lines resistant and susceptible to the three organophosphates.Seasonal fluctuations in susceptibility to organophosphate insecticides were observed in the Katsunuma population of Density-independent population projection trajectories, expressed as the ratios of the number of each chromosome-substituted line to that of line SSS, for which all chromosomes were derived from the susceptible line, showed significant declines in numbers with time for all the resistant chromosome-substituted lines.The declining tendency in the density-independent population projection trajectories of the resistant chromosome-substituted lines could explain the simultaneous decline in the levels of resistance to the three organophosphates, observed in the Katsunuma population in the fall. The development of insecticide resistance in insect pest populations is a population genetic process, in which insecticides select for initially rare resistant mutants within a population . AlthougR factors that, in every respect except insecticide resistance, are deleterious from a survival standpoint.""Since the genes causing insecticide resistance were at low frequency in the population before the insecticide began to be applied, it must ordinarily be true that they are to some extent disadvantageous; otherwise they would have been common. Therefore the selection for resistance should ordinarily involve the replacement of the original genes with Under this theory, it could be expected that there is variation in fitness among resistant and susceptible genotypes, and that resistant genotypes have lower fitness than susceptible genotypes, which could result in the change of frequencies of resistance factors within a population.Drosophila melanogaster is one of the well-established natural populations in Japan )In the previous study, age-specific fecundity and survival probabilities over 19 days, based on each individual, were used for calculating the intrinsic rate of increase for each replication. In this study, the age-specific fecundity and survival probabilities over 19 days were used to construct a 19 × 19 Leslie matrix Fig. , after aDensity-independent population projection trajectories were estimated as the ratios of the number of each chromosome-substituted line, totaled over all age-classes, to that of line SSS for 100 days. 95% upper confidence bounds  were seTM carried out data collection and analyses, and drafted the manuscript. BC contributed to the computer programming and provided the theoretical background. All authors read and approved the final manuscript.


PLoS Biology.)Since the days of ancient Greece, mathematics has been used to describe the world in the hopes of identifying underlying laws of nature. Physicists have long relied on mathematics to understand the behavior and interaction of particles too small to observe directly. Since it's not always possible to determine the behavioral properties of a single atom or electron, physicists characterize the behavior of these particles in terms of probability and the law of averages. Likewise, it's not always easy to tell how a single protein contributes to the behavior of a cell or organism. Faced with increasingly immense datasets—from genomes, proteomes, gene expression networks, cell signaling pathways, and more—biologists are turning to the tools of higher mathematics. High-throughput technologies like genome sequencers and microarrays generate a global picture of genomic or cellular activity, but such datasets have a high noise-to-signal ratio—the details are often subject to multiple interpretations. One way computational methods can help separate the signal from the noise is by determining the likelihood of a given set of interactions and presenting a range of possible network behaviors. When sufficient information about a biological pathway is available, experimental evidence can enhance modeling approaches to help refine the nature and role of putative network behaviors.  and protein products produce the characteristic 14-segment polarity pattern. While the molecules and pathways that generate the segment polarity pattern are well known, little is known about the quantitative nature of their interactions: in what concentrations do the components  exist and what parameters  govern their interactions?One model system ripe for computational analysis is the fruitfly Four years ago a group of researchers led by George von Dassow developed a model of the genetic interactions that define segment polarity, called the segment polarity network. The model used a parameter set of 48 numerical values for each computer simulation of the segment polarity pattern. Since quantitative information about the network was unavailable, the group used random values for each of the parameters, repeating the simulation for nearly 250,000 different random parameter sets. The model proved remarkably robust—the network output was largely insensitive to variation in parameter values, with a surprisingly large fraction of random parameter sets generating the desired segment polarity pattern. That so many random variables could produce the pattern means either that almost any set of parameter values can work or that only a few of the parameters are important. Now, Nicholas Ingolia reveals the mechanism accounting for this robustness and bolsters the model with recent experimental evidence.wingless (wg) and engrailed (en), within specific cells of a “prepattern” laid down early in embryogenesis is converted into the segment polarity pattern by an intercellular signaling network. Wg and en operate through positive feedback loops that activate their own expression, a process that is destined to end up with individual cells in one of two stable states of gene expression . Since each stable state is intrinsically robust—that is, resistant to changing parameters—Ingolia hypothesized that the parameters that generate the robustness of the segment polarity pattern in von Dassow's model are those that produce this bistability.To investigate the reason for the original model's robustness, Ingolia asked whether the parameters of the model could be deconstructed into the properties of individual cells. It's known, for example, that the stable expression of two genes, called wg and en expression. The overall pattern of the model, as well as its insensitivity to parameter variation, Ingolia concludes, emerges from the stable expression states of single cells. Parameters that do not produce bistability within single cells, Ingolia found, almost never generate the correct pattern, while those that do produce bistability are much more likely than randomly chosen parameters to generate the striped segment pattern. When Ingolia added new experimental variables to the model—the signaling protein produced by the sloppy-paired gene and its interactions with en—he could reduce the fraction of parameter sets that satisfied the bistability requirement but nonetheless failed to produce the segment polarity pattern, refining the model to reflect the realities of the cell.Using computational methods to simulate the behavior of individual cells, Ingolia shows that individual cells in the original model adopt three different stable states of Such computational approaches are allowing biologists to gain valuable insights into the real-world properties and behavior of staggeringly complex biological networks. It's been over 2,000 years since Pythagoras proposed that the laws of heaven and earth reflect a numerical harmony rooted in mathematical laws. Whether that notion holds for biology, bit by bit the tools of higher mathematics are peeling back the layers of complexity to identify underlying properties of living systems.


Vestibular rehabilitation (VR) is a well-accepted exercise program intended to remedy balance impairment caused by damage to the peripheral vestibular system. Alternative therapies, such as Tai Chi (TC), have recently gained popularity as a treatment for balance impairment. Although VR and TC can benefit people with vestibulopathy, the degree to which gait improvements may be related to neuromuscular adaptations of the lower extremities for the two different therapies are unknown.We examined the relationship between lower extremity neuromuscular function and trunk control in 36 older adults with vestibulopathy, randomized to 10 weeks of either VR or TC exercise. Time-distance measures , lower extremity sagittal plane mechanical energy expenditures (MEE), and trunk sagittal and frontal plane kinematics (peak and range of linear and angular velocity), were measured.Although gait time-distance measures were improved in both groups following treatment, no significant between-groups differences were observed for the MEE and trunk kinematic measures. Significant within groups changes, however, were observed. The TC group significantly increased ankle MEE contribution and decreased hip MEE contribution to total leg MEE, while no significant changes were found within the VR group. The TC group exhibited a positive relationship between change in leg MEE and change in trunk velocity peak and range, while the VR group exhibited a negative relationship.Gait function improved in both groups consistent with expectations of the interventions. Differences in each group's response to therapy appear to suggest that improved gait function may be due to different neuromuscular adaptations resulting from the different interventions. The TC group's improvements were associated with reorganized lower extremity neuromuscular patterns, which appear to promote a faster gait and reduced excessive hip compensation. The VR group's improvements, however, were not the result of lower extremity neuromuscular pattern changes. Lower-extremity MEE increases corresponded to attenuated forward trunk linear and angular movement in the VR group, suggesting better control of upper body motion to minimize loss of balance. These data support a growing body of evidence that Tai Chi may be a valuable complementary treatment for vestibular disorders. Vestibulopathy decreases whole body dynamic postural control and causes functional limitations -4. Limitmechanisms underlying such improvements should differ substantially. A better understanding of how balance dysfunction interventions affect lower extremity neuromuscular function during ADL may be useful for developing gait training exercises, and for providing a fuller understanding of the link between motor function and balance.Alternative therapies, such as Tai Chi (TC), have recently gained popularity as a treatment paradigm for a variety of human ailments, including balance impairment -13. TC eIn this report, we present preliminary data from a blinded randomized clinical trial comparing the effects of VR and TC on gait function, joint kinetics and trunk kinematics in older adults. While the overall aim of this study was to determine the effects of balance rehabilitation on gait characteristics, we directed our efforts in this paper to better understand the relationship between mechanical energy transfers along the lower extremity kinematic chain (ankle-knee-hip), and forward and side-to-side velocity of the trunk.Our general hypothesis was that adults with balance impairment from vestibulopathy who receive the VR or TC intervention will improve gait function as indicated by time-distance measures. Our specific hypotheses are based on the following rationale: Recent studies in healthy older adults -21, withBased on the above rationale, and the specific treatment programs described in the following sections, we hypothesized: 1) TC treatment will improve lower extremity motor control by increasing ankle mechanical energy expenditure (MEE) contribution, and decreasing hip MEE contributions, to total energy of the leg, more than VR; and 2) that improved trunk control following TC will be positively correlated with improvements in lower extremity motor control, while improvements in trunk control following VR will not be correlated with improvements in lower extremity motor control. The latter may indirectly implicate other mechanisms, most likely improvements in VOR/gaze stability .Fifty-three patients with balance impairment due to vestibular hypofunction were recruited and randomized into two treatment groups: VR, a group vestibular rehabilitation intervention, and TC, a group Tai Chi exercise. Of the 53 patients admitted, 15 dropped out or were excluded prior to completing the intervention. The majority of drop outs were due to a new medical condition unrelated to the study preventing participation  or due to the sudden need to care for an ill family member. Two subjects were eliminated because of lack of force plate data to use in the data analysis . Of the 36 subjects remaining for analysis, 17 subjects were randomized into the VR treatment group  and 19 subjects in the TC group .-1 for the sum of right and left ear caloric stimulation at 27 and 44°C warm water stimulation of both ears and ≤8°·sec-1 slow phase velocity for the sum of 35 cc of ice water stimulation in each ear) and decreased VOR gains during passive rotational testing at up to 50°·sec-1 . Patients with unilateral vestibular hypofunction had damage only on one side, including at least 30% unilaterally reduced caloric response, positional nystagmus while lying with the damaged ear down, and/or confirmatory abnormalities on rotational testing . Patients with bilateral deficits are typically more disabled than are those with unilateral deficits. The average time post-onset of vestibulopathy for the 36 subjects included in the analysis was 3.05 years (range 0.58 – 12 years). All subjects were community dwelling and reported varying degrees of limitations in locomotor activity. Twenty of the 36 subjects were female, and the 36 subjects were 59.5 ± 11.5 years old , 1.70 ± .11 m tall and 83.6 ± 16.5 kg in weight (breakdown by treatment group is shown in the Results section). All subjects had at least one course of VR since the time of onset of their vestibular symptoms. Inclusion criteria required that each subject did not have VR for >6 months from study enrollment. The testing protocol was approved by MGH institutional review board, and all subjects provided written informed consent according to institutional guidelines on human research.Unilateral or bilateral vestibular hypofunction (UVH or BVH) diagnoses were obtained as previously described . BrieflyThe VR and TC treatment interventions were provided in a total of six (3 VR and 3 TC groups) small groups with an average of 8 subjects per group. Each intervention program met once weekly, on separate weekdays, for 10 weeks in the same exercise room. The weekly sessions for both intervention groups lasted approximately 70 minutes. Each treatment program was lead by the same instructor for the three treatment cohorts. The instructors were blinded to the exercises provided to the other treatment program. One or two assistants were available for each session for all treatment groups to insure participants' safety. All treatment sessions included time to: 1) review material introduced in prior sessions; 2) introduce new material; 3) ask questions and share personal experiences or concerns regarding the practices; and 4) cool down and rest.The TC intervention incorporated three objectives outlined in a balance-related TC program developed by Wolf and colleagues ,17. FirsThe VR intervention used in this study was a comprehensive exercise program designed to improve the problems specifically associated with damage to the peripheral vestibular system ,6,10,29.Subjects performed two-to-four gait trials along a 10 m level walkway at baseline testing, and at testing following the intervention program, at their freely selected pace upon the command "Please walk as you normally would, as if taking a brisk walk in the park". Body segment kinematics were acquired at 150 Hz with a four-camera Selspot optoelectric tracking system , used to acquire position and orientation data of 11 segments . Collection of kinematic data and processing is described in more detail elsewhere . KineticParameters selected for data analysis consisted of dynamic gait function (time-distance measures), lower extremity neuromuscular control , and trunk stability .Gait function was assessed with standard time-distance measures ,32, incl(+), the amount of concentric mechanical energy expended with segment-to-segment energy transfer), eccentric transfer (MEE(-), the amount of eccentric mechanical energy expended with segment-to-segment energy transfer), and no-transfer (MEE(o), the amount of concentric and eccentric energy expended without segment-to-segment energy transfer) conditions. The total joint MEE is simply the sum of these components (MEE(t) = MEE(+) + MEE(-) + MEE(o)). Leg MEE is the sum of joint MEE  for different conditions, or totals. Percentage contribution of joint MEE  to leg MEE  was then calculated.Neuromuscular function of the lower extremities was assessed using mechanical energy expenditure (MEE) of the ankle, knee and hip, relative to the total MEE of the leg, and were computed as described previously ,33. BrieTrunk stability was assessed using kinematics of the trunk center of mass , and con(+), MEE(-) and MEE(o) contributions) required significance at α = .017 for at least one comparison, α = .025 for the second comparison, and α = .050 for the third comparison. Families of four members  required significance at α = .013 for at least one comparison, α = .017 for the second comparison, and so on. All p-values given will be unadjusted, but the adjusted α is given for each comparison where appropriate. SPSS for Windows  was used for all statistical analyses.One-way ANCOVA was used to compare change scores between the two groups, using the baseline values as covariates. Paired samples t-tests compared the change in each variable for each group from baseline to post-intervention testing. Pearson correlations were used to examine associations between change scores in lower extremity MEE and change scores in trunk velocities, for each treatment group. Due to the large number of comparisons in this exploratory study, a Ryan-Holm step down Bonferonni approach was used to control for type I errors , using ap = .223), height  or weight . There was no significant difference in proportion of UVH and BVH in the treatment groups , or proportion of men and women in the treatment groups .The two groups were not different in age  for any of the variables examined. There were, however, significant changes pre- and post-treatment within each group. These latter results appear to suggest that clinically important differences in each group's response to the therapies exist. Thus, the remainder of the results presented will focus on the within-groups comparisons.p = .044) and step length (p = .045), but not in gait speed (p = .060) or step width (p = .390); the TC group improved in gait speed (p = .009) and step length (p = .010), but not in stance duration (p = .055) or step width (p = .313).Both groups improved (unadjusted α = .05) following intervention in time-distance measures (see Table (t) for each joint, and the sum of all the joints (leg). Although the total leg MEE(t) change was similar, the distribution of joint MEE(t) were quite different for the two treatment groups. Comparison of the change in percent contribution of MEE for each transfer condition for each joint to leg MEE showed that only the TC group had significantly reduced  relative hip concentric MEE(+) and increased  relative ankle concentric MEE(+), following training. These data are shown in Figure Figure p = .009, adjusted α = .013) peak trunk forward velocity during stance phase of gait following treatment, while the VR group's increase was similar though not statistically significant . There were no significant changes in forward velocity range, nor were there significant changes in peak or range of lateral trunk velocity for either group. The VR group, however, did show a significant increase in peak trunk angular velocity  and range of trunk angular velocity  in the frontal plane. There were no significant changes in trunk angular velocity in the frontal plane for the TC group, and neither group showed significant changes in peak and range of trunk angular velocity in the sagittal plane. These data are summarized in Figure TC group had significantly increased . For the TC group, however, changes in range and peak of forward velocity of the trunk was positively correlated with changes in leg MEE . Figure Correlation analysis between changes scores in leg MEE and trunk kinematics revealed significant relationships for both treatment groups. Most striking was the consistent directional relationship between trunk velocity and leg MEE within each of the treatment groups. For the VR group, changes in range and peak of forward velocity of the trunk was negatively correlated with changes leg MEE  for both treatment groups was observed, confirming our general hypothesis, our data suggest that the mechanisms underlying those improvements differ, and appear to be linked to differences in neuromuscular responses of the lower extremities to the treatment programs. Specifically, our data suggest that changes in the relative contribution of individual joints to total leg mechanical energy expenditure (MEE), and the relationship between changes in lower extremity mechanical energy expenditure and changes in upper body kinematics, are different between TC and VR interventions Figure . Further(t)  for ankle, knee and hip, and total leg MEE(t), for each group. The increases in leg MEE(t), which were similar for both groups, were apparently achieved by different neuromuscular adaptations of the individual joints. Where the VR group appear to increase total MEE(t) of each joint to gain a total MEE increase of the leg, the TC group show a distinctive pattern of substituting ankle plantar-flexor contribution for hip extensor/flexor contribution. Prior studies on the relative roles of ankle and hip kinetics in gait [We found that TC patients significantly increased the contribution of ankle MEE to total leg MEE and decreased contribution of hip MEE to total leg MEE following the treatment program, while the VR group showed no significant change in ankle or hip MEE contributions following intervention Figure . Althoug in gait ,20,24 su(+) for the changes in concentric MEE(+) of individual joints. While both groups decreased the relative contribution of concentric hip MEE(+), only the TC group increased the contribution of ankle concentric MEE(+), while the VR group increased the contribution of knee concentric MEE(+). Concentric energy transfer represents the energy expended by muscles in concentric contraction when energy is being transferred between segments. Because concentric contraction represents work being done by the muscles , we can interpret the above finding as meaning that, for the TC group, a greater proportion in the change in concentric work done by the leg muscles is attributed to the change in concentric work of ankle plantar-dorsiflexors, while for the VR group, this contribution decreases.Figure One possible reason concentric ankle MEE contribution may have increased significantly in the TC group, but not the VR group, is because the TC and the warm-up exercises improved ankle flexibility. Tight ankles  may preclude the optimal structural alignment to coordinate mechanical energy sufficiently to increase propulsion , perhapsAs shown in Figure Because the VR exercise program may increase subjects' awareness of eye and head movement strategies that cause dizziness and instability ,47, a moAlthough the preliminary results presented here suggest the lower extremities may play an important role in the ability of vestibulopathic patients to improve gait function, several limitations of the present study may prevent broad generalization of the results. Our small sample size was perhaps the most important limitation. It is probable that the lack of between-group significant changes, particularly in light of many significant within group differences (pre-post intervention), was due to high variances obscuring group mean differences. Indeed, a larger sample size for controlling type II errors (increasing power), and better control of type I errors for multiple statistical tests, is warranted for future full-scale studies. The large age range within groups may have also contributed to high variability, but note that more heterogeneous samples in fact enhance external validity, including generalizability, of the results. We also did not include a no-treatment control group in the experimental design of this preliminary study. Because vestibulopathic patients may learn to compensate spontaneously, a no-treatment or sham-treatment group would be necessary to determine if changes in gait function are truly a result of the interventions. This is unlikely, however, given the inclusion criteria that all subjects must have had stable symptoms for 6 months and were on average 3 year post-onset of vestibulopathy. Given that both groups improved gait function in our randomized design comparing substantially different interventions suggests that the effects observed were not spurious. It must be recognized, however, that assumed improvements in function, via increased gait speed for example, may be limited ,49. As wWe conclude that VR and TC can successfully improve gait function, as determined by common time-distance measures, in patients with vestibulopathy. We further conclude, however, that TC improves lower extremity motor control more than VR, by selective redistribution of joint energetics, which appears to engender a more vigorous gait and better trunk control. TC, as a complementary treatment to VR, may allow for better control of the trunk through reorganization of lower-extremity motor patterns, elicited from the flowing, controlled TC exercises.The author(s) declare that they have no competing interests.All authors participated in the overall study design, contributed to the interpretation of data and writing/editing of the manuscript, and have read and approved the final manuscript. CAM conceived the hypotheses for this manuscript and carried out the data analysis; DEK was the principal investigator of the project; SWP was the neurologist associated with the project; DMS conducted the patient testing and assisted in development of the vestibular rehabilitation program; PMW conducted the Tai Chi intervention; and SLW was the project consultant.The pre-publication history for this paper can be accessed here: