Self-assessment instruments for measuring burnout, depression, anxiety and wellbeing, and data from regional and national registers were used. Results showed decreased scores on burnout, depression and anxiety, and increased well-being scores and significantly reduced health care utilization in the NBR group. A large movement from ordinary sickness benefit to rehabilitation benefit was observed, which was not observed in the OHS group. The two groups were in different rehabilitation phases, which limited comparisons. The results point to beneficial effects of using NBR for this patient group and for enhancing a stalled rehabilitation process.After a period of decrease, sick leave in Sweden due to psychiatric diagnoses is on the increase. The lack of established rehabilitation programmes for patients with stress-related mental disorders (SRMD) has opened up for the use of garden/nature in a multimodal rehabilitation context . Region Västra Götaland (VGR) started an NBR to offer additional rehabilitation for its employees on long-term sick leave due to SRMD, where initial care had not been sufficient. The aim was to explore whether the mental health and well-being of NBR participants had improved at the end of the NBR and at three follow-ups, and to explore the development of sick leave and health care utilization according to the NBR model ( After a peak in 2002, sick leave spells in Sweden began decreasing. However, during the period 2009 to 2012 this downward trend was interrupted; the number of new cases of illness with psychiatric diagnoses has turned upwards again, and is forecasted to soon reach the same high numbers as in 2005 . Mental Long-term exposure to stress can lead to stress-related illness such as depression or fatigue/burnout, anxiety disorder , and/or A considerable amount of research has explored a wide variety of health effects on humans when exposed to nature environments. These include beneficial effects on cognitive abilities and depleted mental resources ,15,16, rattention restoration theory (ART) [psycho-evolutionary theory (PET) [fascination in a soft and unchallenging way; (ii) offering a feeling of being away from everyday demands; (iii) being compatible with the visitor’s current needs; and (iv) having an extent that gives a sense of a cohesive whole but also space for discovery [et al. [There are essentially two theories claiming to explain the beneficial effects of interacting with nature: ry (ART) , and psyry (PET) . ART hasiscovery . These eiscovery ,15,26,27iscovery . These eiscovery ,28,29. F [et al. .The lack of established rehabilitation programmes for patients with stress-related mental disorders (SRMD) has opened up to a rather new approach: Nature-Based Rehabilitation (NBR), originally developed at the Swedish University of Agricultural Sciences at Alnarp. NBR in Sweden often embraces two parts: (1) traditional medical rehabilitation methods used for SRMD such as relaxation, stress management, physiotherapeutic exercises, body awareness, conversational therapy, and handicraft, all of which are professionally integrated into a nature context; and (2) activities, or simply being, in a garden or/and nature. The number of NBRs addressed to individuals with SRMD has grown rapidly in Sweden in the past ten years. Several studies have reported beneficial health effects related to different types of NBR, for instance the importance of the natural environments in the process of recovery from ED and stress-related mental disorder ,31,32. Ftheory of supportive environments [The favourable effects achieved in NBR are explained in the ronments , assuminBecause of increasing numbers of employees on long-term sick leave due to stress-related disorders, Region Västra Götaland (VGR), a large public health care organization in Sweden, started an NBR directed at their own employees. The conventional rehabilitation of employees in VGR is handled by the region’s own occupational health service (OHS), where a team-based rehabilitation model has been developed for this patient group. The NBR was started to offer additional rehabilitation efforts for employees on long-term sick leave due to stress-related mental disorders, where initial care had not been sufficient. The individuals’ rehabilitation process had stalled and no progress was observed. It was thus of great interest to explore what had happened to the group participating in this new intervention.We therefore decided to perform a follow-up study comparing symptoms of burnout, depression, anxiety, and well-being at the start of the NBR with the situation up to twelve months after participation in the programme. We also wished to assess the registered utilization of sickness benefits and health care. Since the NBR was started by VGR as a compliment to the organization’s in-house OHS, we believed it would be interesting to explore the same type of register data among similar patients who had participated in the conventional OHS rehabilitation.The main aim of this observational follow-up study was to explore the effects of NBR in patients with exhaustion disorder or stress-related mental disorders.To explore whether the mental health and well-being of NBR participants had improved at the completion of the rehabilitation as well as six and twelve months thereafter, compared with the start of rehabilitation (Aim 1).To explore the development of sick leave and health care utilization after completed rehabilitation according to the NBR model and the OHS model respectively (Aim 2).The study participants were all employees at Region Västra Götaland (VGR), and had initially contacted either the in-house OHS or primary care for their mental health problem. Sixteen of the NBR participants were medically examined and treated at the OHS, 13 at a specialist clinic within VGR , four by private practitioners, and the remaining 24 at primary health care centres (PC) . ParticiInclusion criteria for participation in the NBR were, besides employment in VGR, diagnosis regarding stress-related mental illness  with prolonged sick leave (more than three months), and that participants had reached a level of recovery sufficient to transport themselves to the NBR. Individuals with other serious mental or physical illness were not included. Participants were also not to be suicidal or likely to have substance abuse problems. The participants had been on sick leave for three months to twelve years when they started the NBR . The NBR group was comprised of 57 participants (53 women), who participated in the NBR during October 2007–June 2014. Mean age was 45 years (range 26–63); for women the mean was 44.8 (range 26–63) and for men 52.3 (range 35–62). Prior to acceptance and consenting to participate in the NBR, each participant visited the NBR for an interview with the psychotherapist on the rehabilitation team, and was offered the possibility to ask questions about the NBR on this occasion.From a total of 72 participants who had completed the NBR during the period, 57 are included in the analysis concerning burnout, depression, anxiety, and well-being. The reasons for excluding the other 15 were: one had died, one could not be reached to be asked about participating in the study, three declined participation in research, one had inappropriate co-morbidity, and nine did not complete the follow-ups, had too many missing data in the questionnaires, or had no baseline data available. The NBR participants had diagnoses covered under the ICD code F43 category , and/or depression (F32), and/or anxiety (F41).To answer the research questions concerning health care utilization and sick leave, 44 participants  from NBR were included. The discrepancy (57/44) was due to continued collection of data from self-assessment questionnaires six months longer than the time frame for collecting register data for health care utilization and sick leave.As depicted in The OHS consisted of 45 female patients  with more than 14 days of prescribed sick leave (before the rehabilitation started) due to ED, reaction to severe stress unspecified, depression or anxiety as described above for the NBR group.The selection of the OHS group was done in two steps. First, participants were matched as closely as possible to the NBR group concerning age, sex, diagnosis and year of rehabilitation start, giving 190 possible participants in this group. Of these, 151 consented to participate in the study; however, sick leave data returned from the Swedish Social Insurance Agency included only142 participants see . Sixty-eThe study was approved by the regional ethical board in Göteborg, Sweden (Dnr (diary number) 566-12). All participants in the study have signed informed consent after being informed about the study and ethical issues.The majority of participants in the NBR group had previously participated in evaluations of the same NBR during October 2007–September 2012. The data from these evaluations were also used for this study, together with data from participants from the NBR from October 2012–June 2014, and additional register data concerning sick leave, health care consumption and diagnosis.There were two methods of recruitment. Participants who had finished NBR in earlier years were contacted by telephone by the first author, who requested their permission to send them, by post, information about the study, a form for informed consent to participate in the study, and a postage-paid return envelope. These telephone calls gave the participants the opportunity to ask questions about the study.For the participants still taking part in the NBR, at the end of their rehabilitation the rehabilitation team gave them an information sheet about the study, the form for informed consent, and a sealable envelope for the consent form together with the self-assessment instruments for the first follow-up. Some participants chose to give their signed consent directly to the team, while some sent it to the first author by post in the postage-paid return envelope. After receipt from a participant, the team handed over the completed self-assessment forms to the first author, and (if not mailed) also the envelope including the informed consent form. All data were thereafter stored in a locked research archive. The participants had the opportunity to ask questions about the study during the first author’s visits in the group. The participants were all aware of the first author’s role as an independent researcher not involved in the rehabilitation.The patient register at the OHS was used to identify individuals for possible inclusion in the reference group. This selection procedure was carried out by staff at the OHS. The matched 190 patients were contacted by phone, informed about the study and asked for their consent to use data from their medical records. They were asked for permission to send them by post information about the study, a form for informed consent on participation in the study, and a postage-paid return envelope. For a smaller number of patients (13) not contactable by phone, the information and consent form were sent by post without previous contact.The rehabilitation was led by a multidisciplinary team composed of a gardener and a biologist from the “green” sector, as well as a physiotherapist, an occupational therapist, and a psycho therapist  from the health care sector. The rehabilitation included garden activities based on the current season, weekly guided walks in the nearby nature reserve, therapeutic painting, therapeutic group as well as individual conversations, guided relaxation in nature and indoors (mostly mindfulness and breathing techniques), body awareness, and information about stress and stress reactions and the benefits of physical activity, as well as about nature’s role in health and stress reduction. A majority of the NBR group had psychotherapeutic contact outside the NBR, and most were also receiving pharmacological treatment (mostly SSRI).This NBR programme was divided into two parts: 16 weeks of rehabilitation, followed by twelve weeks of gradual return to work or study with more and more time at work and a corresponding decrease in participation in the NBR .The site for the NBR bordered an allotment area, a small brook, and a 222-acre nature reserve. The venue consisted of a small house with a conservatory, a garden, and a greenhouse.The rehabilitation at the OHS followed a team-based method entailing separate assessments of the patient made by a nurse, physician, physiotherapist and psychologist. This rehabilitation model did not include any garden or nature content. After interviews and examinations of the patient, the different professionals on the team made an overall assessment of the patient based on the information obtained from the team members. Individuals in the reference group received an individually planned rehabilitation based on five key principles: increased physical activity (prescribed), counselling, medication, individual-adapted prescribed complete or partial sick leave, and close dialogue with the employer/manager to define the tasks and adaptation of work to facilitate return to work as early as possible, without risking a worsening or recurrence of disease. Forty-five participants in the reference group fulfilled the sick leave criteria of at least one month of sick leave during the six months preceding the rehabilitation.When the NBR model was designed, the VGR management decided to evaluate the health effects of this intervention. Instruments for evaluating participants’ mental health and well-being were chosen according to recommendations by the ISM, a research and specialist clinic within VGR for these types of stress-related disorders. These instruments, described in the following section, were not used at the OHS, however.Nature’s role has been documented in previous studies when it comes to restoring mental and emotional exhaustion ,35,39 anWe calculated the mean for the total score and a cut-off at 4.4 to create a dichotomous variable indicating burnout or not, based on recommendations in a newly conducted validation study by Lundgren-Nilsson and colleagues , which aThe Beck Depression Inventory (BDI-II)  is an esThe Beck Anxiety Inventory  is an esThe Psychological General Well-Being Index (PGWB)  is a quaThe instrument has previously been used to explore quality of life in patients with various symptoms and between patients receiving different therapies, and to evaluate a variety of treatments. It has proven to be sensitive to clinically relevant changes . The PGWSMBQ BDI-II, BAI, and PGWB were distributed only to the NBR participants and at four occasions: at the start of NBR (baseline measure), and at three follow-ups at the end of the two periods  included in the NBR, and six and twelve months thereafter .Rehabilitation compensation is a type of benefit granted to an individual when he/she has been judged to be sufficiently rehabilitated so that he/she can participate in work training, in a work-oriented rehabilitation programme or studies. The rehabilitation must be a part of a rehabilitation plan developed in cooperation with the Social insurance agency.Register data from the Swedish Social Insurance Agency’s statistics were collected to compare the sick leave and compensation for participating in occupational rehabilitation (henceforth referred to as rehabilitation compensation) for both study populations (NBR and OHS) for the periods six months before starting rehabilitation, and six and twelve months after finishing the 16 weeks of rehabilitation. The number of days with full- or part-time sick leave/rehabilitation compensation were collected and calculated. From VGR’s register of health care utilization (VEGA), data for number of visits, type of health care contact, and reason for the visit were collected. However, as the OHS did not report to VEGA, responsible staff at the OHS retrieved equivalent and complementary data from the patient records. The number of visits to the doctor, psychologist, physiotherapist and nurse were merged into one variable covering visits to all these medical professionals. The three periods for measuring sick leave and health care utilization are:Period 1 (P1): six months before rehabilitation to starting the 16 weeks of rehabilitation.Period 2 (P2): from completion of the 16 weeks of rehabilitation and six months ahead.Period 3 (P3): from completion of the 16 weeks of rehabilitation and seven to twelve months thereafter .Descriptive statistics are presented as means and standard deviations (continuous variables). Differences in proportion with 95% confidence intervals (CI) between the baseline measures at start of NBR and each of the follow-ups (end of NBR and at six and twelve months) were calculated for SMBQ < 4.4 according to the method suggested by Newcombe . Althougt-test for paired samples was used to analyse the differences in PGWB scores between the baseline measures at start of NBR and each of the follow-ups (end of NBR and at six and twelve months). The Wilcoxon Signed Rank test was used to analyse BDI-II and BAI. All analyses were performed using IBM SPSS  Statistics version 22 The PGWB raw scores were transformed into metric values according to Lundgren-Nilsson and colleagues , thus maMean burnout scores decreased from 5.2 (SD 0.88) at start of NBR rehabilitation to 4.4 (SD 1.16) at the end of NBR, 4.26 (SD 1.28) at six months, and 4.12 (SD 1.26) at twelve-month follow-up. The differences in the proportion scoring below the cut-off of 4.4 between start and all three follow-ups were statistically significant .Mean value of BDI-II at start of NBR was 23.2 (SD = 10.0), and at the three follow-ups 15.6 (SD = 8.7), 14.2 (SD = 8.0) and 13.0 (SD = 8.7), respectively, showing a movement from moderate to mild depression for the group. The number of participants scoring “moderate” or “severe” depression decreased from 52% (divided into: moderate 29% and severe 33%) at start of NBR to 26% (divided into: moderate 22% and severe 4%) at six-month follow-up, and had decreased further to 21% at twelve-month follow-up (divided into: moderate 17% and severe 4%) . p < 0.0001; Most participants (88%) lowered their depression score after rehabilitation. Analyses were performed with Wilcoxon Signed Rank test and all comparisons showed statically significant decreases at each follow-up compared to start of NBR , and for the three follow-ups 12.8 (SD 10.1), 12.1 (SD 8.4) and 10.2 (SD 7.8), respectively, showing a movement from moderate to mild anxiety for the group.The number of participants scoring “moderate” or “severe” anxiety decreased from 47% (divided into: moderate 22% and severe 25%) at start of NBR to 34% (divided into: moderate 30% and severe 4%) at six-month follow-up, and had decreased further to 19% (divided into: moderate 15% and severe 4%) at twelve-month follow-up .p < 0.0001–0.005; Most participants (63%–71%) lowered their anxiety score after rehabilitation. Irrespective of whether analyses were performed with Wilcoxon Signed Rank test and all comparisons showed statically significant decreases at each follow-up compared to start of NBR , and for the three follow-ups 46.7 (SD = 8.8), 47.8 (SD = 9.4) and 49.1 (SD = 10.7), respectively, showing a gradual increase in mean values for the PGWB scores, indicating improvement in the participants’ self-assessed well-being .p < 0.0001; All comparisons showed statistically significant improvement , as were those for P2 and P3 . On the other hand, there was an increase in number of days with rehabilitation compensation, which 71% of this group were receiving during the last follow-up period, and the differences in mean values between P1 and P2 were statistically significant . Although a decrease in number of days with rehabilitation compensation was observed between P2 and P3, this was not enough to reach statistically significant difference (All participants (NBR and OHS) received sick-leave compensation before starting rehabilitation, and more than 90% also did so to some extent during the follow-up periods (P2 and P3). For the NBR group, a decrease in total number of days with sick leave compensation  was observed . The diffference .t = −5.8; df = 44; p < 0.0001). A decrease in number of sick leave days was observed for P3, and the difference was statistically significant between P2 and P3 . As expected, there were no days with rehabilitation compensation before start of rehabilitation in this group. It was not until P3 that this type of compensation became more frequent (p = 0.063).Contrary to the NBR group, the OHS group showed an increase in total number of days with sick leave compensation , and thefrequent , but evep = 0.063).As expected, there were no days with rehabilitation compensation before start of rehabilitation in this group. It was not until P3 that this type of compensation became more frequent , but evet = 4.6; df = 43; p < 0.0001). The visits remained at the same level for the last follow-up period (P3) . However, the mean number of visits decreased between P2 and P3, showing a statistically significant difference . See For the NBR group the mean number of visits for health care consumption decreased, comparing six months before rehabilitation (P1) to the follow-up for the six-month period after completed rehabilitation (P2). This difference was statistically significant  . For theThe main findings in this study were that participants in NBR showed decreased scores of self-assessed burnout, depression, anxiety, and increased scores of well-being at all follow-ups compared to start of rehabilitation. A significant reduction in health care utilization after rehabilitation was also observed. Additionally, a large proportion of the participants increased their level of activity by moving from ordinary sickness benefit to rehabilitation benefit, an important step towards return to work. Considering the fact that the NBR group comprised employees with severe stress-related mental disorders, leading to a history of long-term sick leave despite initial treatment by ordinary health care providers, these results seem very promising, for the individual as well as from an organizational and societal perspective. The exploration of register data on sickness benefits and utilization of care among patients entering the rehabilitation provided by the in-house OHS as well indicated that some were still in need of additional efforts twelve months after finishing the usual rehabilitation programme, in order to be able to return to work. Thus, it seems that the investment of the organization in NBR as a compliment to the conventional OHS may also be rewarding from an employer’s perspective.et al. [What made this restart of the rehabilitation process so seemingly successful? The nature and garden content of the NBR comprised a large part of the time (42%) in the weekly schedule, and we suggest that this played a significant part in the participants’ improvement in mental health. The regular exposure to nature for a rather long time (approximately 28 weeks) may have been decisive, for example, in more thoroughly restoring depleted cognitive resources, reducing stress, and incorporating the benefits of the outdoor relaxation, physical activities and daylight exposure, and the many opportunities for reflection due to experiences of soft fascination. This long exposure may have resulted in positive effects of more profound and long-lasting character. Some studies have demonstrated the beneficial effects on mental health of longer nature exposure, which may support this interpretation ,36,37,39et al.  showed iEnhanced emotional balance and well-being through nature exposure have been reported ,52, offeThe education about nature during the guided walks may also have played an important part in the observed improvement in mental health among the participants. Possibilities to distance oneself from a problematic health situation and focus on some interesting detail in nature allowed space for new perspectives concerning one’s recovery as well. The expectation of a positive effect made individuals more prone to go out into nature again. This is in line with findings by Johnsen and Rydstedt , showingThe NBR also offered a context of social coherence, which would be beneficial to people who have spent a long time in the home on sick leave. Being treated with tolerance and acceptance by a professional rehabilitation team and other participants in the same situation as oneself has earlier been shown to be of importance in the recovery of individuals with ED and other stress-related mental problems ,31.For the NBR group the number of days with partial or full sick leave continuously decreased from baseline to P2 and P3, and a corresponding increase in days with rehabilitation compensation was observed for the NBR group, indicating that the majority (71%) were involved in occupational training, had started to return to work (RTW) or were studying. For the OHS group the results were quite different, with a substantial increase in days with sick leave benefits for P2 and a decrease during P3, but with no substantial increase in rehabilitation compensation. This indicated that there were several participants in the OHS group who had not reached a recovery level to start RTW at P3.This may partially be explained by the fact that the OHS group were in an earlier phase of their stress-related disorder, some of them being less severely ill and thus not in need of rehabilitation compensation, while others needed a longer time to recover and could eventually become candidates for NBR.The benefits of a strong and continuous coaching for the NBR participants available four days/week may have facilitated return to activity. The close involvement with manager/workplace during the whole rehabilitation may also have contributed to this, but such contacts were also prevalent during the OHS rehabilitation. This is in line with Sandahl and colleagues’  suggestiA similar pattern was noted for health care utilization as for sick leave. Interestingly, the visits to medical professionals decreased significantly for P2 and P3 compared to P1.. The participants in the OHS as well as in the NBR group have the same employer, are highly educated and described as high performing professionals. According to the OHS professionals' experiences, the participants involved in the OHS group are equally motivated to participate in the rehabilitation process to regain health and work as those in the NBR group.Comparing the results for sick leave and health care utilization, in both cases P1 has the highest values for the NBR group and P2 for the OHS group, indicating that the two groups are in different phases when starting the respective rehabilitation processA strength of this study is that the results are based on validated instruments and data from regional and national registers; furthermore, twelve months of follow-up is a longer time frame than several other studies have used to follow up effects. There were established clinically relevant cut-off levels for all instruments for measuring mental health except for the PGWB. However, research using the PGWB has shown that a difference of four to seven points can be used as a measure of clinically relevant changes in well-being .These fiIt may be regarded as a limitation that the study has an explorative design. In order to make more firm conclusions about the effectiveness of NBR compared to conventional rehabilitation without nature content, a randomized, controlled design would have been preferable. Our initial ambition was to have a reference group similar to the NBR group, but it became obvious that the only possibility available within the organization at the time was to observe patients going through the rehabilitation provided by the OHS. A comparison could therefore only be performed with the differences between the groups in mind, as discussed above. The study samples were rather small, which resulted in somewhat uncertain estimates, as indicated by the wide confidence intervals. Many of the changes in the health parameters were clearly statistically significant, however. It is desirable that future studies use a controlled design, comparing an NBR intervention with a comparable rehabilitation programme without nature/garden content, and with a larger study population.All the results of this explorative study show that the additional rehabilitation intervention including nature/garden (NBR) may reinforce the rehabilitation of individuals with stress-related mental illness who are still on long-term sick leave after having received initial rehabilitation but who have not made progress. Besides the positive effects it has for the individual to move along in the RTW process, this is of great economic value from organizational and societal perspectives as well. We find it likely that a larger part of the participants in NBR with very long-term sickness absence would not have started their RTW without an effective intervention. Also, the proportion of similar patients who had received the standard rehabilitation by the organization’s in-house OHS but were still on sick leave a year later could be candidates for NBR. Firm multidisciplinary support on a regular basis, the group design of the NBR and the environmental support from nature and garden, collectively, seem to be a valuable aid towards improved mental health and RTW, as well as in reducing health care utilization.


Classical peripheral vestibular disorders rehabilitation is a long and costly process. While virtual reality settings have been repeatedly suggested to represent possible tools to help the rehabilitation process, no systematic study had been conducted so far. We systematically reviewed the current literature to analyze the published protocols documenting the use of virtual reality settings for peripheral vestibular disorders rehabilitation. There is an important diversity of settings and protocols involving virtual reality settings for the treatment of this pathology. Evaluation of the symptoms is often not standardized. However, our results unveil a clear effect of virtual reality settings-based rehabilitation of the patients' symptoms, assessed by objectives tools such as the DHI (mean decrease of 27 points), changing symptoms handicap perception from moderate to mild impact on life. Furthermore, we detected a relationship between the duration of the exposure to virtual reality environments and the magnitude of the therapeutic effects, suggesting that virtual reality treatments should last at least 150 minutes of cumulated exposure to ensure positive outcomes. Virtual reality offers a pleasant and safe environment for the patient. Future studies should standardize evaluation tools, document putative side effects further, compare virtual reality to conventional physical therapy, and evaluate economical costs/benefits of such strategies. As 8The classical therapeutic approach for vestibular disorders relies on vestibular rehabilitation and symptomatic medication , 5. VestHowever, many factors may negatively affect the outcome of vestibular rehabilitation, including incorrect performance of exercises and the necessity of active efforts and interest from the patient , 8. Due Virtual environments are interactive simulations of real world generated by computers and presented to users through media of varying degrees of complexity . Hardware devices can be added to the equipment in order to monitor movement kinematics or provide simulations of force and haptic feedback to participants –13. GiveAlthough the suitability of virtual reality in balance training of participant with vestibular disorders has already been demonstrated , neitherA comprehensive analysis was conducted to compare the efficiency of virtual reality-based rehabilitation on peripheral vestibular disorders. Following a PICOS standardized format, this study investigates patient > 18 years with old peripheral vestibular disorders (population) in the context of virtual reality rehabilitation (intervention). We compared the impact of peripheral vestibular symptoms using validated vestibular disorder questionnaires. This was performed for different virtual reality designs and protocols (comparison), quantifying the clinical improvement of dizziness (outcome). Results of individual studies were combined under the form of a meta-analysis to quantify the improvement of vestibular disorder with virtual reality (study design).Studies—papers published in peer-reviewed journals excluding conference abstracts—using virtual reality-based settings for vestibular disorders rehabilitation were gathered according to the following strategy. A comprehensive search was conducted in MedLine with the following keywords: “vestibular system,” “vestibular dysfunction,” “vertigo,” “equilibrium,” “balance,” “virtual reality,” “virtual treatment,” and “virtual rehabilitation.” Keywords “treatment” or “rehabilitation” were parts of all keyword strategy to optimize the search. Articles in English, French, Spanish, and Portuguese published from 1946 to August 2013 were included in the search. The search was independently performed twice, and references were cross-checked. In addition, references from all identified studies were systematically looked for to find any supplementary sources and ensure that all relevant studies were selected. Titles and abstracts of the 489 articles identified by the search were assessed for pertinence. Of the 489 articles found on MedLine, 316 articles were duplicates and 143 articles were ignored, mainly because they did not assess our primary subject . Studies dealing with rehabilitation on geriatric population only were also excluded, since many confounding factors may be involved in balance disorders in this particular population. Articles about a one-time diagnostic test using virtual reality without a rehabilitation or treatment process were also excluded (12 articles). Finally, we also excluded studies on vertigo of central, neurological, and/or psychiatric origin (13 articles). Three more articles were excluded for not presenting their results or having incomplete results. An initial sample of 5 articles was thus selected for further analyses from the MedLine database. The exact same procedures using an identical selection strategy were used on Google Scholar and on the Cochrane Central Register of Controlled Trials databases. These subsequent searches provided 2 supplementary articles. Therefore, the final sample was composed of 7 studies.Data from studies meeting inclusion criteria were extracted into a standardized database and cross-checked for accuracy. Information regarding the type of balance disorder and age of the patient was extracted from the text and the tables or obtained from the figures.When possible, three measures of efficiency were extracted from the studies. First, the percentage of improvement on the DHI  after the rehabilitation compared to the baseline on the Dizziness Handicap Index (DHI). Second, the percentage of improvement on another scale used by the authors . In case of multiple scales other than the DHI, the most standardized one was favored. Third and last, the average efficiency  was computed in order to provide a more global evaluation of the improvements and to attenuate the potential differences between the assessment tools used across the different studies.The nature of the device used to deliver the virtual reality exposure to patients was recorded  together with the potential addition of a force platform or a treadmill. Studies were further divided into either “passive” or “active” in terms of virtual reality-based rehabilitation. Passive rehabilitation required only eyes or head movements or staying immobile during the treatment. In contrast, active rehabilitation requested complete motions of the body or muscle groups in order to perform demanding movements .When available, tolerability of the rehabilitation and side effects were noted. Finally, the level of validity of each study was assessed with the Oxford grading scale . The OxfU tests were then used to compare the average efficiency, total exposure time, and the number of sessions between “low efficiency” and “high efficiency” studies as well as between studies using “active” versus “passive” virtual reality settings. When normality test successfully passed, Student's t-tests were used. The average efficiency was analyzed as a function of total exposure time and the number of sessions using simple linear regressions.Spearman rank tests were performed to observe whether total exposure time to virtual therapy and the number of treatment sessions were associated with the efficiency of the rehabilitation process, as measured by the DHI, other scales, and the average efficiency. Studies were also subdivided into either “low efficiency” (<20% of improvement on average efficiency) or “high efficiency” (>20% of improvement). This threshold of 20% represents in most dizziness assessment tools an improvement equivalent to a change of handicap category (no handicap/mild handicap/moderate handicap/severe handicap). Nonparametric Mann-Whitney Seven studies fulfilled our criteria , for a tU tests, P = 0.86 for average efficiency, P = 0.53 for DHI evaluations and P = 0.86 for other scales). Efficacy of the virtual rehabilitation was also compared regarding active versus passive settings. Four studies (57%) used a passive approach, while 3 studies (43%) used a more active setting. However, no difference was observed between passive and active settings on average efficiency , DHI scores  and other scales scores .Efficacy of the virtual rehabilitation was compared regarding the type of device used. Average efficiency varied from 4.65% to 43.5% for goggles/headset and from 4.4% to 42.61% for screen/projection. The type of device used did not have an effect on efficiency  and other scales (4.4–51%)). In studies using the DHI, the mean decrease was 26 points over 100 on the scale, allowing patients to lessen their handicap either from severe to moderate or from moderate to mild.P = 0.24 for DHI evaluation, P = 0.09 for other scales and for average efficiency) nor with the number of sessions . Time per session was not related to efficiency either . However, simple linear regressions revealed that the average efficiency was significantly explained by total exposure time ,  or “high efficiency” , . StudiesSurprisingly, although a majority of studies mentioned that the rehabilitation was well tolerated, the side effects were almost never documented. Particularly, none of the studies evaluated motion sickness and/or cybersickness with a validated questionnaire. When mentioned, side effects and tolerability were only briefly described (5 of the 7 studies). In terms of tolerability, no study reported major issues following the use of virtual reality and no significant incident or fall was reported.Only 4 out of the 7 studies had a control group, with only one study randomized . RatingsThis comprehensive analysis confirmed that the utilization of virtual reality in the context of vestibular disorders could be a very valuable approach. Indeed, an improvement of the patients' symptoms has been documented in all the studies examined. With an average evaluation of the vertigo-related handicap going from moderate to mild at the end of the virtual reality-based rehabilitation, these emerging tools should not be neglected among the therapeutic arsenal when dealing with patients suffering from vestibular disorders. However, despite these promising results, further research is needed to document the exact parameters of an optimal protocol and to define the most cost-effective strategies.In the context of defining an evidence-based strategy of virtual reality-based therapies for vestibular disorders, the relative methodological weakness of the studies examined was a major issue. Indeed, none of the selected studies ranked more than 3 on the Oxford grading scale. More worrying, the majority of studies ranked 1 or 2 . These low ratings were mostly due to the absence of control groups, randomized conditions, and blind experiments. However, it should be noted here that, due to the nature of the diseases and of the rehabilitation interventions, blinding of the protocols is almost impossible to reach, partly explaining the relatively low score observed. Unfortunately, the small size of most of the cohorts combined with nonsystematic evaluations made it also difficult to reach absolute conclusions.While increasing the group sizes or multiplying control groups could be difficult to do in the context of costly experiments involving patients and important resources, efforts should be done regarding the rigorousness and standardization of evaluation. For instance, the DHI was not systematically used. While many scales or questionnaires could be used to document vestibular disorder-related handicaps, the DHI still remains one of the most standard and easy to administer assessment tools . A few sIn a practical point of view, a very important issue is which of time spent in virtual reality-based training and the number of session is the key factor to increase the therapeutic effect. Interestingly, the present meta-analysis seemed to suggest that time spent in virtual reality-based therapy contributed more to the average efficiency than the number of sessions. Results unveil that a minimum exposure time of 120–150 minutes is required to detect a quantifiable benefit for the patient. However, the time spent and the number of sessions are intimately related. Furthermore, the effect of intertrial time (time between two consecutive sessions) has been so far overlooked. This parameter should be documented in future studies.Given that time spent in virtual therapy is clearly of importance, longer sessions in a short period of time could be effective and convenient. However, the total duration of a session is strongly depending on the physical state of the patient. Of note, some of the results of this study might appear contradictory. However, that might be explained by the very size of our sample (only 7 studies met our criterions), limiting the overall power of a few analyses.Peripheral vestibular disorders can be heterogeneous in terms of etiology . One of Virtual reality settings are extremely useful for various pathologies . HoweverThis leads us to a second limitation. None of the studies analyzed answered the question of whether virtual reality-based vestibular rehabilitation should be done alone or in combination with conventional vestibular rehabilitation. Intuitively, one could expect that the combination of various therapeutic protocols would have optimal results. However, this has to be demonstrated.Another consideration limiting the use of virtual reality-based settings in rehabilitation medicine is cybersickness. Indeed, due to unnatural and sometimes conflicting multisensory stimuli, exposure to interactive virtual environments can cause discomfort during or after the session, which is referred to as cybersickness –30. SympThe present meta-analysis demonstrates the promising potential of virtual reality-based treatment for peripheral vestibular disorders. Despite significant differences in terms of protocol used and outcomes evaluation, all studies demonstrated that virtual reality-based rehabilitation strategies had a positive effect and were seemingly well tolerated. The main criterion predicting treatment success and magnitude of symptoms improvement is the total time spent in virtual reality training. The complexity of the setting used does not seem to have a direct impact on efficiency, as important results are possible with inexpensive settings. Thus, virtual reality-based rehabilitation represents a potentially promising new avenue to reduce the costs of peripheral vestibular disorders rehabilitation.In conclusion, some recommendations are proposed for future studies to standardize intervention protocols and evaluation tools, document side effects, determine if virtual reality-based rehabilitation should be combined with classical rehabilitation, and define profiles of patients susceptible to benefit from a virtual reality-based rehabilitation as follows.Recommendations for Virtual Reality-Based Treatment Applied to Peripheral Vestibular DisordersUse only validated assessment tool, including the DHI as primary assessing tool.Document clearly the time and number of sessions spent in rehabilitation and time between sessions.Document virtual reality-related side effects (cybersickness) with validated questionnaire, such as Simulator Sickness Questionnaire (SSQ).Document complications of virtual reality rehabilitation such as falls and fractures.Document symptomatic medication taken by the patient.If possible, document the cost of the device and each session.


Androgen receptor plays multiple physiological and pathological roles in human organism. In the current paper, we describe construction and characterization of a novel stably transfected human reporter cell line AIZ-AR for assessment of transcriptional activity of human androgen receptor. Cell line AIZ-AR is derived from human prostate carcinoma epithelial cell line 22Rv1 that was transfected with reporter plasmid containing 3 copies of androgen response regions (ARRs) followed by a single copy of androgen response element (ARE) from the promoter region of human prostate specific antigen (PSA) gene. AIZ-AR cells remained fully functional for more than 60 days and over 25 passages in the culture and even after cryopreservation. Time-course analyses showed that AIZ-AR cells allow detection of AR ligands as soon as after 8 hours of the treatment. We performed dose-response analyses with 23 steroids in 96-well plate format. We observed activation of AR by androgens, but not by estrogens and mineralocorticoids. Some glucocorticoids and progesterone also induced luciferase, but their potencies were 2-3 orders of magnitude weaker as compared to androgens. Taken together, we have developed a rapid, sensitive, selective, high-throughput and reproducible tool for detection of human AR ligands, with potential use in pharmacological and environmental applications. It has broad physiological functions, including developmental and psychological. AR is also involved in several pathological situations, including genesis of prostatic hyperplasia and prostate cancer function or altered pubertal development due to its mutations , 3. EndoC4 is a 1in vivo experiments were carried out in rats  vector , using Kpn-1/Xho restriction enzymes.5 cells in 60 mm culture dishes in 5 mL of the RPMI-1640 medium. Following 48 hours of incubation, the culture medium was replaced by the selection medium supplemented with hygromycin B (0.5 mg/mL). The selection medium was changed every 3–4 days for the period of 3 weeks until a polyclonal population was selected. Subsequently, the cells were transferred to 10 cm culture dishes at the density 300–700 cells per dish and cultured for additional 2 weeks in the selection medium until small colonies were visible. Thereafter, 23 colonies were sub-cloned to 24-well culture plate to obtain monoclonal populations. Clones 8 and 14 were selected for further characterization of resulting transgenic AIZ-AR cells. The use of GMO at Faculty of Science, Palacky University Olomouc was approved by the Ministry of the Environment of the Czech Republic (ref. 91997/ENV/10).22Rv1 cells were transfected with reporter plasmid p3ARR/ARE-luc2P/minP/hygro (4 μg) using Fugene HD transfection reagent and seeded at density 8×104 cells per well. Following 16 h of stabilization, cells were treated with tested compounds and vehicle . After 24 h, medium was replaced by charcoal stripped RPMI-1640 medium supplemented with 10% of MTT (10 mg/mL) and incubated for additional 2 hours. Following the incubation, MTT assay was measured spectrophotometrically at 540 nm using Tecan Infinite M2000 plate luminometer.AIZ-AR cells were seeded in 96-well plates at density 5x10AIZ-AR cells were treated with 100 nM DHT for 24 hours. Cell lysates containing firefly luciferase, having a catalytic activity corresponding to model ligand-treated cells, were isolated. Tested compounds (10 μM) were added to cell lysates and luciferase activity was measured.4 cells per well. Following 16 h of stabilization, cells were treated with tested compounds. After the treatments, cells were lysed and luciferase activity was measured in 96-well plate format using Tecan Infinite M2000 plate luminometer.AIZ-AR cells were seeded in 96-well plates at density 5x1050 and IC50 values were performed using GraphPad Prism version 6.00 for Windows, GraphPad Software, La Jolla California USA (www.graphpad.com).Student’s pair t-test as well as calculations of ECHuman prostate carcinoma epithelial cell line 22Rv1 was transfected by lipofection with a reporter plasmid p3ARR/ARE-luc2P/minP/hygro. Stably transfected population of AIZ-AR cells were selected using hygromycin B, as described in Materials and Methods section. We obtained 23 hygromycin B-resistant clones that showed the same morphology as parental 22Rv1 cell line. We tested the responsiveness of clones to 5α-dihydrotestosterone (DHT), a model AR agonist. Cells were treated with DHT (100 nM) and vehicle  for 24 hours. Four clones displayed an induction of luciferase activity after the DHT treatment  with fold inductions ranging from 7.6-fold to 12.1-fold . Clones 4 cells per well. Following 16 h of stabilization, cells were treated for 24 h with AR agonists including DHT (0.1 nM-100 μM), testosterone (10 nM) and danazol (100 nM). No significant difference was observed between cryopreserved and fresh cells in terms of fold inductions and EC50 values  after each passage of the cells. The induction of luciferase activity by DHT was stable for more than 2 months of AIZ-AR cells in culture, which corresponds to 27–28 passages. Even though there was some variability between passages, there was no systematic decline or decrease in luciferase induction in both absolute RLU values and fold induction magnitude .In the first series of experiments, AIZ-AR cells were incubated with DHT (100 nM) for 24 h, 48 h and 72 h. Absolute luciferase activity (RLU) progressively grew with increasing time of incubation and ranged between 4000 and 8000 RLU. However, fold induction over the vehicle-treated cells remained nearly constant, regardless the time of incubation . Therefo50 values ranging from 1.2 μM to 5.4 μM  Cytotoxicity of tested compounds (up to 10 μM) using standard MTT test as described in the methods. Of 23 substances, significant cytotoxicity after 24 h was observed for spironolactone, mifepristone, raloxifene hydrochloride, 4-hydroxytamoxifen and tamoxifen citrate, with ICo 5.4 μM ; (ii) In50  values were calculated. In antagonist mode, cells were treated with increasing concentrations of tested compounds in combination with model AR agonists DHT (100 nM) or testosterone (10 nM). Where appropriate, IC50  values were calculated.Dose-response analyses assays were performed in two different experimental layouts. In agonist mode, cells were treated with increasing concentrations of tested compounds and ECIn agonist mode, androgens testosterone, DHT and danazol produced typical dose-dependent sigmoid curves. Antiandrogens cyproterone acetate and spironolactone displayed partial agonist and antagonist patterns, respectively ; Table 350 values for these antiandrogens were approximately 10 times higher in DHT-treated cells as compared to testosterone-treated cells . Interestingly, in concentration of 10-5 M, luciferase activity remained augmented when DHT was used as agonist, while it dropped to 60%- 120% of initial agonist-induced activity, when testosterone was used as agonist . AIZ-AR cell line provides a tool for high-throughput and sensitive identification and characterization of compounds with androgenic and anti-androgenic activity. Cell line AIZ-AR allows detection of androgens as soon as after 8 hours of incubation, and it remains fully functional for more than 28 passages and over 67 days in culture as well as after freeze/thaw cycle.in vitro tool for identification and characterization of synthetic androgens and antiandrogens in the process of drug design and development is of value. Since androgen receptor active substances influence hormonal homeostasis, they are referred as to endocrine disruptors. Indeed, there are numerous reports on the use of gene reporter assays in environmental [Reliable, rapid, sensitive, selective and high throughput tools for assessment of transcriptional activities of nuclear receptors, steroid receptors and xenoreceptors, are needed for various purposes. Drugs targeting androgen receptor are widely used in human pharmacotherapy, e.g. non-steroid antiandrogen flutamide for the treatment of prostate cancer. Therefore, onmental , cosmetionmental  or food onmental .Experimental models differ in their complexity and species-specificity, which has an impact on the reliable and credible transfer of the data to human pharmacology and toxicology. Besides the properties indicated above, the major strengths of AIZ-AR cell line presented here are: (i) AIZ-AR cell line is an exclusively human system; i.e. human maternal cell line, containing endogenous human receptor AR, stably transfected with reporter gene driven by binding sequence from human gene. (ii) AIZ-AR cell line conserves cell signaling stoichiometry; since AIZ-AR cell line contains endogenous human AR, without extra co-transfected AR vector, the stoichiometric ratio between the AR receptor protein and other transcriptional regulators reflects natural situation rather than artificial one with over-expressed AR. The characteristics given above clearly demonstrate significant advancements and added value for AIZ-AR cell line, as compared to yet developed cell lines. Indeed, existing experimental models, such as human AR-LUX  and MDA-


These compounds have been synthesized by various routes from reaction between amine, aldehyde, and phosphite compounds. In order to synthesize α-aminophosphonates, catalytic effect of CuCl2 was compared with FeCl3. Also all designed structures as well as griseofulvin were docked into the active site of microtubule (1JFF), using Autodock program. The results showed that the reactions were carried out in the presence of CuCl2 in lower yields, and also the time of reaction was longer in comparison with FeCl3. The chemical structures of the new compounds were confirmed by spectral analyses. The compounds were investigated for antifungal activity against several fungi in comparison with griseofulvin. An indole-derived bis(α-aminophosphonates) with the best negative ΔG in docking study showed maximum antifungal activity against Microsporum canis, and other investigated compounds did not have a good antifungal activity. The activity of α-aminophosphonates as pharmacogenic agents [The mediates –5. As a c agents  is reporc agents , 8, antic agents , 10, antc agents –13, and c agents .3 [3 [3/Al2O3 [5-SiO2 [3CO2H [3·Et2O [n    [4)n [2·8H2O [4)2·6H2O [2 [α-aminophosphonates using a three- component system composing of aldehydes/ketones, amines, and diethylphosphite under neat conditions. Recently, we have reported one-pot three-component synthesis starting from aldehydes, amines and diethylphosphite using FeCl3 as a catalyst to formation of α-aminophosphonates [3 suffers from being hygroscopic and is also a corrosive material, in this study the catalyst effect of CuCl2 was compared with FeCl3 for α-aminophosphonates preparation.Three-component synthesis starting from aldehydes, amines and diethyl phosphite or triethyl phosphite have been reported by using Lewis and Bronsted acid catalysts such as LiClO4 , InCl3 [3 , AlCl3 [3 [3 , lanthan3 [3 , SbCl3/A[3/Al2O3 , TaCl5-S [5-SiO2 , CF3CO2H2 [3CO2H , scandiu2 [3CO2H , BF3·Et22O [n    , and M(C    [4)n , though, [2·8H2O  or ZrO(C4)2·6H2O  and TiO2·6H2O [2  are repophonates . As FeClα-aminophosphonates have antifungal and cytotoxic activity [α-aminophosphonates was designed having aromatic aldehydes and amines with Cl and methoxy moiety similar to griseofulvin structure. Griseofulvin inhibits the growth of fungal cells by inducing abnormal mitosis. It has been reported that griseofulvin blocked the cells at G2/M phase of cell cycle and caused a significant depolymerisation of the spindle microtubules [α-aminophosphonates in comparison with griseofulvin.As it has been reported that activity , 8, 29, otubules . Becauseotubules , therefoα-aminophosphonates, the three components, aldehyde , aromatic amine , and diethyl phosphate (5.5 mmol), were reacted in the presence of catalytic amount (0.1 mmol) of FeCl3 or CuCl2  in the presence of FeCl3, but CuCl2 was not an effective catalyst like FeCl3. The results of this study are summarized in In order to synthesize or CuCl2 . The rea1, 8, 11, 12, 14, and 20 was carried out in the presence of catalytic amount of FeCl3 or CuCl2  in the presence of FeCl3 . The results are presented in 1, 7, and 9 showed very low antifungal activity against Trichophyton mentagrophytes. Compound 1 also showed very low antifungal activity against Microsporum gypseum. Compound 21 was the most active compound against Microsporum canis. This compound was previously evaluated in vitro for cytotoxicity effect and showed moderate cytotoxicity activity [μg/mL, and the MIC for compound 21 was better than MIC for griseofulvin. Compound 21 is a bis-phosphonate, and it has an indole ring system, perhaps this moiety causes its antifungal activity. Also this compound had the better ΔG in docking study. Nevertheless, it has been reported that aminophosphonates have antifungal activity against phytopathogenic fungi [The synthesized compounds activity ; here thic fungi , 14; ouric fungi ; therefoAll solvents and reagents were purchased from Sigma or Merck Chemical Companies. The products were purified by column chromatography techniques. NMR spectra were recorded on a Brucker Avance DPX 500 MHZ instrument. Mass spectra were recorded on a Hewlett-Packard GC-MS.2O (10 mL). The organic phase was separated and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and the resulting crude material was purified by chromatography on a short column of silica gel  and then recrystallized from petroleum benzine/dichloromethane (4/1) to afford the pure α-aminophosphonates.To a mixture of aldehyde (2 mmol), amine (1 mmol), and diethylphosphite (2.2 mmol) was added FeCl3 in THF (0.1 mmol) and stirred at 60°C for the appropriate reaction time. After completion of the reaction, EtOAc (10 mL) was added to the mixture. The mixture was washed with H1H NMR : 7.15 , 7.04 , 6.98 , 6.90 , 6.74 , 6.64 , 4.72 , 4.12–4.18 , 3.97–4.02 , 3.87 , 3.72–3.77 , 1.32 , 1.18 ; 13C NMR : 147.35 (Ar-C), 146.93 (Ar-C), 146.81 (Ar-C), 145.97 (Ar-C), 129.57 (Ar-C), 127.87 (Ar-C), 114.93 (Ar-C), 114.32 (Ar-C), 110.67 (Ar-C), 63.72 , 56.38 , 55.64 (OCH3), 16.87 , 16.70 ; MS: (m/z%), 363 , 228 (100), 137 (9.3).This compound was synthesized after 120 min (84%. Mp = 95.4°C). 1H NMR : 8.07 , 6.96 , 6.64 , 5.72 , 4.75 , 4.12–4.21 , 3.98–4.03 , 3.85 , 3.70–3.75 , 1.34 , 1.18 ; 13C NMR : 154.06 (Ar-C), 152.21 (Ar-C), 136.66 (Ar-C), 130.45 (Ar-C), 126.53 (Ar-C), 112.88 (Ar-C), 105.12 (Ar-C), 64.03 , 59.74 , MS: (m/z%), 545 , 317 (100), 271 (5), 181 (5.7).This compound was synthesized after 150 min (72%. Mp = 89.4°C). 1H NMR : 8.04 , 7.00 , 6.97 , 6.95 , 6.64 , 5.86 , 4.76 , 4.13–4.2 , 3.95–4.00 , 3.88 , 3.67–3.76 , 1.32 , 1.17 ; 13C NMR : 152.34 (Ar-C), 147.52 (Ar-C), 146.38 (Ar-C), 139.45 (Ar-C), 126.49 (Ar-C), 126.44 (Ar-C), 121.35 (Ar-C), 115.18 (Ar-C), 112.86 (Ar-C), 110.47 (Ar-C), 64.04 , 56.38 , 55.07 (OCH3)MS: (m/z%), 410 , 273 (100), 227 (8.8), 137 (7.7).This compound was synthesized after 180 min (78%. Mp = 138.1°C). 1H NMR : 6.72 , 6.68 , 6.31 , 6.11 , 4.60 , 4.11–4.19 , 3.98–4.03 , 3.84 , 3.81 , 3.75–3.79 , 1.32 , 1.18 ; 13C NMR : 153.77 (Ar-C), 150.23 (Ar-C), 142.66 (Ar-C), 141.55 (Ar-C), 138.04 (Ar-C), 132.17 (Ar-C), 113.25 (Ar-C), 105.21 (Ar-C), 100.5 (Ar-C), 63.65 , 57.10 , 56.91 (OCH3), 56.58 (OCH3), 56.1 (OCH3), 16.88 , 16.70 ; MS: (m/z%), 469 , 331 (100), 300 (3.5), 195 (11.9).This compound was synthesized after 120 min (87%. Mp = 105°C). 1H NMR : 8.04 , 7.01 , 6.86 , 6.62 , 5.87 , 4.74 , 4.13–4.18 , 3.94–3.98 , 3.69–3.74 , 1.32 , 1.16 ; 13C NMR : 152.35 (Ar-C), 149.78 (Ar-C), 149.60 (Ar-C), 139.45 (Ar-C), 127.15 (Ar-C), 126.48 (Ar-C), 120.63 (Ar-C), 112.86 (Ar-C), 111.67 (Ar-C), 111.08 (Ar-C), 63.98 , 56.32 , 55.03 (OCH3), 56.58 (OCH3), 16.85 , 16.70 ; MS: (m/z%), 424 , 287 (100), 241 (7), 149 (2.9).This compound was synthesized after 180 min (80%. Mp = 99.2°C). 1H NMR :6.96 , 6.94 , 6.7 , 6.45 , 4.67 , 4.09–4.17 , 3.96–4.01 , 3.85 , 3.72–3.77 , 2.24 , 1.29 , 1.16 ; 13C NMR : 153.86 (Ar-C), 145.98 (Ar-C), 138.28 (Ar-C), 132.85 (Ar-C), 131.41 (Ar-C), 121.55 (Ar-C), 118.32 (Ar-C), 111.78 (Ar-C), 105.14 (Ar-C), 63.76 , 57.30 , 56.60 (OCH3), 17.47 (CH3), 16.84 , 16.66 ; MS: (m/z%), 457 , 320 (100), 181 (6.6).This compound was synthesized after 120 min (76%. Mp = 107°C). 1H NMR : 7.40 , 6.97 , 6.92 , 6.64 , 6.43 , 4.71 , 4.11–4.19 , 3.95–4.00 , 3.82 , 3.71–3.76 , 2.25 , 1.32 , 1.17 ; 13C NMR : 159.88 (Ar-C), 145.85 (Ar-C), 132.83 (Ar-C), 131.35 (Ar-C), 129.19 (Ar-C), 127.54 (Ar-C), 121.59 (Ar-C), 118.10 (Ar-C), 114.63 (Ar-C), 111.71 (Ar-C), 63.68 , 56.28 , 55.66 (OCH3), 17.48 (CH3), 16.86 , 16.68 ; MS: (m/z%), 397 , 260 (100), 121 (17.8).This compound was synthesized after 120 min (77%. Mp = 102.4°C). 1H NMR : 7.13 , 7.04 , 6.85 , 6.72 , 6.63 , 4.72 , 4.10–4.17 , 3.96–4.01 , 3.88 , 3.71–3.76 , 1.31 , 1.17 ; 13C NMR : 149.52 (Ar-C), 149.14 (Ar-C), 146.87 (Ar-C), 129.56 (Ar-C), 128.65 (Ar-C), 120.63 (Ar-C), 118.84 (Ar-C), 114.31 (Ar-C), 111.54 (Ar-C), 111.25 (Ar-C), 63.64 , 56.83 , 56.30 (OCH3), 16.88 , 16.72 ; MS: (m/z%), 379 , 242 (100), 151 (17.8).This compound was synthesized after 120 min (82%. Mp = 103°C). 1H NMR : 8.22 , 7.30 , 6.99 , 6.93 , 6.71 , 4.82 , 4.03–4.14 , 3.96–3.99 , 3.91 , 3.71–3.76 , 1.28 , 1.17 ; 13C NMR : 147.53 (Ar-C), 146.42 (Ar-C), 143.15 (Ar-C), 136.59 (Ar-C), 133.52 (Ar-C), 126.41 (Ar-C), 126.03 (Ar-C), 122.01 (Ar-C), 121.05 (Ar-C), 116.66 (Ar-C), 115.14 (Ar-C), 110.21 (Ar-C), 64.11 , 56.46 , 55.23 (OCH3), 16.84 , 16.75 ; MS: (m/z%), 444 , 307 (100), 290 (23.5), 273 (41.1), 151 (26.4).This compound was synthesized after 180 min (70%. Mp = 187.4°C). 1H NMR : 7.00 , 6.81 , 6.64 , 6.26 , 6.09 , 4.60 , 4.07–4.16 , 3.93–3.98 , 3.85 , 3.75 , 3.69–3.73 , 1.29 , 1.14 ; 13C NMR : 150.20 (Ar-C), 149.50 (Ar-C), 142.53 (Ar-C), 141.61 (Ar-C), 141.48 (Ar-C), 128.82 (Ar-C), 120.61 (Ar-C), 113.27 (Ar-C), 111.50 (Ar-C), 111.26 (Ar-C), 105.19 (Ar-C), 100.52(Ar-C), 63.60 , 56.90 , 56.32 (OCH3), 56.05 (OCH3), 16.86 , 16.70 ; MS: (m/z%), 425 , 288 (100), 272 (3.5), 1490 (8.3).This compound was synthesized after 120 min (81%. Mp = 103.2°C). 1H NMR : 7.16 , 6.75 , 6.65 , 4.80 , 4.10–4.17 , 3.99–4.03 , 3.85 , 3.75–3.79 , 1.32 , 1.18 ; 13C NMR : 153.76 (Ar-C), 146.92 (Ar-C), 131.96 (Ar-C), 129.61 (Ar-C), 118.96 (Ar-C), 114.27 (Ar-C), 105.23 (Ar-C), 63.72 , 56.81 , 56.57 (OCH3), 56.21 (OCH3), 16.87 , 16.70 ; MS: (m/z%), 409 , 272 (100), 181 (5.4).This compound was synthesized after 30 min (81%. Mp = 109°C). 1H NMR : 7.42 , 7.13 , 6.90 , 6.72 , 6.72 , 6.63 , 4.78 , 4.76 , 4.11–4.17 , 3.96–4.0 , 3.80 , 3.71–3.76 , 1.32 , 1.17 ; 13C NMR : 159.74 (Ar-C), 146.79 (Ar-C), 129.57 (Ar-C), 129.38 (Ar-C), 128.11 (Ar-C), 118.76 (Ar-C), 114.47 (Ar-C), 114.31 (Ar-C), 63.62 , 55.87 , 55.64 (OCH3), 16.85 , 16.68 ; MS: (m/z%), 349 , 212 (100), 121 (3.9).This compound was synthesized after 60 min (76%. Mp = 102°C). 1H NMR : 8.84 , 8.19 , 6.67–677 , 4.79 , 4.09–4.14 , 4.03–4.07 , 3.97-3.99 , 3.84 , 1.31-1.25 ; 13C NMR : 154.6 (Ar-C), 143.17 (Ar-C), 143.06 (Ar-C), 138.53 (Ar-C), 136.66 (Ar-C), 130.09 (Ar-C), 130.06 (Ar-C), 126.38 (Ar-C), 122.15 (Ar-C), 116.67 (Ar-C), 64.19 , 64.02 , 56.66 (OCH3), 56.32 , 16.82 , 16.73 ; MS: (m/z%), 488 , 351 (100), 195 (8.7).This compound was synthesized after 90 min (75%. Mp = 137°C). 1H NMR : 7.53 , 7.38 , 7.29-7.32 , 7.15 , 6.74 , 6.65 , 4.82 , 4.11–4.21 , 3.96–4.01 , 3.70–3.75 , 1.33 , 1.16 ; 13C NMR : 146.80 (Ar-C), 136.35 (Ar-C), 129.60 (Ar-C), 129.02 (Ar-C), 128.34 (Ar-C), 128.30 (Ar-C), 118.82 (Ar-C), 114.29 (Ar-C), 63.72 , 63.66 , 56.50 , 16.88 , 16.64 ; MS: (m/z%), 319 , 182 (100).This compound was synthesized after 90 min (73%. Mp = 77°C). 1H NMR : 6.99–7.01 , 6.82 , 6.63 , 6.29 , 6.08 , 4.65 , 4.59 , 4.07–4.16 , 3.93–3.98 , 3.85 , 3.74 , 3.69–3.74 , 1.29 , 1.14 ; 13C NMR : 150.20 (Ar-C), 149.50 (Ar-C), 149.10 (Ar-C), 142.53 (Ar-C), 141.55 (Ar-C), 128.82 (Ar-C), 120.63 (Ar-C), 113.27 (Ar-C), 111.50 (Ar-C), 111.26 (Ar-C), 105.19 (Ar-C), 100.52 (Ar-C), 63.63 , 63.58 , 57.03 , 56.99 (OCH3), 56.32 (OCH3), 56.23 (OCH3), 56.05 (OCH3), 16.86 , 16.70 ; MS: (m/z%), 439 , 302 (100), 151 (6.6).This compound was synthesized after 45 min (75%. Mp = 115°C). J = 6.1 Hz, ArH), 6.46 , 4.71 , 4.66 , 4.09–4.19 , 3.96–4.01 , 3.89 , 3.71–3.76 , 2.24 , 1.31 , 1.29 ; 13C NMR : 147.45 (Ar-C), 146.17 (Ar-C), 145.09 (Ar-C), 132.82 (Ar-C), 131.38 (Ar-C), 127.24 (Ar-C), 121.65 (Ar-C), 121.13 (Ar-C), 118.21 (Ar-C), 115.12 (Ar-C), 111.79 (Ar-C), 110.63 (Ar-H), 63.91 , 63.73 , 56.41 (OCH3), 56.13 , 17.47 (CH3), 16.85 , 16.68 ; MS: (m/z%), 413 , 276 (100), 137 (10.6).This compound was synthesized after 90 min (64%. Mp = 152.4°C). 1H NMR : 7.01 , 6.95–6.98 , 6.91 , 6.65 : 7.02 , 6.97 , 6.87 , 6.64 , 6.44 , 4.69 , 4.68 , 4.1–4.16 , 3.96–4.01 , 3.9 , 3.71–3.75 , 2.24 , 1.32 , 1.17 ; 13C NMR : 149.61 (Ar-C), 149.32 (Ar-C), 145.95 (Ar-C), 132.84 (Ar-C), 131.37 (Ar-C), 128.03 (Ar-C), 121.56 (Ar-C), 12.43 (Ar-C), 118.20 (Ar-C), 111.79 (Ar-C), 111.66 (Ar-C), 111.12 (Ar-H), 63.81 , 63.62 , 56.38 (OCH3), 56.27 (OCH3), 56.11 , 17.49 (CH3), 16.87 (CH3), 16.72 , 16.68 ; MS: (m/z%), 427 , 290 (100), 151 (9.6).This compound was synthesized after 90 min (70%. Mp = 135.2°C). 1H NMR : 8.87 , 8.18 , 6.99 , 6.87 , 6.69 , 4.8 , 4.09–4.12 , 3.97–4.09 , 4.03–4.06 , 3.89 , 1.23–1.32 ; 13C NMR : 149.81 (Ar-C), 149.65 (Ar-C), 143.15 (Ar-C), 136.56 (Ar-C), 133.52 (Ar-C), 126.39 (Ar-C), 121.98 (Ar-C), 12030 (Ar-C), 116.66 (Ar-C), 111.72 (Ar-C), 110.88 (Ar-C), 64.16 , 63.97 , 56.44 (OCH3), 56.31 (OCH3), 55.77 , 16.84 , 16.76 ; MS: (m/z%), 458 , 321 (100), 165 (14).This compound was synthesized after 120 min (65%. Mp = 161°C). 1H NMR : 8.0 , 7.42 , 6.89 , 6.64 , 6.37 , 4.81 , 4.13–4.2 , 3.99–3.94 , 3.79 , 3.67–3.72 , 1.30 , 1.16 ; 13C NMR : 160.08 (Ar-C), 152.68 (Ar-C), 139.13 (Ar-C), 129.43 (Ar-C), 126.83 (Ar-C), 126.42 (Ar-C), 114.70 (Ar-C), 112.79 (Ar-C), 64.20 , 63.68 , 55.67 (OCH3), 55.29 ; MS: (m/z%), 394 , 257 (100), 211 (18), 121 (3.8).This compound was synthesized after 120 min (76%. Mp = 115°C). 1H NMR : 8.24 , 7.70 , 7.16 , 6.78 , 6.58 , 4.89 , 4.87 , 4.17–4.23 , 4.06–4.16 , 3.90–3.95 , 1.34 , 1.23 ; 13C NMR : 148.07 (Ar-C), 146.06 (Ar-C), 144.49 (Ar-C), 129.79 (Ar-C), 129.06 (Ar-C), 124.19 (Ar-C), 119.55 (Ar-C), 114.24 (Ar-C), 64.16 , 63.9 , 56.48 , 16.84 , 16.67 ; MS: (m/z%), 364 , 227 (100), 181 (23.8), 104 (3.6).This compound was synthesized after 90 min (73%. Mp = 77°C). This compound was previously synthesized .The ligands were drawn in the Hyperchem 8. The geometry was optimized through the molecular dynamic method AMBER and semiempirical method PM3. The microtubule complexed with paclitaxol was obtained from Protein Data Bank (1JFF).The Autodock software version 4.2 was used for the molecular docking process. The grids were constructed around the proteins. The Lamarckian Genetic Algorithm method was used for the global optimum binding position search. A number of 100 cycles of calculation were used in order to get a final binding position as accurate as possible. All the compounds as well as griseofulvin were docked into the active site of 1JFF. The complex of ligand-receptor was viewed by Accelry's Discovery Studio Visualizer. The docking procedure was run, and the maximum negative ΔG was calculated .M. canis, T. mentagrophytes, T. rubrum, E. floccosum, and C. albicans were purified and subcultured on SC, SCC, and PDA media before testing. The stock solution of compounds was prepared in DMSO at a concentration of 200 mg/mL. The compounds were diluted in solid and broth media to obtain final concentration from 0.0625 to 2048 μg/mL, using PDA and RPMI 1640 media. The inocula of the molds and yeast were prepared from 2–10 day mature colonies grown. Fluconazole and griseofulvin were used as positive and the solvents of the compounds as negative blanks.Microorganisms were obtained from the Mycology and Parasitology Department of the Shiraz University of Medical Sciences. Sabouraud dextrose agar (SDA), potato dextrose agar (PDA), and RPMI 1640 were used for agar dilution and microdilution methods. The clinical isolates of fungi including α-Aminophosphonates are valuable compounds to be investigated as bioactive molecules and pharmacological agents. Recently, we have reported one-pot three-component synthesis starting from aldehydes, amines, and diethylphosphite using FeCl3 as a catalyst to formation of α-aminophosphonates [α-aminophosphonates using FeCl3 was compared with CuCl2. The results showed that FeCl3 is more efficient than CuCl2 as a catalyst for synthesis of α-aminophosphonates.phonates . In thisα-aminophosphonates has antifungal activity against M. canis. The docking results show that these compounds are candidate for cytotoxic activity studies.The biological assays show that only an indole containing bis-


Background. The effective development of healthcare competencies poses great educational challenges. A possible approach to provide learning opportunities is the use of augmented reality (AR) where virtual learning experiences can be embedded in a real physical context. The aim of this study was to provide a comprehensive overview of the current state of the art in terms of user acceptance, the AR applications developed and the effect of AR on the development of competencies in healthcare.Methods. We conducted an integrative review. Integrative reviews are the broadest type of research review methods allowing for the inclusion of various research designs to more fully understand a phenomenon of concern. Our review included multi-disciplinary research publications in English reported until 2012.Results. 2529 research papers were found from ERIC, CINAHL, Medline, PubMed, Web of Science and Springer-link. Three qualitative, 20 quantitative and 2 mixed studies were included. Using a thematic analysis, we’ve described three aspects related to the research, technology and education. This study showed that AR was applied in a wide range of topics in healthcare education. Furthermore acceptance for AR as a learning technology was reported among the learners and its potential for improving different types of competencies.Discussion. AR is still considered as a novelty in the literature. Most of the studies reported early prototypes. Also the designed AR applications lacked an explicit pedagogical theoretical framework. Finally the learning strategies adopted were of the traditional style ‘see one, do one and teach one’ and do not integrate clinical competencies to ensure patients’ safety. Augmented reality (AR) supplements the real world with virtual objects, such that virtual objects appear to coexist in the same space as the real world . It has •AR provides rich contextual learning for medical students to aid in achieving core competencies, such as decision making, effective teamwork and creative adaptation of global resources towards addressing local priorities .•AR provides opportunities for more authentic learning and appeals to multiple learning styles, providing students a more personalized and explorative learning experience.•The patients’ safety is safeguarded if mistakes are made during skills training with AR.While information technology has been presented as a driver for educational reforms, technology, by itself, is not a vehicle for learning . To prevThere are two systematic reviews about AR; one is on AR in rehabilitation to improve physical outcomes , and theThe aim of this study was therefore to investigate of the current state of AR in healthcare education and its reported strengths and weaknesses of the reported AR applications for education in healthcare.We conducted an integrative review, as described by In order to present a comprehensive overview of AR relative to healthcare education, we used broad inclusion criteria. An article was included in the review if it was a research paper (*), on AR (**), or on AR in healthcare education (***), and was written in English. The criteria of inclusion and exclusion were further defined as follows in Clarification of criteria terms:•Research paper. There is no widespread accepted set of criteria with which to assess the quality of studies. Further, research paradigm is different across the various members of the academic community, such as developer, educator and doctor. We have not restricted the methodology and the writing style of the research papers but they should contain the following core information; clear description of the context, study aims, research question, study design, sampling, data collection and analysis, and findings. Papers were excluded if they did not describe the core information mentioned above.•AR. Augmented reality, which sometimes is referred to as ‘mixed reality‘, or ‘blended reality,’ is a technology that allows a live real-time direct or indirect real-world environment to be augmented/enhanced by computer-generated virtual imagery information ’ to combine with the terms one another when searching for papers to include. Also, we used symbols like ‘medic * education’ to include more related articles with potentially different endings.EZ independently searched for eligible studies in the six databases using the methods above and identified each article meeting the inclusion criteria. ‘Medical education’ and synonyms were searched in ‘all areas’ in the six databases throughout the search procedure. We began by searching for ‘augmented reality,’ or synonyms, plus ‘medical education’ in all areas to get the overall data. Next, ‘augmented reality,’ or its’ synonyms, were searched within the title or abstract field, but with ‘medical education’ in ‘all areas.’ One reason for this is that we felt the focus terms should be placed in the title or abstract. Another reason is that the papers in which augmented reality was neither in the title nor abstract, were not studying augmented reality when we reviewed them. When the abstract contained insufficient information we sometimes referred to the full text to assess eligibility. This was then discussed with NZ and IM. After confirming that the paper’s title and abstract discussed augmented reality on medical education, the full text was downloaded and printed to re-read and analyze, if it met the review criteria. EZ examined and marked the full texts to select the articles that met the inclusion criteria. AH checked the excluded papers by EZ to ensure we did not leave out any papers that should include. NZ checked the full text and discussed with EZ. IM was involved in the discussions and selection process when necessary. The quality of the studies was then reviewed by all the co-authors for final inclusion.We extracted information specifically on research, technology and learning from the included studies. The characteristics and the results of the included studies were recorded with a standardized data-extraction form. Data were extracted independently and in tripartite for all characteristics. Three main characteristics, including research, technology and learning, and eleven sub-characteristics were described through qualitative content analysis for each of the included studies . Also, wWe found 2,529 papers on AR in medical education in the above-mentioned six databases. After screening the titles and abstracts, we found 270 citations in the titles and 179 in the abstracts that included ‘augmented reality’, ‘mixed reality’ or ‘blended reality.’ These terms were selected to keep focus on the key characteristics that we wanted to scrutinize and identify. After further reading of the title and abstracts, and removal of any duplicate papers, 77 full-text papers were retrieved and reviewed in more detail. Twenty-five articles met our inclusion criteria for data extraction and were analyzed. From the included 25 research papers focusing on AR in healthcare education, 20 were based on quantitative research methods, 3 on qualitative research methods and 2 on mixed research methods. In these studies, AR was applied on 15 healthcare related subjects. Most of studies used their own AR system and 5 groups used the same system.We chose to apply a broad inclusion criteria and no restriction with regard to the papers’ methodology since research on AR is still in an early innovative phase. Methodological quality was presented adapting the Medical Education Research Study Quality Instrument (MERSQI) . QualityThe earliest study on AR in healthcare education was published in 2002 but publications in the field take off starting in 2008 see . Fig. 2 Across the studies we saw high variability in the research aims and also the role of AR in healthcare education . Twelve The research results showed that learners can accept AR as a learning technology, and that AR can improve the learning effect by acquisition of skills and knowledge, understanding of spatial relationships and medical concepts, enhancing learning retention and performance on cognitive-psychomotor tasks, providing material in a convenient and timely manner that shortens the learning curve, giving subjective attractiveness, and simulating authentic experiences see .Most of the included papers (50%) employed mobile laptops. Four studies used smaller mobile devices such as smart phone, tablet, PDA and e-book readers. Seven papers used stationary desktop computers. Three papers did not mention which computing system they used in their studies.Of the included papers, 68% used a camera and marker as a tracking device. Two papers used an electromagnetic tracker but different markers; one a radiographic marker and one used anatomical landmarks. Two papers used sensors. Other tracking systems, such as hybrid optical tracker and Wi-Fi signal, were found in at least one of the included papers. One paper described using a head-and-hand tracking system, but did not provide details on the technology . One didWe identified three themes that related to the strengths of AR in healthcare education.AR was applied in various subjects, such as: joint injection, thoracic pedicle screw placement, laparoscopic surgery, administering local anesthesia, endotracheal intubation, ventriculostomy, forensic medicine, inguinal canal anatomy, diathermy, tissue engineering, alimentary canal physiology and anatomy, disease outbreak, clinical breast examination, cardiologic data, and life support training, all of which are applicable to healthcare education see . We founWhile two studies did not mention participants, the remaining 23 studies included 713 participants representing medical staff, medical students, high school students and children, see . ParticiNinety-six percent of the papers claimed that AR is useful for improving healthcare education. Several aspects were elicited in the different studies such as decreased amount of practice needed, reduced failure rate, improved performance accuracy, accelerated learning, shortened learning curve, easier to capture learner’s attention, better understanding of spatial relationships, provided experiences with new kinds of authentic science inquiry and improved assessment of trainees.Even though every paper in this study had its own research aim and focus, together they gave us a more complete perspective of how AR is being used in healthcare education . Two papWe also identified three themes around the weaknesses of AR in healthcare education.Of the included papers, 80% did not clearly describe which kind of learning theory was used to guide design or application of AR in healthcare education. One claimed that they used activity-based learning but did not tell us how they used it; moreover, the learning strategies are not clearly described in the paper . Two groIn 64% of the included papers it was shown that they are still using traditional methods of teaching practical skills in medical education, whether or not AR was used as a guidance system or as feedback tool. Three included papers (12%) did not describe how the participants used AR to learn. One wrote that students can explore and navigate with AR environments, but that the time allotted was only half an hour and no learning effect was shown .However, a few studies explored other methods. One study investigated AR in teaching using different forms such as; group setting, self-learning or revision of cases . One resFifty-six percent of the papers presented an AR prototype without studying its impact. Five groups studied the ProMIS AR simulator, which was used by colorectal surgeons in their training to improve laparoscopic colorectal skills. The 5 groups contributed with 11 papers. The usefulness, reliability and applicability of the ProMIS AR simulator system were examined, and the systems’ value and validity were also evaluated. ProMIS AR was additionally compared to other systems.In this paper, we have shown an overview of the use of AR in healthcare education, additionally, we have identified the currently reported strength and weakness. The findings suggests a potential role in healthcare education even if most of the AR applications were still in a prototype stage.Most studies said AR is useful for healthcare education, with one exception that did not mention the learning effect of AR. AR is useful because it helps the healthcare learner to understand spatial relationships and concepts, to acquire skills and knowledge, to strengthen cognitive-psychomotor abilities, and to shorten their learning curve and prolong learning retention. Further, it increases subjective attractiveness by providing students with authentic simulated experiences. Moreover, AR offers more conveniences, such as with time.Most of the studies used AR for learning through feedback or as a navigation system. However, a few used AR to offer immersion into a scenario, a participatory reality or a regenerative concept. Some used AR as an innovative interface or meaningful information tool. The others tried AR for remote assessment and training, or simulator practice. One used it to reduce resources.Two pieces of literature relevant to healthcare education, focused on introducing several examples of using AR systems. This review searched six different databases to determine the characteristics of AR in healthcare education, and to distinguish the strength and weakness found in current research. It particularly focused on including studies related to healthcare education. Most of the AR applications found in this review are based on mobile computing systems, especially on laptops. It is different with Carmigniani and Furht’s study where the medical AR application systems are fixed in-doors. While light mobile AR has been predicted to be feasible to develop as real-time AR applications that are locally processed, our findings show that there are still very few examples of light mobile AR . In our Although each study presented a clear research aim, few suggestions were given for choosing an AR model that is better for healthcare education. Moreover, there is not enough evidence to inform the design of suitable learning activities with AR system, where knowledge and skill development could be integrated into the learner’s world. Thus, further research in this area should be taken to clarify the appropriate AR model, instructional designs and how to effectively use AR for healthcare education.To our knowledge, this is the first integrative review that specifically addresses AR in healthcare relative to education. We explored how AR was applied in healthcare education encompassing a broad range of learners, learning strategy, outcomes and study designs. Content analysis and thematic analysis were useful to provide a comprehensive understanding on AR in healthcare education.This review tries to provide a comprehensive description of AR in healthcare education with no research methodology filter. However, it is possible that some studies were missed if the key words did not appear on the title or abstract. The studies were also limited by excluding any non-English studies. This was not only because most of papers were published in English, but also because the authors come from different countries, and English allowed them to reach a consensus on the articles to include in the analysis. It is useful to minimize bias, but we possibly excluded some important papers. Further, an interesting AR application could have been missed because it was not published.AR is in the early stages of application within healthcare education but it has enormous potential for promoting learning in healthcare based on this review of preliminary AR studies. The infancy of AR in healthcare education requires more than the testing and improvement of prototype products, but also needs to identify appropriate learning theories to better guide application of AR in healthcare education.10.7717/peerj.469/supp-1Appendix SIClick here for additional data file.