Cognitive deficits in schizophrenia impair everyday functioning and instrumental daily living activities. These disabilities can be partly responsible for chronicity and institutionalization. We present here a virtual reality (VR) tool in which patients with schizophrenia performed a virtual game in an imaginary town during a 3-month program. In a pilot study, seven patients with schizophrenia (DSM-5), institutionalized for many years, attended weekly 1-h-and-a-half sessions organized by two clinicians. During the first sessions, they listed together the difficulties they experienced in everyday organization and planning. After being familiarized with the joystick and the VR environment, they navigated in the town, and planned actions that were difficult for them to carry out in their usual life . They had to look for alternative routes and practice a switch from a 2D Map to the 3D Map. They also gathered their efforts to share strategies for each action, or discussed the action plan they could generate to solve concrete problems. The pre/post-neuropsychological evaluations showed attention, working memory, prospective, and retrospective memory benefits, but no improvement in planning as assessed by the Zoo map test and the action program subtest of Behavioral Assessment of the Dysexecutive Syndrome. Patients also clinically and functionally improved, gaining autonomy. Pragmatically, they reported a strong energy to elaborate concrete plans to search for jobs, or return to activities in the community. Qualitative assessments showed a benefit in sparing time, planning better, enriched relatedness, and better management of their housework. This VR game opens avenue to rehabilitation for patients with schizophrenia experiencing chronicity in their life, less attendance in daycare units, and a better community living. This program might reduce neurocognitive difficulties and might evolve into a true method for cognitive remediation . Cognition impairments in schizophrenia are found in multiple domains, with direct implications in everyday functioning . These dAlthough neuropsychological tests provide important information about cognitive disabilities, they generally have low ecological validity and, therefore, have limited ability to predict functioning in daily activities . The terIn the psychosis domain, Kurtz et al.  used a vHowever, in the neurocognitive domain, if VR is mainly used to evaluate cognitive abilities in an ecological manner, no program exists to improve executive functioning in a VR environment, supposed to mimic the real world.Our aim was to test a new method to improve cognitive abilities, especially memory, executive functioning, and planning in patients with schizophrenia, using a virtual city. Therefore, we mainly focused our pre–post-neuropsychological evaluations on retrospective and prospective memory, working memory, learning, and planning abilities. A total of twelve 1-h-and-a-half weekly sessions during a 3-month program were delivered in groups of a maximum of six patients. As VR provides an immersive non-stressful environment, we wanted to propose a VR program to patients with schizophrenia who were institutionalized, with long-time use of daycare programs of therapeutic activities. These patients, because of their very ritualized way of living, were considered as more chronic than other patients and less susceptible to accept spontaneously a direct access to rehabilitation perspectives, such as job employment or professional training. Also, it was a challenge for our unit, because institutionalized patients are difficult to drive to innovative therapies, and to orient toward external activities that take place in the real world. This very preliminary open study was a clinical trial with raters who were not blind to assessments and to treatments, with no randomization, and no control arm.Our hypothesis stated that a VR environment improves patients’ cognitive abilities, mainly in prospective memory and planning, with a clinical benefit and a benefit in social functioning, quality of life and self-esteem, assessed in a pre/post comparison before and after the VR program.Ten outpatients (in two different groups) meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)  criteriaThis study took place in our Reference Center for Cognitive Remediation and Rehabilitation , in a collaborative partnership with a specialized unit for memory assessment via VR .The virtual town was developed and created by the LMC unit. It consisted of virtual urban environments built with LMC software EditoMem [based on3DVIA Virtools Dev 5.0 software (3dVIA Virtools)] allowing us to create virtual environments inspired by photos of Paris and game scenarios.These urban environments have been previously used in healthy individuals and patients to assess episodic, spatial, retrospective, and prospective memories as well as working memory . In Several specific elements are located in the town, such as a bank and several shops offering a large diversity for shopping . Hobbies are also represented with a cinema and a “mediatheque,” which is a typical French structure where you can freely borrow various types of media. Centers for healthcare also exist with a pharmacy, a dentist practice house and a laboratory for blood analysis. Cafes, restaurants, squares, and a public garden are represented. These different places could be memorized and used as memory cues to orient the navigation, as visual landmarks, or could be a theme for discussion . Also, participants, while playing during the VR game, received their own personal 2D map of the virtual town, which they had to complete with street names and mark city’s symbolic places. This map could always be referred, while navigating, to help orientation and train switching from 2D to 3D virtual spaces  conduct the group sessions. During 60 min, one after the other, the participants have to navigate in the VR town, sharing a joystick. While one of the members in the group navigates, the others are helping him, in an interactive and collective effort. Participants have to find their way , to memorize their itinerary (which involves memory for details and topographic memory abilities), to plan different actions , depending on the instruction they have to follow. After 1 h of navigation and several participants navigating in the town, all the participants in the group discuss during the last 20 min of the session about their actions and the possible transfer to everyday life they can imagine. At the end of each session, a task to perform at home is given, directly linked to the theme of the session . Two different versions of the virtual town have been used, successively versions 1 and 2 during the 12 sessions for the first program (6 sessions for Version 1 and 4 sessions for Version 2). During the two program sessions, we improved and enriched the city, adding more landmarks. Indeed, we added several bakeries, butcher’s shops, and drugstores. We also added a travel agency, two cinemas, a theater, more restaurants and coffee shops, a dairy store, and a florist. Thereby, for the second program, we used a version that could cumulate the different locations existing in Version 1 and the different locations existing in Version 2 for the 12 sessions.-Sessions 1–4: Familiarization. How to navigate with the joystick? Orientation in a 2D environment; shifting from map to 3D on the screen. Preliminary interactive discussions: everyday life examples that could be sources of emotional distress, problems encountered in everyday life, planning difficulties but also daily activities for which participants have no difficulties. The latter point is to identify the areas where there could be sources of solutions for the group. Encouraging the strategies found by the group. Discovering the VR town on the screen: paying attention to the names of streets, shops, and supermarkets. Categorizing the shops; reporting them on the 2D map. Also, each participant selected a virtual personal address for his/her home in one of the virtual streets. Clinicians encouraged them to imagine their apartment according to their aspirations and preferences. They also asked participants to explain what determined their choices of a particular place.-Sessions 5–10: Planning and navigation. Discussion around personal strategies to navigate efficiently. Then, on the basis of the difficulties evoked by the groups, different scripts were prepared by the two clinicians: e.g., explaining your route to a pedestrian, trying different routes for the same goal and taking them afterwards. The action scripts tried to mimic as best as possible the everyday life, giving opportunities to participants to relate personal events or difficulties when they navigated .-Session 11: Route-finding using the map of the Parisian subway. Navigating from each home address to the big railway station and enunciating all the different steps.-Session 12: Summary of the entire program. Remarks and comments from the group. Satisfaction questionnaire to encourage criticism and suggest evolution of the program.Procedure of the different sessions and thematic contents:Two assessments were done, at W0 before the VR program, and W12 after the end of the last session. For each assessment, there was one clinical interview done by a psychiatrist rater who was not blind for the assessments (Isabelle Amado), and the neuropsychological evaluations done by a neuropsychologist, also not blind to the assessments (Lindsay Brénugat-Herné and Zelda Prost) and also involved in the management of the VR sessions. The interviews and the assessments at W12 also collected the subjective opinions of the participants concerning the program and the subjective benefits or harm they perceived.–Brief Psychiatric Rating Scale [BPRS ] provide–Global assessment functioning scale (GAF) . This sc–We assessed the social autonomy of patients with a French scale: the Social Autonomy Scale (EAS) . This sc–The Schizophrenia questionnaire for Quality of life [S-QOL ]: scale –The self-esteem rating scale .–Attention, visual scanning abilities, and speed processing: D2 cancellation test . The sco–Verbal and visual working memory: respectively, the digit span subtests of the WAIS-III  and visu–Verbal learning: Grober and Buschke verbal learning test . The par–Executive functioning: Zoo map test and action program subtests of the Battery for assessment of dysexecutive syndrome [BADS ]. Scores–Visuo-spatial abilities: Rey–Osterrieth Complex Figure Test (RCFT) , 36. Tot–via a joystick two times in the same urban environment  in which they had to pick up a friend at the train station . In the first navigation, named the retrospective memory test, subjects were asked to pay attention to the elements/events they encountered along the way and their spatiotemporal contexts. Directly after this navigation phase, forced-choice visual recognition tests were carried out to assess the performance related to retrospective components of episodic memory taking into account the feature binding skills . The number of correct recognitions (yes-no response) was recorded regarding (1) factual elements , (2) spatial references with questions for “egocentric where” , and (3) temporal order .Retrospective and prospective memory virtual test , 20: aftBefore the second navigation to test the prospective memory performance, and approximately 20 min after the first navigation, subjects were instructed to encode a list of 16 action–intentions from verbal cues and figures presented on a screen: 12 event-based with incongruent or congruent cue actions  and 4 time-based actions . The encoding was rehearsed three times to allow subjects to store up clue actions. If at the third rehearsal, subjects obtained a recall of action–intentions below 8, the prospective task was not administered. Being again immersed in the virtual town, they were requested to stop walking at the appropriate time or place, and tell the experimenter what they had to do. We recorded the total recall of intentions at the third rehearsal before navigation (learning score), the number of correct stop at the appropriate scene or time and the number of correct related action. Then, we asked the participants to recall the list of intentions after navigation [for similar scoring method, see Debarnot et al. . For each score, mean and SDs were expressed.Participants were seven men and one woman. Their mean age was 38.6 12.1), years of education was 12 (1.1). Duration of disease was 13.2 (7.6). All patients were treated, the mean and SD values for chlorpromazine equivalents were162.7 (150.1); for details of treatment, see Table 2.1, yearBPRS was also clinically assessed (see Table p < 0.001), as well as for GAF scores (p < 0.01) ; when going through the different dimensions, the W12-W0 change for the EAS-personal care dimension was significant (p < 0.05) as well as the EAS-affective life (p < 0.05) and financial control (p < 0.05). For the S-QOL questionnaire, as well as the Insight short form questionnaire, no difference was found for the total scores between W12 and W0. Concerning the SERS, no significant difference was found either between W12 and W0 – and it was not either for positive or negative scores of the SERS.For psychosocial evaluations, there was a significant improvement for the EAS-Total score : D2 cancelation test: the KL score was significantly different at W12 comparatively to W0 (p < 0.05), and so was the GZ-F score (p < 0.05). However, there was no significant change for the GZ score (p = 0.22), or for the F% score (p = 0.19). For the Code subtest of the WAIS-III (p < 0.05), as well as for the Copy-Code (p < 0.05).WAIS-III  assessed–Verbal and Visual Working memory: When considering the standard scores of the Digit Span, there was a very significant difference when comparing W12 to W0 (p < 0.01), but any difference appeared for the forward span (p = 0.25) and the backward span (p = 0.14). No significant difference was found for the standard score of the visuo-spatial span subtest (p = 0.09) or for the forward span (p = 0.11), but a significative difference was found for the backward span (p < 0.05).–Verbal learning: no change was reported for the Grober and Buschke test (1987) whatever the score (p > 0.10).–Executive functioning: no change was observed either for the score of sequence, time of planning, time of execution, or Number of errors for the Zoo map 1 and 2 test (p > 0.05), nor for the action programs (p = 0.21) of the BADS.–Visuo-spatial organization: the RCFT revealed no significant change, either for time (p = 0.37), or for total scores (p = 0.10).–Retrospective and prospective memory: for the VR Retrospective memory Test with binding apprehension, there were significant differences at W12 compared to W0, for the “Where” egocentric recognition scores (p ≤ 0.05), and the “When” recognition score (p < 0.05). The difference was not significant for the “What “recognition (p = 0.09).p = 0.05), and performing correct actions (p < 0.05). There was no difference in learning action–intentions before navigation and cued recall after the navigation.Concerning the VR Prospective memory test, event-based component was improved during the navigation unlike time-based component. Participants appeared to be more efficient after remediation, stopping at the correct place . One participant went to the employment agency searching for a job. Three participants aimed to return to work, or decided to begin training. One participant wrote a paper in a scientific review to talk about his distressful experience when he was hospitalized and reported the fruitful benefit of the combination of CR and therapeutic activities .In this study, we proposed to chronic patients with schizophrenia, institutionalized for years in a daycare therapeutic activity center, a VR program focused on cognition, mainly visuo-spatial abilities and planning. Our first hypothesis was that this VR environment improves patients’ cognitive abilities, prospective memory, and planning. Furthermore, we hypothesized a clinical benefit and an improvement in social functioning compared to their functional status before the program.Following our first hypothesis, we observed a significant improvement in the KL and GZ-F sub-scores of the D2 cancelation test. Also, there was significant improvement in the WAIS-Code and Copy-Code. The need to navigate, to develop a good visual orienting in the virtual town, and to establish good landmarks all along the itinerary required an ability to focus on details of the virtual environment . FurtherClinically, the BPRS and the GAF scales were very significantly improved. These benefits corroborated the qualitative reports done by the patients. These improvements were noticeable for symptoms as well for qualitative reports of everyday functioning. However, when examining carefully the GAF scores, although there was an average significant improvement, there also was a large variability of the scores after the program. Nevertheless, when examining the BPRS scores, the substantial improvement represented 19.6% of the total scores. This percentage of improvement was similar to what is generally admitted for a pharmacologically active treatment. Hence, this VR program could have a positive, noticeable clinical incidence. However, this result must be tempered by several limitations: the rater was not blind to the treatment, the size of the sample was rather small, and lastly there was no control group to allow a strict comparison versus therapy as usual or versus another treatment-arm. Concerning psychosocial evaluations, there was a significant improvement in the global score of the EAS, with a better personal presentation, a gain in autonomy and improved affective and social relatedness. However, neither the self-esteem, nor the quality of life, nor the insight questionnaires were significantly improved. This has to be considered with a larger group of subjects, or maybe over a longer period of time, as the program only lasted 3 months. This interval is rather short to raise a substantial change for either insight or self-esteem.These outpatients suffering from schizophrenia or schizoaffective disorder were all chronic users of daycare institutions. They were unemployed, going routinely for years to weekly therapeutic activities, with limited autonomy and complaining of stress and difficulties in their everyday functioning. Two of them were even taking clozapine, indicating a severe form of the disease. The only positive common point when the program began was that they were willing to evolve in their lives. At the end of the program, all reported benefits, with several qualitative points that seemed crucial benefits in everyday functioning: better rhythm in their life, less stress, gain of time, better ability to plan, many things to do at home, concrete things done in their life. The treatment was perfectly well tolerated. The two dropouts happened after the first sessions of the program, probably due to an insufficient motivation to continue. One has to note, however, that a patient did not want to come for the neuropsychological part of the post-program evaluation. This might be due to the challenge this evaluation might represent for some of them. It could be important for the future to put the participants at ease concerning the tests, explaining them that these results will have no incidence for their outcome, treatment, or way of care.Disconfirming our initial hypothesis, there was no improvement in standard tests of verbal learning and planning. This could be accounted for by several facts: first, the limited power of the tests, due to the small sample. Second, one can notice that the scores obtained by the patients at W0 were high, reaching maybe a ceiling effect. Third, we selected for planning the zoo map test and action planning of the BADS. The zoo map test assesses planning abilities to set up an action plan to solve a problem, define a route for visiting some enclosures in a zoo. This exercise is far from mimicking daily life. Indeed, the participants showed difficulties perceiving the link with the planning abilities required to the everyday life. In addition, the action programs and the zoo tests were not sensitive enough to detect slight variation of performances. Noticeably, ceiling effect was found at W0 for all participants except one at the program action of the BADS, even while participants complained planning difficulties in everyday life activities. However, at W12, patients obtained longer time of planning and execution with the same number of errors, at the Zoo map test, when compared to W0. To explain this discrepancy, we could argue that many participants were penalized, not because of planning disabilities but for taking more time to plan their route. In addition, the action planning and the zoo tests do not provide a sufficiently sensitive quotation that could detect slight variations in performances. It could be better for the next groups to select other tests, such as the modified commission test , to obtaWhen considering all the positive comments the participants reported, this VR program is undoubtedly an asset for our Center for Cognitive Remediation and Rehabilitation. Despite the small number of patients who participated in the program, all the patients who completed it successfully improved, clinically and functionally. Although not demonstrating a substantial neuropsychological improvement in planning, patients showed attention, working memory, prospective, and retrospective memory benefits. Therefore, our initial hypotheses are only partially confirmed. However, the perspective for this program has been highly enhanced by these pioneering results. Patients are truly evolving in a rehabilitation pathway. They are asking to complete this experience with a cognitive remediation program, or to participate in a social cognition group in order to keep progressing in social interactions. One participant even decided to write a paper in a scientific review, on his own, to describe his unique experience . He rela« In this paper I want to describe my latest professional experience. Even if this page of my life had a bad ending issue, it is important for me to evolve in a constructive way for my future and to better apprehend my illness. It is by confronting myself with the world of work that I can improve my self-knowledge and paradoxically accept my handicap (…) With the help of cognitive remediation and sector teams I realized (…) that I had to think positively about the traumatic events that happened at work and to drive my own evolution in a positive and fruitful manner. (…) Now, I know more about my illness and I accept it. I know my limitations and I acquired a form of stability in life. » .One of the most important limitations is what has been already mentioned, namely the limited sample included in the group. The second point was the non-parallel versions of some assessments, mainly the prospective and retrospective VR tasks. Also, the participants had very diverse treatments with large variations in the dosage and compounds delivered. However, this study was assessed with patients who are institutionalized and in ecological clinical conditions, containing therefore an exemplarity of users who could visit daily a daycare therapeutic Parisian center.Virtual reality worlds offer great promises for the future. For the next groups, we plan to develop different versions of the VR program to induce more flexibility and to increase the training for patients by discovering different areas and new routes during their navigation, develop the complexity of scripts and maybe introduce interactive avatars. In the near future, we will introduce a whole network of public transportation (metro and bus) to enable discussions in the group around travel itineraries, as well as some unpredictable events to oblige patients to be more flexible in their routine action plans, while navigating in a non-stressful environment. We think that these points can be highly helpful for patients to manage their daily lives.These fruitful results encourage our teams to promote serious games as real cognitive remediation methods. Hence, with larger samples, we would have opportunities to demonstrate benefits also in planning, executive functioning, or even social cognition. Also, this program could be helpful for patients with schizophrenia with strong disabilities in daily living, who stay years in residential care unit for example, or living in apartments with a strong clinician support. Thanks to this program, we could expect that the supportive action of the clinicians who help patients to gain independence in life will be reduced or will focus on the remaining deficits insufficiently improved by the program. More generally, these new VR worlds open avenue for innovative rehabilitation programs for patients with schizophrenia.IA and PP supervised the project. IA was in charge of the clinical assessment. LB-H and ZP were in charge of the neuropsychological assessment and the program sessions. CD was in charge of the program sessions. EO was the engineer who conceived the virtual reality program. MS collected the data and was in charge of the statistical analysis. M-OK and all the participants already mentioned were involved in the redaction of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In vitro amplification assays, such as real-time quaking-induced conversion (RT-QuIC) are used to detect aggregation activity of misfolded prion protein (PrP) in brain, cerebrospinal fluid (CSF) and urine samples from patients with a prion disease. We believe that the method also has a much broader application spectrum. In the present study, we applied RT-QuIC as a pre-screening test for substances that potentially inhibit the aggregation process of the cellular PrP (PrPC) to proteinase (PK)-resistant PrPres. We chose doxycycline as the test substance as it has been tested successfully in animal models and proposed in clinical studies as a therapeutic for prion diseases. The RT-QuIC-reaction was seeded with brain tissue or CSF from sCJD patients and doxycycline was then added in different concentrations as well as at different time points. In both experiments, we observed a dose- and time-dependent inhibition of the RT-QuIC seeding response and a decrease of PK resistant PrPres when doxycycline was added. In contrast, ampicillin or sucrose had no effect on the RT-QuIC seeding response. Our study is the first to apply RT-QuIC as a pre-screening assay for compounds inhibiting the PrP aggregation in vitro and confirms that doxycycline is an efficient inhibitor of the PrP aggregation process in RT-QuIC analysis. C) called scrapie prion protein (PrPSc). TSEs include spontaneously (sporadic), genetic and acquired forms of CJD. In humans, sporadic CJD (sCJD) is the most common form of prion disease, followed by genetic CJD (gCJD) and iatrogenic CJD (iCJD). TSEs are non-curable neurodegenerative disorders with an average survival time of 6 months after onset. According to the protein-only hypothesisSc  is the principal causative agent which is composed of an abnormally misfolded, multimeric, and PK-resistant form of the host’s PrP, which can induce, or seed, its own propagation by recruiting and converting the cellular and protease-sensitive prion protein, PrPC.Transmissible spongiform encephalopathies (TSE) are a group of neurodegenerative disorders, such as Creutzfeldt-Jakob disease (CJD), which are characterised by the conversion and accumulation of a disease-associated, proteinase K (PK)-resistant, misfolded isoform of the cellular prion protein , or real-time quaking-induced conversion (RT-QuIC), use the high aggregation and seeding activity to amplify miniscule amounts of PrPres to a detectable level.Various in vitro amplification systems to detect misfolded PrPres in human cerebrospinal fluid (CSF) as a pre-mortem test is an important innovation, because it permits the study of the aggregation processes of misfolded PrPresin vitro for the first time2res seed in human CSF or brain tissue to a detectable level. Aggregated PrPres can be monitored in real-time by fluorescence dye analysis using a fluorescent plate reader. The kinetic of the signal detection is used to evaluate the efficiency of the reaction.The adaptation of res is the main causative agent of prion diseases, most potential substances tested for therapy are targeted against PrPres, against the conversion process of PrPC in PrPres or against the PrPres aggregation.Until now RT-QuIC has been applied in routine prion disease diagnosis and to study the seeding of different prion strains4567res in animal models910The tetracycline, doxycycline, has already been reported to bind to PrP and to decrease the amount of infectious PrPUntil now there has been no treatment available for prion diseases, although a number of compounds have shown positive effects in animal models91011res by adding doxycycline in different concentrations and at different times to the reaction mixture, which was seeded with brain tissue or CSF from CJD and control patients. We monitored thioflavin-T (Th-T) fluorescence and the kinetic curves obtained during aggregation of recPrP in the presence and absence of the drug. The fluorescence signals of the RT-QuIC reactions were characterised by their areas under the curve (AUC). Finally, we compared the amount of PK resistant PrPres after RT-QuIC analysis and in brain tissue in dependence from doxycycline treatment.In the present study, we applied the RT-QuIC assay to analyse the impact of doxycycline on the conversion and aggregation of PrPPatient CSF samples were collected through routine activities of the German National Prion Disease Surveillance Center, based at the University Medical Center Göttingen. Brain samples  were obtained from ten sporadic CJD (sCJD) patients typed as codon 129 MM1 and VV2. PRNP mutation was excluded by sequencing of PRNP. CSF samples were taken from 19 definite sCJD patients, typed as codon 129 MM1 or VV2 and 12 control patients without prion disease. Patients used as controls exhibited either a clinically or pathologically definitive alternative diagnosis.−3 in 1x PBS (Biochrom).Before use, brain and CSF samples were stored at −80 °C. Blood-contaminated CSF samples were excluded. The study conformed to the Code of Ethics of the World Medical Association, all study participants or their legal next of kin gave informed consent and the study was approved by the local ethics committee in Göttingen (No. 24/8/12). All samples were anonymised with regard to personal data. Brain samples, obtained from the Department of Neuropathology, University Medical Center, were homogenised (10% w/v) in a lysis buffer containing 1% SDS (Sigma), 100 mM Tris/HCl (Sigma-Aldrich), 100 mM sodium chloride (Roth) and 100 mM EDTA (Sigma-Aldrich) and then diluted to 10C (Thermo Fisher Scientific/Prionics) was seeded with 15 μL CSF or 15 μL of brain homogenate at a dilution of 10−3 to a final volume of 100 μL in a 96-well black optical bottom plate (Fisher-Scientific). Each patient sample (brain and CSF) was analysed in triplicate. Prepared plates were sealed with sealing tape (Nunc/Sigma-Aldrich) and incubated in a FLUO Star OPTIMA plate reader (BMG Labtech) at 42 °C for 80 hours with intermittent quaking cycles, consisting of one-minute double-orbital quaking at 600 rpm followed by a one-minute incubation break. Beta-sheet formation kinetic was determined by measuring the Th-T fluorescence signal (450 nm excitation and 480 nm emission) every 30 minutes in relative fluorescence units (rfu).The RT-QuIC was performed as reported before6C, which consists of the Syrian hamster PrP (residues 23 to 137) followed by sheep PrP (residues 141 to 234 of the R154 Q171 polymorphic haplotype), as described before8For RT-QuIC, we used chimeric recPrPresidues 3 to 137 To analyse the influence of doxycycline (Sigma-Aldrich), ampicillin (Fluka), sucrose (Sigma-Aldrich) and bovine serum albumine (BSA) (Sigma-Aldrich) on the RT-QuIC seeding response, we resolved all substances in RT-QuIC reaction buffer. To investigate the influence of the time point after a substance was added to the reaction on the RT-QuIC response, we added 5 μL of 10 mM doxycycline, ampicillin or sucrose to the reaction mix . The treatment occurred either directly or after different time points  after the RT-QuIC has been started.®-Block (Roth) for 10 min. The samples were sucked through the membrane in a Bio-Rad Microfiltration Apparatus (Bio-Dot SF) using a diaphragm pump . Slots were rinsed with 200 μL 0.1% desoxycholate before and after the application of gradually diluted samples in volumes of 180–360 μL.Brain tissue was homogenized 1:10 in in PBS including 0.5% desoxycholate (Fluka). DNA was removed by DNAse I [5 μg enzyme/mg brain tissue (Applichem)] for 30 min at 37 °C. The membrane adsorbtion assay was performed as described previouslyThe membrane was decontaminated in 4 M guanidine thiocyanate  for 30 min, which is also crucial for epitope retrieval. Blocking steps with 3% hydrogen peroxide  and casein 0.2%  were performed before the primary antibody mAb 3F4 was applied at 1:3000 for 60 min at room temperature. Antigen-antibody reaction was visualized on x-ray films using an HRP-coupled goat anti-mouse antibody  and a chemiluminescent substrate .Orrú et al.We followed a modified protocol published by PK was inactivated by heating the samples at 65 °C for 30 Min.Western blotting was performed according to a protocol as described beforeWe used the PrP specific antibody SAF32  in a dilution 1:500. Briefly, after PK-treatment samples were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) (15% w/v polyacrylamide) and transferred to polyvinylidene difluoride (PVDF) Hydrobond-P membranes (Amersham). Protein-labeled PVDF-membranes were probed with SAF32 overnight at 4 °C. Visualization of protein bands occurred by using an enhanced chemiluminescence (ECL) detection system solution using Chemicon system (Bio-Rad).1-way ANOVA and Tukey’s post hoc test. Graphically means and standard errors are shown for each group.AUCs were calculated using Excel 2010 and for convenience divided through 1000 and groups were compared in GraphPad Prism 6.05 (GraphPad Software), using −3  to RT-QuIC reactions seeded with brain tissue from sCJD (MM1) patients (10% v/w) in a dilution of 10−3 .Sc type effects on the RT-QuIC seeding responseFluorescence intensities were measured in rfu. RT-QuIC reactions without doxycycline were used as a reference . To exclWe found that doxycycline inhibited the RT-QuIC seeding response in a dose-dependent manner. The seeding response was significantly decreased when doxycycline was applied in a concentration of 0.1 mM, and a complete inhibition of the seeding response was achieved after application of 1 mM of doxycycline  and 2A.To determine whether doxycycline might also influence the PrP seeding response in CSF, we added doxycycline to RT-QuIC reactions seeded with CSF from sCJD (MM1) patients.Doxycycline was added in different concentrations (0–2 mM) as well as at different time points  to the RT-QuIC reaction. For a quantitative comparison, we defined the AUC as the seeding parameter of interest.We found that doxycycline inhibited the RT-QuIC seeding response in a dose-dependent manner. A decrease in the RT-QuIC seeding response was obtained when doxycycline was applied in a concentration of 0.5 mM and a complete inhibition of the seeding response was achieved after application of 2 mM of doxycycline  and 2B. In order to analyse the effect of doxycycline on the time course of the PrP seeding process, we added doxycycline at different time points  to the RT-QuIC reaction seeded with CSF from sCJD (MM1) patients. As a reference we used untreated reactions seeded with CSF from the same patients.When doxycycline (0.5 mM) was added within the first 24 h, we observed no seeding activity of PrP . Interestingly, when doxycycline was added at later times after reaction had started (after 48 or 72 h) the RT-QuIC seeding response was reduced compared to the untreated controls .Control experiments were performed by adding the antibiotic ampicillin and sucrose, in different concentrations (0–1 mM) and at different times (0–72 h), to the RT-QuIC reaction seeded with CSF from sCJD (MM1) patients.Neither ampicillin nor sucrose affected the RT-QuIC response in sCJD patients . CSF froIn another control experiment, we analysed the impact of bovine serum albumin (BSA), which is known to interact with Th-TMoreover, we were interested to know whether the doxycycline effect might be restricted to a certain PRNP codon 129 genotype or to a specific sCJD subtype. We analysed doxycycline treated RT-QuIC reactions, which were seeded with brain and CSF derived from sCJD VV2 patients. The obtained data indicated that the doxycycline effect is neither restricted to the codon 129 genotype nor to the prion type .−3 in PBS) or CSF from sCJD patients. After 55% of the total experiment duration of 233 hours, we obtained an increase in signal intensity of >10,000 rfu ; in the second phase we added doxycycline  directly into the RT-QuIC reaction. From the time of doxycycline treatment, we stopped the shaking process and incubated the samples at 42 °C until the end of the run as illustrated in To discover whether shaking would influence the anti-prion activity of doxycycline, we started an experiment with two phases. In the first phase, RT-QuIC reactions were seeded with brain tissue  brain homogenates. Interestingly, we observed that a doxycycline (1 mM) treatment reduced PK-resistant PrP in the RT-QuIC reaction compared to untreated reactions . This regregates .Sc. Unfortunately, most of the suggested compounds were not effective in treating the disease in humans. Drugs that have been tested often inhibited the propagation of PrPSc in cells or mice, but they were either not tested in humans because of their high toxicity or their failure to pass the blood brain barrier, or they showed a lack of a disease-relevant effect.Over the last 30 years a number of potential prion disease treatments have been investigated in experimental prion disease models or in clinical trials1018The translation of the experimental data to an application in humans has been hampered by the lack of suitable screening assays that mimic the disease relevant-conditions in humans. In our study, we used CSF and brain tissue from sCJD patients as seeds for the RT-QuIC reaction. Both seeds revealed an equal doxycycline effect, suggesting that less infectious sCJD-CSF is suitable for studying the potential effects of individual compounds on the RT-QuIC seeding response. The results of this study suggest that doxycycline binds to the seed particles in the RT-QuIC process and thus inhibits the transformation and the aggregation step.Sc. Since not all substances inhibiting the RT-QuIC response are potential therapeutics of a prion disease, we suggest that the RT-QuIC will not replace animal experiments in therapeutic research but we consider this test as quite useful to exclude substances without any anti-prion effect.Moreover, our findings propose the RT-QuIC assay as a pre-screening test for therapeutic substances targeting PrPin vitro amplification of PrPres in human CSF and brain tissue. Until now this methodology has been applied for the purpose of diagnosing human prion diseases and studying prion type properties in seeding4567res directly using CSF samples from affected symptomatic patientsThe RT-QuIC assay allows the C to PrPres. For proof-of-principle we used doxycycline as a compound, which has been shown to suppress the formation of infectious PrPres and to prolong the survival time of infected hamsters910The huge potential of this methodology prompted us to test whether RT-QuIC might be suitable as a potential screening platform for substances that inhibit the conversion or aggregation process from PrPFurthermore, our data indicated that RT-QuIC reactions seeded with CSF are more resistant to the effects of doxycycline despite having a smaller AUC compared to brain seeded reactions. Possible explanations are (i) different amounts or (ii) different structures of PrP seeds in brain and CSF. In particular the structure of the seed may have an influence on the affinity to doxycycline which may result in different seeding capacity of both seeds.The exact mechanism for how doxycycline exerts an anti-prion effect has not been studied in detail; however, some data are available. Doxycycline may directly bind to PrP and thus prevent the conversion process10Control substances without any known anti-prion effect, such as ampicillin and sucrose, revealed no significant influence on the RT-QuIC signal response of samples seeded with CSF from sCJD patients.Moreover, we tested BSA, which has no known anti-prion effect but it can interfere with Th-TTo decrease the number of falsely classified anti-prion compounds, we suggest that substances with a known interference with Th-T or with other chemicals from the reaction buffer, which change the reaction conditions (such as a change of the pH or digest the rec PrP substrate), and which show abnormal RT-QuIC seeding kinetics should be excluded from analysis.Studies in animal models revealed that the duration of doxycycline treatment had an impact on the survival time of infected animalsres aggregates into smaller seeds).This prompted us to add doxycycline at different times to the RT-QuIC reaction and to study its influence on the RT-QuIC seeding response in connection with shaking. The idea was to measure (i) whether doxycycline only prevented the start of the PrP seeding, (ii) if it reduced the RT-QuIC seeding response signal and (iii) if shaking is required,  when 200 mg doxycycline were administered orallyOur observation that the effect of doxycycline inhibiting the PrP conversion depended on a concentration higher than 0.5 mM 222 μg/mL) gave rise to speculation on reasons why this compound has not been effective in clinical trials so far. First, the disease stage is extremely important − the administration at early or pre-symptomatic stages is likely to be most effective because of limited brain damage and a lower amount of infectious PrP2 μg/mL gIn conclusion, our study demonstrates that RT-QuIC is suitable as a testing platform to evaluate the potential efficiency of compounds to inhibit the PrP conversion process. In contrast to previous methods, this testing platform is suitable for use in biological fluids from symptomatic patients. This has a huge translational potential for drug screening for potential efficacy in treating these devastating prion diseases in humans.How to cite this article: Schmitz, M. et al. Application of an in vitro-amplification assay as a novel pre-screening test for compounds inhibiting the aggregation of prion protein scrapie. Sci. Rep.6, 28711; doi: 10.1038/srep28711 (2016).


The 2010 Consensus on Science and Treatment Recommendations Statement recommended that short video/computer self-instruction courses, with minimal or no instructor coaching, combined with hands-on practice can be considered an effective alternative to instructor-led basic life support courses. The purpose of this study was to examine the effectiveness of a simplified cardiopulmonary resuscitation (CPR) training program for non-medical staff working at a university hospital.Before and immediately after a 45-min CPR training program consisting of instruction on chest compression and automated external defibrillator (AED) use with a personal training manikin, CPR skills were automatically recorded and evaluated. Participants’ attitudes towards CPR were evaluated by a questionnaire survey.versus that before was significantly greater , interruption of chest compressions was significantly shorter , mean depth of chest compressions was significantly greater , and the proportion of incomplete chest compressions of <5 cm among all chest compressions was significantly decreased . Of the 159 participants who responded to the questionnaire survey after the program, the proportion of participants who answered ‘I can check for a response,’ ‘I can perform chest compressions,’ and ‘I can absolutely or I think I can use an AED’ increased versus that before the program .From September 2011 through March 2013, 161 participants attended the program. We evaluated chest compression technique in 109 of these participants. The number of chest compressions delivered after the program A 45-min simplified CPR training program on chest compression and AED use improved CPR quality and the attitude towards CPR and AED use of non-medical staff of a university hospital. Bystander-initiated cardiopulmonary resuscitation (CPR) and the automated external defibrillator (AED) have major roles in the ‘chain of survival’ for both out-of-hospital and in-hospital cardiac arrest ,2. The evia a CPR skill report system, and a questionnaire survey on the participants’ attitudes towards CPR and AED use was conducted before and immediately after this training program. The purpose of this study was to examine the effectiveness of a simplified CPR training program for the non-medical staff working at a university hospital.The 2010 Consensus on Science and Treatment Recommendations (CoSTR) Statement recommended that training should aim to ensure that learners acquire and retain the skills and knowledge that will enable them to act correctly during actual cardiac arrests, and short video/computer self-instruction courses, with minimal or no instructor coaching, combined with hands-on practice can be considered as an effective alternative to instructor-led basic life support (BLS) courses . In SeptThis was a prospective observational study that was approved by the Ethics Committee of Osaka University Graduate School of Medicine. The institutional review board waived the need for informed consent. We surveyed participants who attended this CPR training program from September 2011 through March 2013. Those eligible to participate in this program were non-medical staff working at our university hospital.The simplified CPR training program consisted of instructions and practice on chest compressions and AED use with a personal training manikin, and the total time of this program was 45 minutes. We used the CPR Training Box APPA-KUN® obtained from the non-profit organisation Osaka Life Support Association, Osaka, Japan, as the personal training manikin Figure A. Doctorvia the CPR skill report system APPA-KUN Pro®   Figure B. This CBefore and immediately after the 45-min CPR training, participants’ attitudes towards CPR and AED use were evaluated by a questionnaire survey. The question items included ‘Can you check for a response?’, ‘Can you perform chest compression?’, and ‘Can you use an AED?’. The questionnaire survey was given to all participants, and replies were anonymous. The participants provided one answer for each multiple choice question.p < 0.05 was considered statistically significant. All statistical analyses were performed with JMP 9.0.2 for Windows .All data are represented as mean ± standard deviation (SD). The Wilcoxon signed rank test was used to compare the differences between before and immediately after training, and the Wilcoxon rank sum test was used to compare the differences between the first-time and the second-time participants in the evaluation of CPR skills. A value of p < 0.0001)             of the 161 participants. The responder group comprised 56 men and 103 women with a mean age ± SD of 42.5 ± 14.2 years, with 95 first-time, 59 second-time, and 5 third-time or more participants.After the program as compared with before, the proportion of participants who answered ‘I can check for a response,’ ‘I can perform chest compressions,’ and ‘I absolutely can or I think I can use an AED’ increased  , who answered ‘I can’t or shouldn’t perform chest compression’ was smaller (6 [10.2%] vs 49 [51.6%]), and who answered ‘I absolutely can’t or I think I can’t use an AED’ was smaller (15 [25.4%] vs 48 [50.5%]) than that of the first-time participants. After the program as compared with before, the proportion of participants who answered ‘I can check for a response’ was greater , who answered ‘I can perform chest compressions’ was greater , and who answered ‘I absolutely can or I think I can use an AED’ was greater   or short periods of untreated arrest –10]. In. In10]. In this study, we successfully demonstrated an improvement in the quality of CPR after the simplified CPR training course Figure . The 201In this study, we conducted a questionnaire survey to evaluate participants’ attitudes towards CPR and AED use and demonstrated an improvement in their attitudes after the training Table . Our resWe found that the quality of CPR and the participants’ attitude towards CPR and AED use were better in the second-time participants than in the first-time participants before CPR training Figure , Table 2The 45-min time of this training program was shorter than that of conventional BLS or ACLS courses, and this training could be conducted by at least one instructor. Therefore, less burdens on time and expense exist for either the participants or the instructors. Because our program improved the quality of CPR and attitude towards CPR and AED use of the participants, this program could be considered not only in medical but also in non-medical institutions when implementing CPR and AED use.As limitations of the present study, first, due to restrictions of time and the number of available CPR skill report systems, the evaluation of CPR skills was performed for only 30 seconds on 109 participants in whom cooperation was voluntary. Second, we did not test the practical skill of the participants on the AED due to restrictions of time. Further study is needed to evaluate the appropriate use of an AED after the training program. Third, there is no data on longer-term retention of skills. Forth, whether the participants of this CPR training could actually perform CPR in an emergency situation is unknown.A simplified 45-min CPR training program combining instruction and practice in chest compression and AED use improved the quality of CPR and the attitude towards CPR and AED use of the non-medical staff working at a university hospital. Further study to reveal the optimal interval for conducting the CPR training program to maintain the quality of CPR and a positive attitude towards CPR and AED use is needed.The authors have no conflicts of interest to declare in relation to this manuscript.TH, TI, and TS designed the study. TH, HM, TS, and KY collected and generated the data. TH wrote the first draft. TH, TI, HO, KY, TM, YF and TS analyzed the data and helped to draft the manuscript. All of the authors read and approved the final manuscript.


BCR-ABL1 transcripts are crucial for managing patients with chronic myeloid leukemia (CML). Although real-time quantitative polymerase chain reaction (RT-qPCR) can be measured on an International Scale (IS), this has not become fully universal. By using a WHO international standard panel established for calibrating secondary standards based on the IS, we have previously developed an RT-qPCR kit, ODK-1201, for quantification of major BCR-ABL1.Detection and quantitation of BCR-ABL1IS.In this study, the reliability of kit-specific conversion factor 1.12 was validated by exchanging patients’ samples between three local clinical laboratories and a reference laboratory. The mean bias of the local method after IS conversion was 1.6 fold lower than the reference method. The clinically-useful sensitivity of the kit was further evaluated for monitoring patients with deep molecular response. Based on the correlation of the IS values between ODK-1201 and the reference laboratory method, the detection level of the kit was estimated as 0.0032 % BCR-ABL1 on the IS in 2 h after RNA extraction, thus contributing to standardization of molecular monitoring in CML.ODK-1201 is a highly sensitive one-step RT-qPCR system for detecting  BCR-ABL is a constitutively active tyrosine kinase generated by the Philadelphia chromosome translocation, and is recognized as the underlying pathogenetic mechanisms of chronic myeloid leukemia (CML)  , as established in the IRIS trial  were carried out to identify of the performance of ODK-1201 and to get the laboratory-specific CF, sponsored by Otsuka Pharmaceutical Co. Ltd. Total 468 CML patients were recruited for these studies, and peripheral blood samples were taken after written informed consent in 24 institutions in Japan, between July 2012 and October 2013. These studies were conducted in accordance with the Declaration of Helsinki, and its design was approved by each hospital’s Institutional Review Board. The samples were firstly analyzed in three commercial laboratories, BML, Inc., SRL, and LSI Medience Corporation  in Japan, and thereafter in SA Pathology, Adelaide, Australia, a recognized reference laboratory  was added to a mixture of 13 μL of mix solution (R1) for RT-qPCR and 2 μL of Mn(OCOCH3)2 solution and applied to ABI™ 7500 Fast Dx system. The assay conditions have been described previously , and analyzed according to the suggested method for calibration of secondary standards (http://www.nibsc.org/documents/ifu/09-138.pdf). The panel comprises four ampoules, each containing freeze-dried BCR-ABL1-positive and -negative cells at various ratios from 0.01 to 10 % BCR-ABL1IS. RNAs were isolated from each ampoule with a QIAamp RNA Blood Mini Kit (QIAGEN) and were subjected to the measurement of major BCR-ABL1 and ABL1 mRNAs with the ODK-1201 kit. The CF of the ODK-1201 was calculated by comparing the values of % BCR-ABL1/ABL1 obtained with the kit with those from the WHO standard panel. The RT-qPCR method carried out at the Adelaide reference laboratory has been previously detailed  in BML, RNeasy Mini Kit (QIAGEN) in SRL, or RNeasy Lipid Tissue Mini Kit  in LSI, respectively. The study diagnostic kit in this study was coded ODK-1201. It is based on a HawkZ05 Fast One-Step RT-qPCR Kit . In this kit, reverse transcription and quantitative PCR are performed in one tube. The analysis was carried out on an ABI™ 7500 Fast Dx system . In the quantitation with this kit, specific regions of major The ODK-1201 kit-specific CF was 1.12 determined by using the WHO standard panel by following the method for calibration of secondary standards as outlined in White et al. . The calBCR-ABL1 values from the reference and the local laboratories were converted to the IS by multiplying by their specific CFs. The samples with positive BCR-ABL1 values were converted to the IS using the CF 1.12 and compared , and then sent to the reference laboratory. None of the samples was degraded. The BCR-ABL1 value of 0.10 % BCR-ABL1IS) between the reference method and the ODK-1201was determined as 84 % (N = 43/51) of samples.The overall concordance of the data between ODK-1201 and the reference laboratory systems was acceptable Fig. . After cBCR-ABL1IS. To verify the clinically-useful sensitivity of the ODK-1201 kit, we tested the correlation between the two methods in the assessment of 46 clinical samples with IS between the lowest positive value (LPV) and 0.1 % BCR-ABL1IS. A high correlation coefficient (r = 0.89) was found  to standardized baseline (as 100 % BCR-ABL1IS) established in the IRIS study, but not deeper molecular response . In contrast, when BCR-ABL1-negative samples were analyzed by the kit, BCR-ABL1 transcripts was never detected, suggesting low false positivity of the kit (data not shown). Of note, the measurement can be carried out using only 7 mL of blood, a sample which is smaller than the previously recommended volume (Baccarani et al. The achievement of MMR has been recognized as the therapeutic goal for chronic-phase CML patients based on the results reported on the IRIS trial and subsequent ones (Baccarani et al. BCR-ABL1 using commercial kits.The variation of results obtained by RT-qPCR is due to each stage of the procedure, including sample collection, transportation time from clinics to laboratories, RNA extraction, reverse transcription, and the actual quantitative PCR (Branford et al. BCR-ABL1 based on the IS, which contributes a useful tool for evaluation of deep molecular responses and standardization of treatment in CML.ODK-1201 is a rapid one-step high sensitivity RT-qPCR system for detecting


Community health workers (CHWs) in Mozambique ) are key actors in providing health services in rural communities. Supervision of CHWs has been shown to improve their work, although details of how it is implemented are scarce. In Mozambique, APE supervision structures and scope of work are clearly outlined in policy and rely on supervisors at the health facility of reference. The aim of this study was to understand how and which aspects of supervision impact on APE motivation and programme implementation.Qualitative research methodologies were used. Twenty-nine in-depth interviews were conducted to capture experiences and perceptions of purposefully selected participants. These included APEs, health facility supervisors, district APE supervisors and community leaders. Interviews were recorded, translated and transcribed, prior to the development of a thematic framework.Supervision was structured as dictated by policy but in practice was irregular and infrequent, which participants identified as affecting APE’s motivation. When it did occur, supervision was felt to focus more on fault-finding than being supportive in nature and did not address all areas of APE’s work – factors that APEs identified as demotivating. Supervisors, in turn, felt unsupported and felt this negatively impacted performance. They had a high workload in health facilities, where they had multiple roles, including provision of health services, taking care of administrative issues and supervising APEs in communities. A lack of resources for supervision activities was identified, and supervisors felt caught up in administrative issues around APE allowances that they were unable to solve. Many supervisors were not trained in providing supportive supervision. Community governance and accountability mechanisms were only partially able to fill the gaps left by the supervision provided by the health system.The findings indicate the need for an improved supervision system to enhance support and motivation and ultimately performance of APEs. Our study found disconnections between the APE programme policy and its implementation, with gaps in skills, training and support of supervisors leading to sub-optimal supervision. Improved methods of supervision could be implemented including those that maximize the opportunities during face-to-face meetings and through community-monitoring mechanisms. Numerous countries around the world have established community health programmes as a means to expanding access to health services among vulnerable populations, and these programmes are considered a vital component of reaching the health-related Millennium Development Goals . With thDuring this period, different APE-training curricula, implemented mainly by non-government organizations (NGOs) supporting the Ministry of Health (MoH), resulted in CHWs with wide variations in their scope of work mainly taking care of single “verticalized programmes” such as HIV/AIDS or tuberculosis . NGOs imIn this revitalized model, APEs receive a 4-month residential training covering health promotion, disease prevention, testing and treating malaria in children and adults, diagnosing diarrhoea and dehydration, using oral rehydration solutions and diagnosing and treating acute respiratory infection in children. Additionally, APEs are trained to provide first aid and to detect danger signs in children, adults and pregnant women [The APE programme has established protocols for programmatic supervision involving interaction between the province and district supervisors, district and health facility supervisors and health facility supervisors and APEs. Supervision of APEs is explicitly described as the responsibility of health workers, usually qualified nurses, from the health facilities of reference for a particular catchment area , 7. EachDespite revitalization of the APE programme, considerable challenges remain regarding its successful implementation, including the supervision system. In available reports, a number of barriers were described about the human resource management of this cadre , 9. Of pSupervision has been linked to motivation and performance of health care workers. Motivation is defined as “an individual’s degree of willingness to exert and maintain an effort towards an organization’s goals”  and is awww.reachoutconsortium.org) which has the goal of improving the equity, effectiveness and efficiency of community health workers in six countries, including Mozambique. It was carried out in Manhiça and Moamba districts using qualitative approaches. Data collection was done from August to beginning of September 2013. The selection criteria of these districts were based on geographical situation, having an established APE programme and distances. A qualitative study was chosen as most appropriate to reach the objective of this study, because it could obtain in-depth insight into how supervision of APEs was conducted and what made it facilitate or hinder APE motivation and performance [Data collection was conducted as part of a multi-country study under the REACHOUT consortium  focusing on aspects related to supervision, motivation and performance. We used IDIs with the purpose of exploring strengths and weaknesses of community services and barriers and facilitators to APE performance. The IDIs assured that participants could be interviewed in their rural communities and avoided issues of hierarchy affecting group discussion .Semi-structured topic guides were developed in English first (as part of the multi-country study), translated into Portuguese and back-translated for consistency. IDIs with APEs included questions on recruitment, incentives, motivation, training and support, roles and tasks, supervision and communication. For supervisors, we added questions on barriers and enablers of supervision and on management and training issues. Community leader interviews included issues of community engagement and ownership, selection and support of APEs, knowledge of APEs’ roles and expectations. The topic guides were piloted in an area that was not included in the study and adaptations to probes and questions were made. For some APEs and community leaders (those with no or only primary education), it was necessary for interviewers to explain concepts in the local languages of Ronga and Xichangana, despite Portuguese fluency being a selection criteria for APE recruitment.Standard procedures and tools were used to ensure correct and complete data. Daily debriefing sessions with all data collectors were held to discuss key findings, refine lines of inquiry and summarize extensive field notes and observations. The interviews were digitally recorded, and Portuguese transcripts were made of each IDI by the interviewers who also rechecked each other’s transcripts against the recordings for quality assurance. The transcripts were independently read in Portuguese in pairs by a group of four researchers  to identify key themes and develop a coding framework. This process used open-coding , combineWe interviewed a range of APEs, health facility and district supervisors and community leaders. These were purposively selected from the two districts to represent different profiles, as outlined in our “From the data analysis, there were five key emerging themes related to the interaction between APEs and supervisors that illustrate a range of factors that participants felt influenced the motivation and performance or both groups. First, supervisors acted as important links between health systems and communities; second, there were gaps in policy content and a mismatch between policy and practice leading to irregular and infrequent supervision; third, the skills and approach to supervision were important in determining APE motivation; fourth, supervisors themselves felt largely unsupported; and lastly, we also found that APEs received support and monitoring from the community and a high level of community engagement in “supervising” their work.“They tend to evaluate using the monthly summaries. Observe the number of cases treated, number of pregnant women, new-borns, adults and children, transferred cases, people who had been treated for malaria, number of lectures and participants. They want to know how many people I have attended to, and if this is to reduce or increase.” Supervisors provide an important link between the APE programme and the health system on the one hand and between the programme and communities on the other. In both districts, the supervisory system appeared to be organized into the four levels described by policy: APE, supervisor at health facility of reference, district supervisor and provincial supervisors with a largely functional reporting system at district and provincial levels. However, the collecting of data for monitoring purposes which is transferred in an upwards direction, was often not discussed with, or fed back to, APEs who felt unaware of their own performance and the state of the programme in general. Supervision was instead mentioned as a data-gathering exercise for monitoring and evaluation of the APE programme.“I think that they evaluate me through supervision. When they come here they want to know what will work, see the log book, seeking to know if I have doubts. Soon when coming to supervision I have to express my doubts; the supervision facilitates me, and I know how my work is going.” While general programme data were not fed back, this APE also described requesting and receiving immediate feedback:“When I receive supervision visits, I ask about things that I cannot do, and they show me how to do them. So we learn things we don’t know how to do during the supervision, and we like that.” “Supervision is always seen as good and important for the type of work we do. We APEs are not ‘doctors’. We have very limited knowledge in many things we do and a supervisor must always be there to teach new things and remind us about what we have learnt.” Both supervisors and APEs agreed on the potential of supervision for capacity strengthening of the APEs. Supervisors described the need to teach and mentor APEs and often helped them with their monthly reports, technical advice on promotion or prevention and with clinical queries. The support and ongoing education provided was appreciated by the APEs as expressed by these two representative quotes:“Even my community will not respect me when they don’t see my superiors coming here.” .The presence of supervisors in the community was welcomed and was seen by APEs and community leaders as enhancing the credibility of the programme as well as that of APEs in their respective communities. Conversely, their absence undermined perceptions of APEs and of the health system as pointed out by this APE:“In this one year only 22 APEs worked, and three people already gave up. I’m sure that if the process continues so many will give up, only because of the subsidy. The first complaint is that it is little, and even then it does not appear monthly; the delay influences them a lot. …Every day that passes there is a message that comes to us asking about the subsidy. They always send messages asking about the allowance: when will it come out? We are now on 21 August, and this is the fifth month that we do not have a subsidy.” Additionally, when subsidies were not paid or stock-out of medicines occurred, the supervisors, as the accessible human face of the system, had to provide explanations and negotiate. The supervisors felt caught between administrative and management issues around APEs’ subsidies that they were not in a position to solve and perceived this as undermining their credibility to respond on behalf of the health system they represented:“I as supervisor I do not feel good when I go to a community for supervision and require a lot from the APE while after that the APE will ask me about the subsidy and the answer will always be the same: we are still dealing with that but they will never receive such money.” Delayed subsidies limited the motivation of supervisors to visit and oversee APEs, as supervisors did not feel comfortable demanding more work knowing that APEs were not receiving their subsidies on time and were demotivated.“We also have difficulties with transportation in that a motorcycle sometimes does not have fuel. I waited one month following the request without receiving the fuel. Also there is the issue of faults: most of the time or almost always I have to do maintenance of the motorcycle, because waiting for the district means stopping, and how many activities will that affect? Rather than waiting for the district, I’m going after it myself.” According to APE programme guidelines, the frequency of supervision for district to facility level is quarterly and for facility level to APE level is monthly in two ways: during report delivery and collecting of drug kits at the health facility and during actual supervision visits at the community level. Although the supervision system is organized according to a timetable, both APEs and supervisors pointed out that it rarely occurred on the scheduled dates and was both infrequent and irregular. The lack of transportation, long distances to travel and difficult access to communities were identified as factors that negatively affected regular supervision. In some cases, supervisors spent more than 2 months without carrying out supervisory activities. While most supervisors identified lack of resources as the problem, some also pointed to poor coordination within district health directorates as the cause of delays in the allocation of fuel and other logistical needs for regular supervision to take place. Other issues mentioned included pending maintenance of their motorbikes as explained by this supervisor:“Working as an APE supervisor has not been easy, because I’m alone, and when I go out for supervisory activities, other activities are stopped, but I cannot let the activities of the APEs suffer because of the others. I always have to run behind time. Sometimes I cannot do oversight on the scheduled dates, and I have to go after working hours.” The same supervisor describes the impact of dual roles, a sentiment echoed by all the other supervisors interviewed:“I had my last supervision in June last year and so far not yet had any other visit that demotivates me because it seems that I was forgotten.” Roughly 2 years since the beginning of the programme, some communities and APEs had only received two supervisory visits. The infrequency and irregularity of supervision was felt by many participants to negatively affect the performance of the programme and of individual APEs in achieving objectives. This situation can make APEs demotivated, reduce the communication between APEs and health facility coordinators and reduce the effectiveness and efficiency of the programme interventions, as this APE pointed out:“When he comes here he looks at the record book and then just focuses on what I did wrong. He says that he is doing that to support me but I don’t think so. Sometimes I prefer to not share my gaps with him or even if he couldn’t come here”. Supportive supervision emerged as a strong determinant of motivation among the APEs, and an approach that relied on fault-finding rather than support was reported as a strong demotivating factor. While APEs identified this as a problem, the supervisors did not. Many appeared to regard checklists as a key (and only) tool required for supervision, determining fault-finding as the correct way of supervising and feeling comfortable with it. This approach, however, may have made it harder for them to identify and deal with problems at all. Some APEs stated that when a supervisor is mainly looking for the bad things, they tended to hide their gaps during subsequent supervision visits.“My supervisor has supported me in many ways and I believe he has good skills for his job, but when he comes to supervise me he only takes the log book and begins to observe and often does not give me report about my work … where I should improve” In fact, most of the supervision described by the APEs was based on checklists with the supervisor focusing on issues present on the list , and roles that were not on the list  were described as not being taken into consideration; neither was constructive feedback given, as illustrated by this typical quote from an APE:While few APEs had experience or expectations of supportive supervisions, they identified factors and skills that motivated them and that are traditionally linked to this approach, such as listening, praising good work, joint problem-solving and non-judgemental attitudes.“I am supervisor since the APE programme was revitalized here, but I have never been trained. They (superior level) gave me some tips during my supervision on how to conduct a good APE supervision, but like others I may one day be transferred to another site and be replaced by someone else who doesn’t have any skills or even knowledge regarding the programme”. Despite the fact that APE supervisors should be trained according to the manual, it was found that training of health facility supervisors was overly focused on how to complete checklists. In addition, supervisors mentioned that individuals who had been trained had been transferred from one health facility to another or from one district to the other, leaving the supervision tasks with staff unaware of the roles and tasks of the APE programme as this supervisor explained:“Most of the things I know I was not taught, I acquired supervision skills by doing what I was supposed to do and by reading all the tools regarding APEs supervision”. Districts supervisors may be in a better position in terms of supervision skills than health facility supervisors, as they are full-time APE programme managers at the district level. Despite this, they did not receive any initial training for supervision but learnt by doing.Some supervisors learnt how to conduct supervision through their own supervision from their superior level, and this they also described as focused on fault-finding. Thus, the APE supervisors used the same approach when supervising the APEs. Health facility supervisors were supported by district supervisors providing logistical arrangements and occasionally accompanying visits to the field, often taking the opportunity offered by researchers, NGOs or other visitors travelling to see APEs. There were no arrangements described for refresher training of supervisors, meetings of supervisors or other sources of support and capacity development.“We coordinate with the community leaders. For example, the community leader controls the activities, so I have to be informed about how they are working. He gives me the information. They sometimes go with the APEs during the lectures about health promotion and disease prevention to see how the APE is working with the community.” The communities were also involved in monitoring and accountability of APEs, and the health facility supervisors and the district supervisors linked with community leaders to find out how the APE is working. Regarding this, a supervisor said:“In the meetings we used to have here in the community we ask the population if our APE is working well or not and we give the report to the nurse when she comes.” “We are always available to help our APE and we have an obligation to see how it is working. For example, the drugs kit can only be opened in our presence to ensure control of the drugs because they must be used for this community and for the goodness of this community and if we see something wrong we must report the health facility.” This was backed up by interviews with community leaders, who described the community as having a governance function that provided oversight and a degree of control, as well as support, of the APEs’ work, ensuring that drug kits were opened in their presence, that feedback was gained from wider community members and that reports were reviewed before submission.“The community leaders and people here in the community follow all my work. They almost know everything that happens here in the community. Even my monthly reports that I send to the health facility they want to see first.” This APE also confirmed a high level of community engagement with monitoring his work:Community-monitoring, while not formal health system supervision, represents a different kind of influence on APE motivation. In our context, it seems to be functioning alongside, and in some respects better than, formal supervision. Through its supportive approach, positive feedback and lack of fault-finding and checklists, it becomes more in line with how supervision might function to motivate community health workers and opens the possibility of a partnership that links this to formal supervision.Our findings indicate that supervision was structured as dictated by policy documents, and APEs considered supervision and the accompanying mentorship as a key factor in maintaining their motivation. Supervision also provided APEs with a sense of belonging to a health system emphasizing the connection between them and their health facilities and an enhanced credibility in their communities. However, in practice, the supervision of APEs through community visits by supervisors was infrequent and irregular. When it did occur, supervision was perceived to focus more on fault-finding than being supportive in nature and did not address all areas of APEs’ scope of work – factors that APEs identified as demotivating. Supervisors from reference health facilities in turn also felt unsupported and perceived this to negatively impact on their performance as supervisors. They had a high workload in health facilities, where they had multiple roles, and they felt unable to dedicate appropriate attention and time to the APEs under their supervision. Lack of logistical and financial resources for supervision activities was identified as a challenge, and supervisors felt caught up in administrative issues around APE allowances that they were unable to solve, as these depended on higher hierarchical levels of the health system. Many supervisors were not trained in supportive supervision. Community governance and accountability mechanisms represent a potential for additional support but were only partially able to fill the existing gaps in supervision of APEs by health system staff.The role that supervisors play in acting as a bridge between CHW programmes and the health system on the one hand and between the programmes and communities on the other is described elsewhere , 23, 24.The importance of a coordinated approach to supervision from the health system perspective is key if universal health coverage is to be achieved in an equitable manner and with services of sufficient quality . HoweverOur findings strongly endorse the desire for supportive supervision approaches both from APEs and from supervisors, who feel under supported and lack role modelling of supportive supervision approaches themselves. Supportive supervision is a process described as promoting quality in health system functioning by strengthening relationships, focusing on the identification and resolution of problems and helping to optimize the allocation of resources – promoting high standards, teamwork and better two-way communication . Such apThe proximity of communities and the relative remoteness of the health system and its representatives mean that communities often take on a governance and accountability role in relation to their local community health programme. Designing a supervision system based on approaches used within the formal health system may be inadequate unless it is adapted to build on links with the community as well . CommuniThe importance of supervisor training skills and knowledge emerged as a key theme in our findings, and this has also been described in a review of supervision and mentoring for remote rural health workers . HoweverOur study has a number of limitations. We used qualitative methods and are thus unable to comment on the representative nature of our sample. The number of supervisors included in our study was small, and we are not able to present disaggregated data between health facility and district-level supervisors for reasons of confidentiality. The impact of CHW profile on issues of empowerment, ability to speak out to supervisors and understanding concepts of supportive supervision would require a larger data set and better balance of genders, with more targeted questioning to enable a full gender analysis to be conducted. APEs and community leaders for interviews were selected with the help of supervisors, although all available APEs in the districts were sampled, wherever possible.Our study suggests the need for developing a supportive approach to supervision as an important next step in the two districts. There is a need for solutions that are sustainable and viable for implementation in resource-constrained settings such as the study sites (which reflect the majority of districts in the country). A group approach to APE supervision combined with support and training for supervisors would ensure a supportive supervision strategy that efficiently uses the short time that supervisors have to conduct good supervision. This would also allow APEs to develop problem-solving skills as a group through peer support and supervisors to come together for a common training to explore and build on their existing strengths. Training APEs on what to expect from supervision, empowering them to seek advice and encouraging them to seek support from community-monitoring systems can further empower APEs as community agents.This study adds to the limited body of literature on supervision of APEs in Mozambique and discusses these in the light of data and evidence from other community health worker programmes. We identified the importance of regular supportive supervision as a key determinant to APE motivation and a potential way of improving APE and programme performance. A range of barriers to the supervision system under the revitalized programme should be addressed. APEs in the previous programme felt abandoned due to the lack of supervision, and this appears to be a recurring constraint in the revitalized programme. While some APEs indicated that they want more supervision, constraints in supervision frequency arose at both the facility and district levels, relating to budget and access issues but also to supervisors’ dual roles and limited means of transport. Using community-monitoring in motivating and empowering APEs represents a potential additional supportive mechanism but cannot address all of the identified issues without linkage to the formal health system and supervision structures as well as efforts to create supervision structures that are supportive and problem-solving rather than managerial and fault-finding. Tailored solutions would be required, as each district/community has its specific characteristics, and challenges are not always similar in all parts of the country. Furthermore, when supervision does take place, feedback and thus learning opportunities should be the focus so that both supervisor and APE can positively contribute to enhanced community health.


Successful mentorship enhances quality of life, hope for recovery and empowers people with anorexia nervosa (AN) to develop health-promoting strategies, with immeasurable benefits for both mentor and mentee.To develop and evaluate, in consultation with stakeholders , a mentorship support program for people with AN in NSW.This study is a mixed methods participatory action research (PAR) project. Participants are pivotal in the development and design of a tailored program. Researchers work closely with stakeholders to bring and evaluate change, through cycles of learning and reflection, actively engaging participants in the research process.During workshop discussions, participants (4 mentors and 5 mentees) defined the program, examined roles and responsibilities, partnerships, interaction, use of funds, conflict resolution and risk management. The workshop, conducted informally in a setting that simulated a home environment, reduced anxiety levels. Uncertainty evolved into an appreciation for the program, development of new relationships, learning that everyone had similar reservations yet reassurance that people were there to support and encourage recovery. Participants were positive and optimistic for the program's trial.PAR is an apt research method for actively engaging stakeholders in the development of a tailored program to support recovery.


Simulation-based education (SBE) has seen a dramatic uptake in health professions education over the last decade. SBE offers learning opportunities that are difficult to access by other methods. Competent faculty is seen as key to high quality SBE. In 2011, in response to a significant national healthcare issue – the need to enhance the quality and scale of SBE - a group of Australian universities was commissioned to develop a national training program - Australian Simulation Educator and Technician Training (AusSETT) Program. This paper reports the evaluation of this large-scale initiative.train-the-trainer model, which offered up to three days of workshops and between four and eight hours of e-learning. The Program was offered across all professions in all states and territories. Three hundred and three participants attended workshops with 230 also completing e-learning modules. Topics included: foundational learning theory; orientation to diverse simulation modalities; briefing; and debriefing. A layered objectives-oriented evaluation strategy was adopted with multiple stakeholders , methods of data collection  and at multiple data points (immediate and two months later). Descriptive statistics were used to analyse numerical data while textual data (written comments and transcripts of interviews) underwent content or thematic analysis.The AusSETT Program adopted a For each module, between 45 and 254 participants completed evaluations. The content and educational methods were rated highly with items exceeding the pre-established standard. In written evaluations, participants identified strengths  and areas for development  of the Program. Interviews with participants suggested the Program had positively impacted their educational practices. Observers reported a high quality educational experience for participants with alignment of content and methods with perceived participant needs.The AusSETT Program is a significant and enduring learning resource. The development of a national training program to support a competent simulation workforce is feasible. The Program objectives were largely met. Although there are limitations with the study design (e.g. self-report), there are strengths such as exploring the impact two months later. The evaluation of the Program informs the next phase of the national strategy for simulation educators and technicians with respect to content and processes, strengths and areas for development.The online version of this article (doi:10.1186/s12909-016-0548-x) contains supplementary material, which is available to authorized users. The lowest rated learning objective was for describe the basics of programming manikins .A mean of 5.06  was reported for Qualitative responses for module evaluation covered three areas: i) what worked well; ii) what needs improvement; and iii) things that participants had learned. As the data collected provided a large body of information, only selected responses are included.There were many successes with the modules such as the “open” small and large group discussions, high quality facilitation, the opportunity to learn from each other, debriefing exercises especially with observing different styles of debriefing, the use of non-clinical scenarios for learning about SBE principles, e-learning exercises and debriefing resources, the reference to educational theory relevant to SBE and the breadth of simulation modalities.“It was a great discussion-based learning experience, drawing on others’ knowledge and experiences to create themes around simulation and debriefing; The faculty were extremely supportive”“Different simulation modalities and the understanding that you don’t need the best simulator to achieve the outcome”“I enjoyed the hands on part of the module where we designed a simulation exercise and needed to give feedback; Also the chance to meet other people trying to do the same thing or with other ideas/experience was great; As I am very new to this area it was all a bit daunting, so hearing some of their tips/techniques was helpful”These successes are illustrated by examples of text from a core module (C2):“The response boxes need to allow for editing. After brainstorming some ideas and submitting I realised that I could not re-enter to finalise my ideas; Scrolling between 2 pages to re-read quotes then meant that what I had entered into the text box had been lost; Quite frustrating…” (C1)“The computer interface; Many of my responses were partially or fully deleted on submission; I was unable to then edit the response after submission and 90 % of my scenario was not loaded; I found this extremely frustrating and do not feel the saved answers reflect well either what I actually wrote or my effort in this module.” (E1)“Couldn’t access the pebblepad” (C2)“I have had difficulties accessing many of the links and the audio component, so that made it difficult; There was also a huge amount of readings required making it very lengthy to work through” (E2)The need to improve the learning management system, the use of the e-portfolio and more time for completing the preparation prior to attending workshops were raised by the participants.“I think AusSETT needs to have a clearer idea of where this project is going, as the presenters just didn’t have the answers about the next few steps; I worry that by the time the project is developed fully, I will have forgotten what I am supposed to train others in.” (C2)Some participants also expressed the need for information about when the next phase of the Program would commence.Participants were requested to list up to five things they had learned during each module. This provided further insight to whether the objectives of the sessions were met. Only responses from a core module (C2) are presented as the data collected yielded a large amount of information. Some of these statements covered one or more of the successes reported above. The top five results – practical SBE skills, reinforcement of important processes in SBE, access to resources for SBE, theories that inform SBE and generic teaching approaches - suggest that the module offered consolidation and/or development of knowledge and skills Table . The modNine interviews were carried out between August and November 2012. Each interview took between 18 to 30 min with 239 min of data obtained. Feedback from the interview triangulated the end of the module evaluation data. Overall, positive general thoughts and feelings for the Program were reported and reinforced the earlier data. The interviews identified an overarching theme: the impact of the Program. Three specific areas of impact were noted; a) personal; b) organisational; and c) professional community. Verbatim statements from the interview data are presented in Table The results support the notion that the AusSETT Program was an important national initiative. The interviews and observations indicate the value that participants place upon the program and how access to the Program has resulted in significant goodwill in the healthcare simulation professional community. The overwhelming sense was that participants had high standards, were aspirational for their practices and wanted to make a difference using simulation as an educational method. However, the impact of the Program cannot be fully measured until the participants themselves offer simulation educator and technician training.Many strengths of the Program were primarily structural. They included the building of a significant and enduring repository of contemporary resources (e-learning and workshops), and its offering in urban and rural regions, across jurisdictions, simulation modalities and professions. The Program also had a national profile with the representativeness of the development team. The module review process enhanced the strength of the structural factors.Enabling structural factors from participants’ perspectives included being identified to attend the Program, some dedicated time off work to focus on professional development, networking associated with spending time immersed in SBE and offering the Program free of charge to participants. Other enablers included the access to e-learning. In fact, the e-learning also formed a significant structural constraint, particularly with respect to the functionality of features. Additionally, participants largely resisted the use of PebblePad, which did not seem related to the tool itself but to its use in this particular context. At a higher level, a constraining factor was that, at the time of the Program delivery, the next steps were not known to the Program faculty. Although HWA had longer-term goals, the mechanisms of government, especially in relation to budgets, did not permit sharing of plans in a more timely fashion. This created a barrier for engagement by individuals and institutions with the Program.Participants and workshop observers identified the types of active learning opportunities as a strength of the Program. Indeed, participants identified a key point of learning as including a series of ‘processes that worked well’, which were modelled during the process factors. The need to have skilled facilitators was reinforced by workshop observers; this may be a key enabling process factor for any future Program.Participants’ reported that they largely met learning objectives. Where objectives were not met as well as our pre-set standard, this may have related to the relative inexperience of some participants. Although observers reported alignment of content with perceived needs of participants, this may not have been achieved in every workshop as not all were observed.It is worth noting is that there was no assessment associated with the AusSETT Program so we have no way of knowing if participants did achieve competence relevant to the learning objectives. This may be seen as both an enabling factor – in terms of access - and a constraining factor – in terms of accreditation – depending on perspective. Our philosophical view was that we wanted to provide continuous professional development and that at this nascent stage of development of a national community of practice of healthcare simulation educators and technicians, assessment may not have been well received. Also, within the funding model it was not possible to offer robust assessment, but this may be a future step.Overall, the evaluation results give some indication that a national program for simulation educators and technicians is valuable for supporting others in using simulation as an educational method, at least from the perspectives of those who participated as future ‘trainers’. There is one major caveat. Many participants had no or limited experience with simulation and very few had formal qualifications. Indeed the first reason given for enrolling with the program was to “develop, expand or consolidate” skills. The AusSETT program was intended for experienced simulation experts, who could support others, not for those who were novices. In many ways this suggests that a ‘training’ program rather than a ‘train-the-trainer’ (‘educate-the-educator’) program may be more aligned with participants’ needs. However, the question of training others will only be fully answered once the AusSETT alumni have had an opportunity to offer professional development to other cohorts. However, there is no question that the Program promoted individual development and ignited interest in SBE in local facilities.The contractual agreement strongly influenced some elements of the Program’s development and implementation and some of the language used to describe simulation practices – such as those of educator and technician. Although the opportunity to pilot the Program is likely to have reduced the scale of iterative development, the actual adjustments to the Program were minimal. The funding body requested a train-the-trainer model but in many respects we adopted a perspective of ‘educate-the-educator’, especially with respect to sharing theoretical underpinnings of many facets of simulation-based education.The strengths of the study were the objectives-oriented program evaluation design, mixed methods, multiple sources of data (participants and subject matter experts) and the multiple data points collecting baseline, immediate responses after e-learning and workshops and then those in the longer term (two-months), at least for some participants.independent researcher (JH) to play a leading role in data analysis. Finally, in the absence of data-driven accounts of similar programs, it is not possible to discuss our findings in that context.Limitations of the study are that not all participants gave permission to publish their data which accounts for some of the discrepancies in reporting. The data is self-report which may not reflect the actual practices of participants. As internal evaluators, our own biases and assumptions may have influenced the data analysis and that which we have chosen to share from the very large data set. However, we employed an In summary, the evaluation of a national ‘train-the-trainer’ program for simulation educators and technicians suggested the value and need for a nationwide approach to training educators in simulation methodologies. The multi-layered objectives-oriented evaluation identified strengths and weaknesses of the Program with specific recommendations for improving its’ content and processes. We hope that sharing the details of learning objectives and our broader experiences may inform others embarking on simulation educator and technician training course development. The ‘national’ identity was achieved through the scale and diversity of the program in terms of simulation modalities, the geographical spread, breadth of professional disciplines, range of educational methods and the multi-institutional development.