Integrating primary care and behavioural health services improves access to services and health outcomes among individuals with serious mental illness. Integrated care is particularly promising for racial and ethnic minority individuals given higher rates of chronic illnesses and poorer access to and quality of care compared to Whites. However, little is known about integrated care implementation in non-White populations. The aim of this study is to identify facilitators and barriers to successful implementation of primary care-behavioural health integration in a multilingual behavioural healthcare setting.Seven focus groups and five semi-structured interviews were conducted with 41 patients and 5 providers participating in integrated care in a community mental health clinic in California serving Asian immigrants.Themes generated from constant comparative analysis suggest limited system-level preconditions and cross-organisational dynamics challenged integrated care. At the same time, changing organisational culture and practice, improving patient-provider and provider-provider communication, and increasing patient involvement enhanced clinical outcomes and facilitated successful implementation.Findings highlight the importance of patient involvement, peer services and interdisciplinary communication to successfully implement integrated care in the face of linguistic and operational challenges in settings serving multilingual and multicultural patients. Individuals with serious mental illness   on avera345678911121112Primary care-behavioural health integration is defined as “the care that results from a practice team of primary care and behavioural health clinicians, working together with patients and families, using a systematic and cost-effective approach to provide patient-centred care for a defined population” . There i71617Several studies have demonstrated the potential effectiveness of primary care-behavioural health integration in increasing the use of physical healthcare services and enhancing quality of care as well as health outcomes among individuals with serious mental illness 202122. S202124251624This study took place in a large non-profit community mental health clinic in a metropolitan area of California. The clinic provided comprehensive outpatient behavioural health services to more than 2,000 patients annually. Their patients were mainly low-income Asian immigrants of which 90% spoke a primary language other than English.In 2010, the clinic obtained government funding to initiate their Primary Care Integration program. The program collocated services in which primary care providers were embedded in the behavioural health setting . The intThrough this program, patients received primary care services and regular behavioural health care management in the same facility. Patients attended appointments with their assigned primary care physicians every three months. Bilingual/bicultural behavioural health care managers also joined primary care visits with patients to aid on language translation and follow-up on recommendations. The interdisciplinary team used an electronic health record system to coordinate appointments, obtain and share patients’ lab results, and to provide e-prescription. The psychiatrist, wellness coordinator, integrated care program administrators, care managers and primary care providers also held regular case conferences to discuss patients’ treatment goals and outcomes. As part of the program, integration of physical health care and wellness education was expected to be included in routine care. Patients might also be recommended to join various wellness activities based on their needs and availabilities. These wellness activities were typically staffed by a bilingual instructor and co-facilitated by a peer worker. Peer workers, who have lived experience of serious mental illness, were trained and supervised by behavioural health providers.The primary care integration program was a four-year effort. During the final year, the authors collaborated with the staff in recruitment and data collection for this qualitative study to examine factors that supported (i.e. facilitators) or hindered (i.e. barriers) the implementation of the program.The Health Behaviour Framework provides an overview of both contextual and individual factors that could influence patients’ health behaviours and outcomes . It is cThe authors emailed and recruited five providers/administrators  for interviews. There were in total 36 behavioural health providers and 3 primary care providers in the program. These five providers/administrators were purposively selected for the study, based on their knowledge of and involvement in the planning and implementation of various aspects of the program, which allowed for rich and diverse perspectives . ProvideAt the time of recruitment, 250 patients were enrolled in the program, 41 joined focus group discussions via convenience sampling. Recruitment flyers were distributed in individual and group meetings at the clinic. Patient characteristics were summarized in Table Between March and May 2015, the authors conducted five one-hour semi-structured interviews with providers/administrators in English over the phone. In July 2015, the second author and bilingual staff conducted seven semi-structured focus group discussions with patients. Each one-hour group consisted of six to seven participants, with one bilingual staff as the interpreter. The groups were administered in languages concordant to participants. These languages were Cantonese, Vietnamese, Khmer, Mien and English. Participants were compensated with a $20 gift card. All interviews and discussions were audio-recorded.Bilingual/bicultural researchers transcribed the recordings into English. Constant comparison method was used , whereinTo enhance the credibility of the findings and ensure they are reflective of participants’ experiences, strategies to triangulate data sources and analysts were used . First, Current findings identified five themes that described the facilitators and barriers as crucial to successful implementation of integrated care. The themes were summarized with sample illustrative quotes in Table From the outset, providers identified four gaps in the macro system of healthcare that challenge optimal implementation of integrated care. A foremost struggle was the lack of training in clinicians regarding primary care behavioural health integration. Other providers said that in an integrated care setting, additional training and time were required to modify interventions in ways that best engaged their patients and responded to patients’ needs.Second, particularly in the context of serving a multilingual and diverse patient population, providers reported a constant struggle with inadequate resources to overcome cultural and linguistic barriers unique to the Asian immigrant population. Behavioural health providers said it was difficult to recruit multilingual clinicians who had knowledge, experience and willingness to work with non-English speaking populations with serious mental illness. The behavioural health clinician said she ended up being the instructor for most of the wellness activities because she was not able to find other instructors who felt comfortable to do so.Third, behavioural health and primary care providers expressed concerns about the current reimbursement system that does not compensate for increased workload in integrated care setting. A behavioural health provider said:“It has to be coming from the legislature all the you know, the state, and the government on the needs to have a different type reimbursement program for integrated care. Especially primary care, they are facing like you know from 10–15 minutes to half an hour visit. It is a lot of cost. And they don’t get compensated for that.”The primary care physician stated her belief that the primary care clinic was losing money from their involvement in the integrated care program because it was difficult to obtain reimbursement for services rendered. Furthermore, other providers reported that the paucity of continuous funding hindered sustainability of the program. The program coordinator said many staff viewed the funding for the program as time-limited and therefore were not willing to make more permanent changes in support of integrated care efforts.Despite the clinic could secure a space for providing colocation of services, patients and providers discussed the challenge of physical capacity, specifically access to facilities large enough to hold wellness groups as part of the integrated care program. A behavioural health provider explained that they had been using donated space at a church to conduct some wellness group activities. However, this facility was small and not always available. Whereas there was an intention to increase wellness programming, the existing physical barriers limited the variety of wellness activities held and the number of patients that could benefit from them.The primary care integration program was the first formal working relationship between the primary care and behavioural health providers serving mutual patients. Providers on both sides admitted that the differences between two organisations made it difficult to work together and put the integrated care model in practice. The primary care physician said:“I feel like the first year it really did take a whole year to get started and to just kind of acclimate because everyone was so different in their perception and vision of what the primary care integration project should be.”Providers raised challenges in creating a shared vision of integrated care, clarifying roles and responsibilities between behavioural health and primary care, and developing a mutual understanding of the administrative procedures  required for the integrated care program. Providers also reported working under constraints due to different protocols in two organisations. For example, the primary care physician mentioned they had to work around the issue of patient eligibility and billing for this program because primary care followed a different set of admission and insurance criteria required by federally qualified health centre. Providers expressed the importance of an interdisciplinary team to share vision, goals and priorities. They wished they had spent more time and opportunities on staff networking to build a cohesive team.Despite the myriad of organisational challenges, providers agreed that there were gradual changes that led to a new culture and operational system for integrated care. Behavioural health clinician reported seeing an increased willingness in care managers to work with medical providers. Primary care physician, on the other hand, took initiative to communicate more frequently with care managers and acknowledge the importance of behavioural health interventions. Providers recognized a change in mentality from “your patient, my patient” into “our patient” and viewed their patients as shared within the team. Providers also reported changes in the conventions of their jobs to improve service delivery. Care managers conducted more follow-ups with their patients on primary care providers’ recommendations; whereas primary care physicians spent more time with patients learning about their mental health conditions.Behavioural health providers explained that these changes occurred in the context of continuous access, exposure and education on each other’s work. The behavioural health clinician and program coordinator said they took time to educate the care managers and primary care physicians about holistic wellness and invite them to see the different parts of the program and how they could apply in their practice. The program coordinator said:“I really think that the immediate providers see the benefit and really they have different takes towards the care, the approach.”Both behavioural health and primary care providers reported using formal and informal communication channels to exchange information and provide structures for accountability, differentiation and coordination of care. The psychiatrist, primary care providers, care managers and other behavioural health staff held regular case conferences to discuss patients’ treatment goals and progress. A few providers mentioned using daily informal check-ins amongst themselves to avoid patients falling through the cracks of the system and ensure services from different parties were provided to meet the patients’ needs. Information exchange allowed providers to integrate their services for patients and be better informed about the feedback of their recommendations. Additionally, some patients saw their linguistic barriers and discomfort with primary care providers in discussing mental health issues being removed by having linguistically matched care managers at primary care appointments, thus improving patient-provider understanding.Providers reported using an information sharing system to facilitate the integration between behavioural health and primary care. In the second year of the program, behavioural health providers obtained funding to develop their electronic health record system. The program coordinator explained that they used the system in three ways: (1) psychiatrists made e-prescriptions and checked for potential interactions among patient’s different medications; (2) behavioural health providers obtained lab results to keep track of patients’ health and progress; (3) primary care providers had access to the system to schedule patients’ appointments. Despite some legal and technical barriers, providers valued the electronic health record system as it allowed immediate access to information at anytime from anywhere, and to coordinate appointments or treatment efforts, which was “especially important in this hard-to-reach population when no-shows are common”.All providers recognized the importance of involving patients’ knowledge, strengths, needs, perspectives and participation in supporting the implementation of integrated care and enhancing patients’ clinical outcomes. They saw patients as “navigator[s] of their own recovery” and valued patients’ awareness and abilities to manage their health. Providers reported more discussion with patients regarding their vital signs and health data. Family members were also invited to wellness activities with patients in order to reinforce health and wellness management at home.Peer involvement was another initiative in the integrated care program. Several patients shared their experiences in volunteering and assisting certain parts of the integrated care program, such as recruiting patients, co-facilitating wellness activities, and providing support in language translation. These patients reported their experiences of leadership motivated them and their peers. Behavioural health providers said they created positions for peer leaders and recruited patients who had received training from the clinic. Parts of the training focused on culturally responsive and therapeutic engagement, and being sensitive to legal as well as ethical issues. The clinic encouraged peer involvement by providing supervision and acknowledging their services with stipend or gift cards. Providers described peer leaders as “valuable workforce member[s]”, since peer leaders provided additional resources and unique expertise to support integrated care implementation under an already taxed environment.The study provides insights into the implementation process of primary care-behavioral health integration and highlighted facilitators and barriers of employing a co-located care model in settings serving multilingual and multicultural patients. Our findings suggested that limited system-level preconditions and cross-organisational dynamics hindered integrated care implementation. At the same time, improvements in organizational culture and system , improved patient-provider and provider-provider communication, and increased patient involvement helped facilitate the implementation process. Based on these findings, we provided recommendations for future implementation.  used in many integrated care settings. Streamlining funding structures and providing continuous funds are required to sustain integration . For exaAt the organisational level, the findings highlight the importance of considering organisational culture and top-down involvement as they shape the ability to move beyond minimal collaboration to closer integration of care . OrganisAt the providers’ level, the formation of an interdisciplinary team and effective communication between primary care and behavioural health providers have long been acknowledged as necessary to improve the physical health of individuals with serious mental illness. Our providers adopted various inter-professional communication strategies, such as regular case conferences and informal referral procedures, that promoted team effectiveness . Operati41At the individual level, patient involvement is underscored as an active intervention ingredient by our providers and patients. They reported that communicating to patients about their health data and involving them in decision making, service delivery and informal peer support increases patients’ self-efficacy, sense of responsibility, and motivation for individual behavioural change. Shared decision making has been frequently advocated in recovery-oriented behavioural health care and medication management, but seldom used in behavioural interventions for persons with serious mental illness . The exp4546Integrated care programs are increasingly incorporating peer support leaders into delivery of services; yet the process of implementing and ways of supporting peer support leaders in integrated health care settings are still unclear . Our stuOur study had several limitations. Convenience sampling was used for recruitment in this traditionally hard-to-reach population, and possible selection biases were noted. Most patients in the focus groups received both integrated care services and wellness activities versus those who only received integrated care services, thus the focus groups were not expected to be representative of all patients. The sample of our providers, who came overwhelmingly from behavioural health versus primary care, might not be representative of all providers; however, this was reflective of the integrated care team that was mainly composed of bilingual behavioural health clinicians. Given our study was conducted in one ethnic-specific community mental health clinic in California, it is acknowledged that the transferability of our findings is limited to Asian American adult immigrants with serious mental illness who were receiving care in a metropolitan area. Asian immigrants are a heterogeneous population and current findings should be interpreted with caution when applying to a particular Asian ethnic group. Multilingual staff were employed as interpreters in focus group discussions to facilitate understanding between researchers and patients. The risks of misinterpretation and social desirability bias were noted. Nevertheless, our findings provide important directions to implement integrated care in high disparity, ethnic-specific and multilingual populations.Addressing health disparity requires prevention and care for comorbid medical conditions. Promotion of healthy behaviours, early diagnosis and coordinated management, and integrated care between the mental health and medical systems are necessary. For linguistically and culturally diverse populations with serious mental illness, future integrated care efforts should focus on incorporating ways to engage patients in treatment, decision-making and service delivery processes, remove structural barriers for systems change, create opportunities to promote inter-professional team building and functioning, better allocate resources, and increase funding to build capacity for long-term sustainability . PresentThe additional file for this article can be found as follows:10.5334/ijic.3719.s1Table S1Themes and Examples from Patients and Providers.Click here for additional data file.


This study examined whether exposure to smoking and vaping cues the urge to smoke or vape. It extends previous studies on first-generation cigalikes  and second-generation devices  by including third-generation tank system devices (larger bulky units). In an online experiment, participants were randomly assigned to view one of four videos, which included smoking, vaping , or neutral cues. The primary outcome was urge to smoke. Secondary outcomes were urge to vape, desire to smoke and vape, and intention to quit or remain abstinent from smoking.UK adults varying in smoking (current or former) and vaping (user or non-user) status (n = 1120) completed the study: 184 (16%) failed study attention checks meaning 936 were included in the final analysis. Urges to smoke were similar across cue groups. Urges to vape were higher following exposure to vaping compared to neutral cues. There was no clear evidence of an interaction between cue group and smoking or vaping status. The lack of cueing effects on smoking urges is inconsistent with previous research, raising questions about the ability to assess craving in online settings. The impact of e-cigarette use (vaping) is debated within global public health communities; there is evidence that it is an effective smoking cessation aid , 2, but The impact of differences in available spaces on smokers and vapers is unknown. Exposure to smoking or vaping cues has the potential to increase smoking or vaping urges, which is particularly concerning for former- or non-users in public areas. In shared spaces, exposure to smoking cues could increase smoking urges, or reduce vaping urges, among former smokers and those trying to quit through vaping, undermining smoking abstinence. It is also possible that exposure to vaping in shared spaces could cue vaping urges in smokers, increasing the desire to reduce or quit smoking through vaping.Previous research on the impact of vaping cues has focussed on cross-cueing effects. For example, passive exposure to first-generation cigalike e-cigarettes  can increase desire to vape and smoke, whereas exposure to tobacco cigarettes may only increase desire to smoke . SimilarWe aimed to directly compare the impact of viewing different e-cigarette cues , to tobacco smoking or neutral cues among people with different smoking and vaping backgrounds. We hypothesised that smoking urges following exposure to vaping cues would be higher relative to neutral cues and lower relative to smoking cues, and that smoking urges would be lower following exposure to tank system vape cues relative to cigalike cues.This online study used a between–subjects design. Participants were allocated to one of four stimulus groups  according to their smoking and vaping status . Participants were randomised to view one of four video cues –13. EachThe study was hosted on the Qualtrics online survey platform . ParticiSelf-reported craving for tobacco was measured pre- and post-intervention using the brief questionnaire of smoking urges (QSU-Brief) , 17, witParticipants who expressed an interest were shown an information statement explaining the study. They were told the purpose was to provide feedback on videos for future research, to avoid them paying undue attention to their desire to smoke or vape. Participants willing to continue completed a tick box consent page. Participants then completed screening and demographic questions, baseline ratings of smoking and vaping craving, alongside filler questions. They then viewed one of four one-min cue videos according to their condition, followed by video-related cover questions and questions on craving and intention to quit smoking or remain abstinent. Finally, participants were asked what they thought the purpose was of the study. Attention check questions were embedded within the questions and participants who failed these were excluded post-randomisation and replaced to ensure high data quality. At the end of the study, participants were provided with debriefing information and contact details of the research team.Two-way ANCOVAs were used to assess the impact of exposure to video cues  on: i. post-intervention smoking and vaping urge scores, and ii. post-intervention desire for a cigarette and e-cigarette scores, for the four smoking and vaping status groups , using pre-intervention score as a covariate. Two-way ANOVAs were used to assess the impact of video cue on secondary outcomes (intention to quit or remain abstinent) for the four smoking and vaping status groups.Further details of the study methods, materials, additional measures and statistical analysis plan can be found in the preregistered study protocol .A total of 1120 participants completed the study. 184 (16%) failed attention checks and were excluded post-randomisation,There was no clear evidence of an interaction effect between video cue group and smoking and vaping status group for either ANCOVA models: smoking urge  and vaping urge . Therefore, the interaction was dropped from the model in favour of a single model to estimate main effects with greater precision.There was no clear evidence of a main effect between the four video cue groups on smoking urge : there was no evidence of a difference in smoking urge between: i. vaping cues (combined) and neutral cue , ii. vaping cues (combined) and smoking cue , or iii. cigalike and tank system vaping cues  : urges were higher following exposure to both cigalike  and tank system vaping  cues compared to the neutral cue  and weak evidence of a difference on desire to vape , which was higher following exposure to cigalike  and tank system  cues compared to the neutral cue . There was weak evidence of a main effect of video groups on intention to remain abstinent from smoking , which was higher following exposure to the cigarette cue compared to the neutral cue  , or correctly identified the purpose of the study (n = 421).The smoking and vaping urge and desire scores were heavily skewed towards the minimum scores (being 10 and 0 respectively), demonstrating possible floor effects. A comparison amongst video cue groups between those participants at floor or above found that the proportions were similar across groups.This online study found no evidence of a cross-cueing effect of exposure to vaping cues on smoking urges or exposure to smoking cues on vaping urges, or an interaction between cue exposure effects and smoking or vaping status. Similarly, there was no evidence of a cueing effect on participants’ reported desire to smoke, or intention to quit smoking. There was some evidence of exposure to smoking, relative to neutral, cues increasing intention to remain abstinent in former smokers, and of vaping, relative to neutral, cues increasing vaping urges and desires.The limited cueing effects on smoking urges were unexpected. One possibility is that previous studies have overestimated the impact on smoking urges of exposure to vaping or smoking cues; however, given differences in study methodology, it is more likely that the lack of effects reflect—at least in part—limitations of the materials and setting used in the current design. For example, King and colleagues  used conVideos have been used in previous cue reactivity studies , and havIt is possible that the online setting precluded control over other aspects of the environment in which participants completed the study, which could have influenced their responses. Both nicotine dependence and deprivation influence cue reactivity . It is pThe current study found no evidence that exposure to videos of smoking or vaping cued smoking urges and no evidence of interaction effects between cue exposure and smoking and vaping status. These findings may be explained as a consequence of using video cues with neutral contexts within an online setting, which allowed for minimal control over participants’ recent smoking or vaping activity. Future studies should exercise caution when using an artificial setting to assess craving.Using videos of smoking or vaping behaviour with limited contextual details may have been insufficient to elicit smoking cravings.It was not possible to control for a minimum period of smoking or vaping abstinence in the online setting.We did not measure nicotine dependence which could have influenced cue reactivity.


Abnormal sensory-based behaviors are a defining feature of autism spectrum disorders (ASD). Dr. A. Jean Ayres was the first occupational therapist to conceptualize Sensory Integration (SI) theories and therapies to address these deficits. Her work was based on neurological knowledge of the 1970’s. Since then, advancements in neuroimaging techniques make it possible to better understand the brain areas that may underlie sensory processing deficits in ASD. In this article, we explore the postulates proposed by Ayres  through current neuroimaging literature. To this end, we review the neural underpinnings of sensory processing and integration in ASD by examining the literature on neurophysiological responses to sensory stimuli in individuals with ASD as well as structural and network organization using a variety of neuroimaging techniques. Many aspects of Ayres’ hypotheses about the nature of the disorder were found to be highly consistent with current literature on sensory processing in children with ASD but there are some discrepancies across various methodological techniques and ASD development. With additional characterization, neurophysiological profiles of sensory processing in ASD may serve as valuable biomarkers for diagnosis and monitoring of therapeutic interventions, such as SI therapy. Autism Spectrum Disorder (ASD) is a neurological developmental disorder clinically characterized by impairments in social interaction and communication and restricted or repetitive patterns of behavior, interests or activities . In 2018Over the past 40 years, research on sensory processing in those with and without ASD has enhanced our understanding of how the brain processes sensory input. As early as 1963, Ayres conducted some of the first studies examining sensory problems in a wide range of developmental disorders. Through her work, she conceptualized an intervention approach now referred to as Ayres Sensory Integration (ASI) to treat the sensorimotor foundations of academic skills and other higher order abilities  . The theSensory Integration and the Child [Much of the technology used today to study brain structure and function was not available to Ayres when she developed her theoretical explanations and interventions. Currently, researchers use methods such as structural and functional Magnetic Resonance Imaging (MRI), eye-tracking systems and electroencephalogram (EEG) to generate information about brain processing. We can now use data collected from these new methodologies to examine their consistency with Ayres’ theories of ASD and consider their implications for SI. The first aim of this paper is to review three aspects of sensory processing deficits in ASD that Ayres discussed in he Child : registrappropriate motor and behavioral responses to stimuli. In her work Sensory Integration and the Child, Ayres [Sensory Integration and the Child [Sensory Integration and the Child are the two main publications in which Ayres delineates her views of SI and ASD. The theory that disruptions in the limbic system also contribute to motivation deficits in ASD is further found in unpublished archival documentation of Ayres’ work and lectures preserved at the University of Southern California (USC) library archives [Sensory processing involves perceiving, organizing and interpreting information received through sensory systems  in order to produce an adaptive response. The term “sensory integration” as used by Ayres  refers td, Ayres  observedhe Child , Ayres ahe Child  investighe Child . Althoughe Child  and the archives .Components of impaired sensory integration in ASD according to Ayres.Registration: Registration is the detection of sensory sensations within the central nervous system. Ayres  used theModulation: Modulation is the ability of the brain to regulate inhibition or propagation of neural signaling. Sensory modulation reflects adjustments made in response to continual physiological processes to ensure adaptation to new or changing sensory information. Ayres  defined Motivation: Ayres  describeGiven the research tools available at the time, Ayres  establisAs previously stated, Ayres  suggesteThe term, limbic system, refers to a specific set of regions thought to encompass emotion-related brain regions. The system is comprised of several subcortical nuclei and cortical structures including the insula, hypothalamus, hippocampus, parahippocampal gyrus, amygdala, fornix, mammillary body, septal nuclei, cingulate gyrus and dentate gyrus on both sides of thalamus . These rConsistent with Ayres’ theory, current research has thoroughly documented that individuals with ASD have both structurally and functionally atypical emotion-related brain regions ,26,27,28Studies of neural activation (function) in emotion-related brain regions have similarly reported abnormal functioning in ASD. The amygdala in particular has been consistently found to be dysfunctional. Neuroscience research published at the time of Ayres’ career reported that the amygdalae contain a larger proportion of neurons that signal valance than other emotional-related brain regions and are responsive to motivationally significant stimuli . Ayres pHyperactivation in the amygdala to eye contact may indicate a modulation dysfunction in ASD in which some have proposed an indication for why individuals with ASD avoid eye contact with others ,55. ThisThe insula is an important emotion-related region not identified by Ayres that is involved in registration deficits in ASD . The insTogether, current neuroimaging research supports Ayres’ framework by providing evidence that emotion-related brain regions are structurally and functionally different in individuals with ASD compared to TD individuals. Further, research findings suggest that these regions are important for registration of sensory information and that they are disrupted in a way that impairs sensory modulation. These differences, however, are multifaceted and may depend upon methodology . Individual regions, such as the amygdala or insula, are part of a much larger emotional processing network and are physically and functionally connected to other regions. The connectivity between these regions and other brain regions also contribute to SI disruptions in ASD and are discussed below. Functional task-based MRI studies that directly investigate how different sensory experiences are processed in ASD are reviewed later.While characterization of brain regions provide insight into ASD dysfunction, a systems level approach in the last decade has provided additional understanding into how sensory information is communicated within and between networks. Recent research has examined network functioning of specific regions, including emotion-related brain regions in those who are TD and individuals with ASD. Although there are some inconsistencies , signifiIn addition to task-based connectivity networks, several functional networks are intrinsic to neural functioning and are thought to be related to different aspects of sensory processing . These networks closely resemble functional networks that are active when performing tasks ,78 and aAn increasing number of neuroimaging studies examine neural processing during exposure to specific kinds of sensory input  ,86. ThesCascio and colleagues  found taIn a set of complementary studies, high-functioning youth with ASD and age- and Intelligence Quotient-equivalent TD youth were presented with adverse sensory stimuli during an functional magnetic resonance imaging (fMRI) scan ,91,92,93In a follow up study, Green and colleagues  investigConscious registration of sensory stimuli results in one of two reactions: to respond to the stimuli or to deliberately ignore it  and the nucleus accumbens (NAC)  and is iIn addition to the reward system, other brain regions help drive and reinforce seeking behavior which also may be consistent with the “energizing effects” Ayres  describeThis paper revisits Ayres’  primary While registration has not explicitly been tested at the neurological level, Ayres’  frameworIn addition to “limbic” regions, Ayres’ hypothesized that the vestibular nuclei are involved in sensory registration. In the 1970’s, several important papers were published implicating the vestibular system in ASD ,144,145.Research providing evidence for registration impairments also provides evidence for modulation deficits in ASD. Hypo- and hyper-responsiveness to sensory stimuli (now listed as diagnostic criteria in DSM-5  and its Ayres’ third postulate regarding motivation, is her least cultivated. Ayres provides little theory regarding the neurological mechanisms that are involved in “wanting to do something”. However, she did describe several symptoms in individuals with ASD that may contribute to their reluctance to respond to sensory stimuli or to do new and different things . These cWith the advancement of neuroimaging and other innovative technologies, scientists have begun to map the structure and function of the brain areas that may underlie sensory processing deficits in ASD. Ayres’ predictions about sensory registration, modulation and motivation are strongly supported by the findings of various studies. Ayres observed sensory heterogeneity in ASD and predicted that it would have implications for therapy. She theorized from her own work that individuals with modulation but not registration deficits would respond better to SI therapy. Stratifying sensory phenotypes of ASD with neurological markers may lead to improved individualized therapy. However, today very little research has linked ASD neurosignatures to therapeutic outcomes. Further research is necessary to better understand the relationship between neural abnormalities in ASD and therapeutic approaches intended to ameliorate sensory impairment symptoms and to promote easier participation in everyday life activities. To our knowledge, no published studies have specifically investigated the neural response to Ayres sensory integration therapy in individuals with ASD. Research is needed to examine whether intervention using a sensory integration approach will help improve sensory registration and/or modulation impairments in ASD by developing a more efficient network connectivity.


Dear Editor,We have read with great interest the article by Yan et al.  demonstrOlder patients have a higher incidence of peripheral vascular disease, atherosclerosis, hypertension, and arterial calcification. High prevalence of medial vascular calcification in fistula blood vessels was found in 75% of diabetic males with end-stage renal disease (ESRD) . DiabetiCalcification process progresses as dialysis vintage increases, and this is confirmed by the lower incidence of vascular access calcification in incidence patients . IdeallAlthough, there is a complex interaction of factors that may affect the patency of an individual AVF, several prospective studies reported reduced effect of diabetes on primary access survival, in proximal AVFs ,10 suggeWhether diabetes is a more powerful adverse factor of access patency compared to arterial calcification burden in diabetics receiving autogenous fistulas should be further investigated. Thus, should we need another meta-analysis distinguishing AVFs with medial calcification versus AVFs without medial calcification in diabetics? Notably, if the long-term benefit of RCF is lost, it may be prudent to select the brachial artery for AVF creation in diabetics with extensively calcified vessels . FurtherIt will be critical to carefully examine the vessel inflow and outflow of the AVF since the presence of small-diameter vessels at anastomosis sites is an important risk factor for AVF failure . PreviouBased on the above described views and anatomic restrictions regarding fistula construction in diabetics with calcified forearm arteries, strong evidence is required before a profound change in strategy in this cohort of patients. In other words, it is not a simple meta-analysis question of AVF failure in diabetics versus nondiabetics in ESRD. As such, all the above factors constitute limitations of this study and at least deserve adequate mention. Furthermore, other risk factors for fistula survival  should not be overlooked.


Mechanical ventilation can initiate ventilator-associated lung injury (VALI) and contribute to the development of multiple organ dysfunction. Although a lung protective strategy limiting both tidal volume and plateau pressure reduces VALI, uneven intrapulmonary gas distribution is still capable of increasing regional stress and strain, especially in non-homogeneous lungs, such as during acute respiratory distress syndrome. Real-time monitoring of regional ventilation may prevent inhomogeneous ventilation, leading to a reduction in VALI.Electrical impedance tomography (EIT) is a technique performed at the patient’s bedside. It is noninvasive and radiation-free and provides dynamic tidal images of gas distribution. Studies have reported that EIT provides useful information both in animal and clinical studies during mechanical ventilation. EIT has been shown to be useful during lung recruitment, titration of positive end-expiratory pressure, lung volume estimation, and evaluation of homogeneity of gas distribution in a single EIT measure or in combination with multiple EIT measures. EIT-guided mechanical ventilation preserved the alveolar architecture and maintained oxygenation and lung mechanics better than low-tidal volume ventilation in animal models. However, careful assessment is required for data analysis owing to the limited understanding of the results of EIT interpretation. Previous studies indicate monitoring regional ventilation by EIT is feasible in the intensive care setting and has potential to lead to lung protective ventilation. Further clinical studies are warranted to evaluate whether monitoring of regional ventilation using EIT can shorten the duration of ventilation or improve mortality in patients with acute respiratory distress syndrome. Acute respiratory distress syndrome (ARDS) is not rare in the intensive care unit and has been studied for decades; however, ARDS-related mortality remains unacceptably high. Mechanical ventilation (MV) is often required to provide adequate gas exchange in patients with ARDS but can injure the lungs and cause poor outcomes . MechaniAlveolar overdistension and/or repetitive collapse and reopening of alveoli are responsible for the development of VALI. The use of low tidal volumes and limiting plateau pressures, referred to as lower tidal volume ventilation (LTV) in association with permissive hypercapnia , decreasElectrical impedance tomography (EIT) is a clinically available, noninvasive technique that provides dynamic tidal images of gas distribution at the patient’s bedside . EIT enaIn this narrative review, the authors summarize the animal and clinical data to assess the feasibility and efficacy of monitoring regional ventilation by EIT. Additionally, the roles of EIT to improve lung protective ventilation management for patients with and at risk of ARDS are discussed.EIT is a monitoring tool that can visualize the ventilation distribution by measuring the regional increase in impedance caused by inspired gas , 10. BioEIT measures to quantify the degree of inhomogeneous ventilation have been proposed. Several EIT measures adopt the same concept but are represented by using different computation methods and notations. A taxonomy of EIT terms and alternative terms with definitions and explanations has been provided in a previous review published in 2016 . In the Tidal impedance variation (TIV) represents impedance change generated by inspired gas during a tidal breath, calculated as the difference of impedance between the maximum and minimum values at end-inspiration and end-expiration.Global TIV is the sum of impedance changes in all pixels across the whole image, which consists of a matrix of 32 × 32 pixels. It has been demonstrated that global TIV correlates with tidal volume. Regional TIV, characterizing regional ventilation, is calculated by the sum of impedance changes in the pixels within the selected region of interest (ROI) in horizontal layers or quadrants Fig. . TIV is During mechanical ventilation, compliance can be calculated using driving pressure and tidal volume. Though following the trend in compliance is crucial in managing respiratory failure where the lung mechanics change frequently, the information derived from only global parameters might be insufficient to recognize the physiologic phenomenon accurately. EIT can monitor local impedance changes in various regions sectionalized at the discretion of the user. Locally distributed volume in a certain lung region can be estimated by regional TIV, which makes it possible to assess the regional characteristic of a ventilated lung . RegionaBy monitoring regional compliance in different lung areas, e.g., non-dependent versus dependent areas in the lung, one can realize how inhomogeneous ventilation is under certain ventilatory settings owing to non-uniform regional compliance.2O [Zick and colleagues reported that after induction of ALI in pigs, regional compliance of the lung area decreased despite PEEP being increased from 5 to 10 cmH2O . ApplyinBy monitoring regional compliance at the pixel level during a PEEP trial, one can assess the regional lung area that might have overdistension and/or collapse (ODCL). During a decremental PEEP trial with a fixed driving pressure, the compliance in each pixel changes in response to the level of PEEP. This shows the highest compliance and identifies the best pixel compliance to the specific level of PEEP. When regional (pixel) compliance reduced by lowering PEEP from a specific level, the behavior of its pixel compliance represents collapse; whereas, when a similar reduction of compliance is seen by increasing PEEP, that indicates overdistension. The degree of collapse and overdistension at each PEEP level is calculated according to the formulas. For the calculation of collapse, the change in compliance for each pixel at a given PEEP level compared with its best compliance across all PEEP steps is calculated first ,Thereafter, the accumulated collapse for the entire lung at each PEEP step is calculated as a weighted average summed up for all collapsed pixels, where the weighting factor is the best pixel compliance estimated by applying the formula :The cumulated overdistension is calculated in the same way. By labeling those affected pixels showing reduced compliance at each PEEP level in the EIT image, the areas of possible ODCL are visualized Fig. . In addiCosta and colleagues performed EIT measurement and chest computed tomography (CT) simultaneously and compared the results using this technique during a decremental PEEP trial in two ARDS patients . They foThe center of ventilation (CoV), which was originally introduced by Frerichs et al., represents a vertical shift of the ventilation distribution along a gravitational axis. They created ventilation profiles using 64 ROIs equally divided between the right and left halves of functional scans, which elucidate how ventilation distribution deviates from a geometric center of the chest’s diameter by simple visual examination  Fig. 2)2). When CoV has been used in many experimental and clinical studies for evaluating recruitment or derecruitment of the lung –20. FrerThe global inhomogeneity (GI) index represents the spatial extent and dispersion in the distribution of tidal breath, i.e., the overall degree of spatial heterogeneity of ventilation. This EIT measure is computed according to the impedance variation in each pixel representing the volume of distributed air within predefined lung regions. The differences in impedance variation between each pixel and median value of all pixels are calculated and normalized to the sum of impedance values according to the formula below ,x and y = the DI of pixel xy, DIlung = DI of all pixels in the pre-defined lung) is an EIT measure that can show temporal delay in regions of the lung, i.e., the temporal heterogeneity occurring in the ventilated lung by focusing on the relationship between impedance change and the ventilation time course in each pixel. It monitors the delay in regional impedance to reach a certain impedance change, which is normally set at 40% of its maximal impedance value during a slow inflation maneuver . RVD is tmax − tmin = inflation time, i = each pixel) is defined as the standard deviation of RVD in all pixels. A smaller RVDI indicates a more homogeneous distribution. Furthermore, some EIT machines can plot the area affected by ventilation delay in a color-coded RVD map; therefore, one can see the exact site where the delay is occurring and its degree of delay by the scaled color on the map.RVD has been used as another EIT measure in research investigating the homogeneity of ventilation –27. MudeIntratidal gas distribution (ITV), originally described by Löwhagen et al., exhibits the way the inspired gas distributes in the lungs during the tidal breath at each region . Being dx-axis, time from the start of inspiration; y-axis, percentile contribution to global TIV). In this case, two lines (ITV curves) representing the contribution of the ventral and dorsal regions to the inspiration are plotted on the graph and the behavior of the ITV curves is reflective of the characteristics of regional ventilation [When the lung region is divided into two ROIs, i.e., the ventral and dorsal regions, impedance changes from the beginning of inspiration to a certain time point in each region are expressed as a fraction of the contribution to global impedance change. For example, in spontaneous breathing with healthy lungs, the air distributes more to the dorsal region owing to the active movement of the diaphragm at the early phase of inspiration, showing more than a 50% contribution in the dorsal region to the global TIV  Fig. . After btilation –32.Fig. Clinical research and case reports have demonstrated the usefulness of EIT monitoring in the respiratory management of patients with ARDS and in patients without pulmonary pathology. ARDS lungs have large regional mechanical heterogeneity; therefore, determining ventilator settings to achieve uniform ventilation distribution in ARDS is valuable to prevent VALI. Various EIT research groups have been focusing on seeking optimal ventilatory settings by using EIT measures in experimental and human studies , 33–37. 2O to 40 cmH2O, in 5 cmH2O increments, and the shift correlated well with the decrease in shunt fraction.The most frequent approach used to determine the optimal PEEP at which inhomogeneous ventilation is minimized is the PEEP trial Fig. . An EIT-2O with no RM throughout the surgery. The results showed significantly better gas exchange, higher end-expiratory lung volume, and lower driving pressure in the individualized PEEP group (average 18.5 cmH2O), indicating more homogeneous ventilation in this group. In addition, the GI index was significantly lower in the individualized PEEP group. Thus, individualized PEEP selection might be achieved by using RVDI or the GI index in combination with a PEEP trial.A PEEP trial can also be performed in the operating room to seek the optimal PEEP level. Recently, clinical research has been reported by Nestler et al., in which RVD was used for individualized ventilatory settings in anesthetized, morbidly obese patients during laparoscopic surgery . PatientOn the basis of information previously described, RVD and GI have been chosen to quantify ventilation inhomogeneity. However, one must consider that there is a limitation when using pixel-based analysis. Because all the structures in the thorax have their own resistivity to electricity, researchers need to determine the lung field for the subsequent analysis of EIT measures by selecting a certain threshold to avoid contamination from non-lung tissues. Pixel-based analyses, such as ODCL, RVD, and GI, are calculated based on such a determined area, and their results can be affected by a predefined lung ROI . In addiAlthough there is no established methodology or confirmed evidence that improves the outcomes of patients with ARDS, RM could play a role in minimizing ventilator-induced lung injury. However, the methods for the assessing recruited lungs without taking CT are scarce in clinical practice. Evaluating the effect of RM using EIT measures has been addressed by several EIT researchers –42. Beca2O in the ventral and 22 cmH2O in the dorsal region. In the other patient, the highest regional compliance was not detectable; no response to PEEP change in either the ventral or dorsal regions was observed, indicating that the lungs were nonrecruitable. Another technique to estimate lung recruitability was reported by Zhao and coworkers. They conducted research using a modified GI index and examined the relationship between the GI index and lung recruitability using a constant low-flow inflation maneuver in both ARDS and lung-healthy groups [Before performing RM, determination of recruitability is required when the lungs are suspected to be vulnerable to high inspiratory opening pressures. EIT has the potential to determine recruitability without applying excessive opening pressure by measuring the regional compliance during a PEEP trial. Camporota reported two ARDS cases that required extracorporeal membrane oxygenation (ECMO) . The paty groups . The modRescue therapies such as prone positioning, special ventilatory modes, muscle relaxants, and ECMO are applied when low tidal volume ventilation with a high PEEP cannot maintain gas exchange in severe ARDS. The effects of these therapies on regional ventilation distribution have been examined in case reports and previous research –47. KotaPrevious research investigating ventilation distribution during assisted modes with preservation of spontaneous breathing has been demonstrated , 49. OveIn EIT measurements, the position of the electrode belt determines the accuracy and validity of the analyzed data. If the belt is placed at the lower thoracic level rather than in the proper position, the diaphragm may interfere with impedance changes, leading to misinterpretation of the results . AdditioPrevious studies indicate regional ventilation monitoring by EIT is feasible in the intensive care setting and it has potential to lead lung protective ventilation management. Further clinical studies are warranted to evaluate whether regional ventilation monitoring using EIT can shorten the duration of ventilation or improve mortality in patients with ARDS.


In order to offer our patients, the “state of the art” treatment in gynaecology, we need a structured teaching program for trainees concerning the gynaecological skills. In recent years, training and education in endoscopic surgery has been critically reviewed. Clinicians, both surgeons as gynaecologists who perform endoscopic surgery without proper training of the specific psychomotor skills, are at higher risk to increased patient morbidity and mortality. The traditional apprentice-tutor model is no longer valid for developing all skills necessary in gynaecological surgery, particularly in endoscopy. Endoscopic training should happen at both the theoretical and the practical skill level. The acquisition of the correct knowledge regarding general laparoscopy, hysteroscopy and standard level procedures is as important as learning the necessary psychomotor skills to successfully perform endoscopic manipulations. Training in the operating room can only start when it is proven that knowledge and skills are present.To learn and train total abdominal hysterectomy by laparotomy there are inexpensive simple models that can be used, which are easy to reproduce. The development, construction, cost, and utility of a low-cost and anatomically representative vaginal hysterectomy simulator also has been described.The complexity of modern surgery has increased the demands and challenges to surgical education and the quality control. Today it is generally accepted that the traditional apprentice-tutor model is no longer valid for training all skills necessary in Gynaecological surgery and more specifically endoscopic surgery . This agConsequently, six leading professional organisations in gynaecology, the ESGE, EBCOG, EAGS, ENTOG, ACOG and AAGL, have issued a joint recommendation regarding endoscopic surgical training and quality assurance. This recommendation states that each hospital teaching endoscopic surgery should provide an endoscopic dry lab for training and improving the physician’s proficiency in endoscopic surgery skills.The rationale behind this recommendation is that endoscopy demands both psychomotor and surgical skills. It is vital that these psychomotor skills are trained and tested in a safe environment prior to training in the operating room, as it reduces patients’ morbidity and mortality rates, it reduces the patients’ exposure to unskilled trainees and it greatly increases educational efficiency.In this section, examples of training simulators are provided, some of which are mentioned by commercial name or brand. Please note that many different training tools are available and that the field of simulation is continuously developing. Recommendations and advice on specific training simulators or tools may be found at ESGE.Knowledge acquisition and psychomotor skills training need to happen via a structured approach, which only allows trainees to progress in the programme when clearly defined and measurable goals have been attained and assessed. A recent study shows that training of basic laparoscopic psychomotor skills (hand-eye coordination) prior to training of suturing skills improves both the acquisition and the retention of more advanced laparoscopic tasks, such as laparoscopic intra-corporeal knot tying , which fTraining trainees to become proficient gynaecological surgeons should not start with training in the OR, but instead in a simulation setting . A strucThe following steps can be defined in this approach:Basic endoscopic training (dry lab): Knowledge acquisition of general endoscopic principles and techniques combined with basic practical endoscopic skill training.Start of in-OR training: After the trainee has proven to be in possession of the necessary basic endoscopic knowledge and practical skills, the in-OR training can be started. In this phase, the trainee can assist an expert endoscopist mentor and is exposed to basic OR practices and teamwork.Advanced endoscopic training (dry lab): Knowledge acquisition of standard level procedures and training of advanced practical skills.Start of in-OR surgery: The skills laboratory phase is past and live surgery may be undertaken, according to a stepwise approach starting with close supervision and simple procedures and step by step expanding to less supervision for simple procedures and moving on to more complex ones.This approach aims to train and assess the necessary endoscopic skills in a dry lab setting as much as possible, before moving onto live patients in the OR. The benefit of this is threefold:Trainees are much more secure when they enter the OR as they are more confident that they have acquired the necessary knowledge and skills;Expert mentors do not loose time teaching basic skills, can receive proper assistance from trainees and can focus more on the procedures at hand;The patient receives better care due to proper trained trainees and is much less exposed to unskilled trainees.Endoscopic training should happen at both the theoretical and the practical skill level. The acquisition of the correct knowledge regarding general laparoscopy and standard level procedures is as important as learning the necessary psychomotor skills to successfully perform endoscopic manipulations. Training in the operating room can only start when it is proven that knowledge and skills are present.The acquisition of general endoscopic knowledge and, at a later stage, of standard level procedures can happen prior to or in parallel with practical skill training. To make this type of training as affordable as possible, it can be offered as an easily accessible structured e-learning programme in combination with self-evaluation modules which the trainee completes and his or her own pace.This knowledge acquisition can be further supported by one or more group-based sessions and should always be followed by an official assessment of the trainee.Example: The Winners Project e-learning programme offers free of charge online tutorials and theoretical assessment of laparoscopic and hysteroscopic knowledge.As it is widely accepted that dry lab training prior to training in the OR reduces patients’ morbidity and mortality in all endoscopic surgical disciplines, it is critical that practical skills can be trained in-house by using a structured approach with validated methods and training tools. Furthermore, a management platform is required to facilitate this structured approach regarding data collection and report generation.To achieve a structured programme, it is vital that the necessary support software is available that can manage all data collection. This collection of data occurs at two levels: the profiles and experience of the trainees, and the results of the training and test sessions that are carried out. Ideally, such a system should offer the possibility to view the progress of the trainees over time, to compare the training results with peers by means of a benchmark according to exposure level and to automatically issue all relevant reports and potential certificates.For basic skills, very simple models are described to train the surgical skills:foam rubber tube, which can be used to train e.g. suturing skills or manufacture a simple vaginal cuff model;tubular balloons that can replicate the ureters  and the tubes Cloths for suturing and knotting trainingBalloons to replicate ovarian cystectomyTo learn and train total abdominal hysterectomy by laparotomy there are inexpensive simple models that can be used, which are easy to reproduce . When coThe development, construction, cost, and utility of an inexpensive and anatomically representative VH simulator has been described. After multiple materials and solutions were evaluated and tested, a VH and posterior/anterior compartments repair simulators that incorporated strengths from each concept has been constructed  Geoffri.The advised dry lab setup for training laparoscopic skills includes the following:Pelvic trainer: The pelvic trainer simulates the ports that are used when performing a laparoscopic procedure on a patient. Their main goal is to restrict the movement of the instruments and to necessitate the use of an endoscopic camera. Together with training models, they form an ideal combination to train skills like camera navigation and proper hand-eye coordination.Training models for laparoscopic psychomotor skills: The training model is placed inside in a pelvic trainer and provides a number of exercises which will train the basic laparoscopic instrument handling skills, like camera navigation and hand-eye coordination, including bimanual coordination.Training models for laparoscopic suturing skills: The laparoscopic suturing skills model is placed inside a pelvic trainer and allows to perform stitching and knotting exercises and various levels of difficulty.All-in training model for laparoscopic psychomotor and suturing skills example: Encilap all-in training modelUsing a tubular balloon, it is possible to make a longitudinal incision to replicate the salpingostomy, and a complete cut for salpingectomy.Using a balloon filled with water involved by a second balloon, it is possible to make the translation of an ovarian cystectomy .The advised dry lab setup for training hysteroscopic skills includes the following:Female genital model To make the simulation as close to real life as possible, it is advisable to use female genital models in which the training models can be placed.Training models for hysteroscopic psychomotor skills The training model is placed inside the female genital model and provides relevant exercises which simulate all possible movements during a hysteroscopic procedure. Example:Training models for diagnosis Training of diagnostic cases is typically done by means of lectures and videos. However, using simulated models offers a significant benefit over traditional methods as they teach the trainee how to enter the cavity and proceed with caution, to identify the anatomical position of the abnormalities, to properly formulate what can be seen, to present this to their peers and to stipulate a resulting diagnosis. The diagnostic training models are placed inside a female genital model.Skills in outpatient clinic:Placement of Intra Uterine DevicePlacement of subcutaneous implantsEndometrial biopsyColposcopy (with biopsy)LLETZ of the cervixBasic (core) conventional surgical skills:Punch biopsy under local anaesthesiaSurgical marsupialization of cystSurgical excision of abscessMore advanced (core) conventional surgical skillsLaparotomy with minimal adhesiolysisSalpingo-oophorectomy by laparotomySimple anterior vaginal repairimple posterior vaginal repairMyomectomy of subserous myoma by laparotomyColpocleisis (at least in simulation setting)Basic (core) endoscopic skills:Laparoscopy:Diagnostic laparoscopyDiagnostic laparoscopy with tubal testingSimple laparoscopic adhesiolysisLaparoscopic sterilizationLaparoscopic removal of ectopic pregnancy  or salpingectomyLaparoscopic needle aspiration of simple cystsLaparoscopic electrocoagulation of the ovarySimple laparoscopic ovarian cystectomyLaparoscopic salpingo-oophorectomyHysteroscopy:Diagnostic hysteroscopyDiagnostic hysteroscopy with tubal testingHysteroscopic polyp resectionHysteroscopic myoma resection type 0-1 (< 4 cm)According to Harden et al.  and ThomNeeds: implement gynaecological skills training in prior to clinical activitiesAims and objectives: develop uniform and structured educational and training programs in EuropeContent: structured educational, training and assessment program in gynaecologyOrganisation of content: Free access to peer reviewed tutorials with self-evaluated models; Acquiring psychomotor skills with dry lab inanimate models; Standardized validated evaluation of the above skills; Entering the clinical teaching program if appropriate.Educational strategies: Structuring from knowledge to skills, and then to clinical activity; Objective evaluation module for each of the above; Objective evaluation methodology of the tutors.Teaching methods: Accessible, validated and affordable; Standardized dry lab training exercises; Internet access; Apprentice-tutor model after theoretical knowledge and psychomotor skills acquisition.Assessment: objective structural exercises evaluation, certification, preferably external assessors, reports by tutors or supervisors, scales of self-assessment, continuous and end-of course assessment, exams for theoretical knowledge evaluation.Communication: local scientific societies, teaching hospitals committees, trainees, tutors/supervisors.Educational environment: Local infrastructure with access to knowledge  and dry labs; Larger skills labs for surgical competences with a dedicated training environment where you acquire inter-professional team skills, dedicated endoscopic clinical teaching facilities .Process: Inform national societies about the content of the program. Provide them different tools needed for applying the program: - Free access to peer reviewed tutorials with self-evaluated models (like GESEA program); - Acquiring psychomotor skills with dry lab inanimate models ;Acquiring surgical competences using accessible and inexpensive models  following a “step by step” simulation program.Providing standardized validated evaluation of the above skills (online score platforms); If appropriate entering into the clinical teaching program.The European Academy of Gynaecological Surgery, together with the ESGE, has elaborated a well-balanced diploma curriculum: Gynaecological Endoscopic Surgical Education and Assessment (GESEA) programme which is based on a structured approach similar to what is proposed in this document .The GESEA Diploma Programme currently consists of two active levels, a Bachelor level and a Minimal Invasive Gynaecological Surgeon (MIGS) level.The GESEA Bachelor (level 1) is open to all endoscopists and specifically aimed at trainees. It starts with the bachelor tutorials on the Winners E-learning platform and is followed by practical psychomotor skill exercises in for laparoscopy (LASTT and SUTT1) and hysteroscopy (HYSTT1). The exam consists of a theoretical test and practical tests and the obtained certificate serves as a license to enter the OR as the programme provides the necessary skills needed to start in-OR training.The GESEA MIGS (level 2) is open to both gynaecologists and reproductive surgeons and starts with more in-depth tutorials on the Winners E-learning platform. The training exercises feature advanced practical psychomotor skills  and the obtained certificate serves as a license for conventional gynaecological laparoscopic and hysteroscopic surgical interventions.To be following this program, one will require access to (minimum):Inanimate models for open surgical skillsEndoscopic GESEA programInfrastructureCORE: Dry Skill lab installed with computer access for online video tutorials, endoscopic hardware and training tools preferentially accessible to all surgical disciplines. Virtual reality trainers are acceptable but do not have an advantage above the low cost inanimate models.ELECTIVES: Virtual reality trainer, inter-professional team skills, cadaver training and animal training courses. Live surgical sessions or streaming learning sessions. To profit from professional training environment it should be organised in regional or even supra-national training centres.The correct education and training on gynecological skills should be supported on tested and validated models allowing a uniform and effective implementation. This structured teaching program, supported on adequate simulation tools, may be diffused among trainees resulting at the end in an improvement on the health care offered to our patients.


Cellular transplantation for repair of the injured spinal cord has a rich history with strategies focused on neuroprotection, immunomodulation, and neural reconstruction. The goal of the present review is to provide a concise overview and discussion of five key themes that have become important considerations for rebuilding functional neural networks. The questions raised include: (i) who are the donor cells selected for transplantation, (ii) what is the intended target for repair, (iii) when is the optimal time for transplantation, (iv) where should the cells be delivered, and lastly (v) why does cell transplantation remain an attractive candidate for promoting neural repair after injury? Recent developments in neurobiology and engineering now enable us to start addressing these questions with multidisciplinary expertise and methods. This is consistent among transplants of either tissue blocks6 or freshly prepared, mechanically dissociated cell suspensions8. Chemically dissociating and culturing this developing tissue yields a more selected population of neuronal and glial restricted progenitors . Until recently, the ability to characterize the phenotype of these donor cells has been elusive. Yet identifying and selecting specific donor cells is becoming crucial for effective treatment of the injured nervous system. Rebuilding functional neuronal networks within the injured spinal cord with transplanted cells will require donor neuronal elements that are capable of appropriate network formation and function. This has led to the notion of Who, What, When, Where and Why , and are they used alone or in combination with other cells ? What is the target organ  and target network  for repair? When are the donor cells being transplanted  and what is the internal milieu of the injured nervous system like at that time? Where should donor cells be transplanted ? Why transplant cells for repair?Advances in stem cell biology and cellular engineering have paved the way to a new era of cell transplantation. Several decades of pre-clinical and clinical research have shown that developing neural tissues, or the neural precursor cells that can be derived from them, can be transplanted into the injured central nervous system, integrate with surrounding host tissue, and promote both anatomical repair and functional improvement. From this research, it has become clear that donor tissues contain a highly heterogeneous population of neural phenotypes. The focus of this discussion will be on the use of neural cells for treatment of spinal cord injury (SCI). Tissues isolated from the developing spinal cord are inherently rich with the essential building blocks for repair: neuronal precursors , glial precursors , vascular endothelial cells, microglia, and extracellular matrix and Why ? Who areThe focus of the present review is on transplantation of neural precursor cells (NPCs)—the cells within and cultured from developing neural tissues. Our increasing understanding of these spinal cord-derived neural elements and how they can contribute to repair guides us toward tailoring cell therapies for treating SCI. Some discussion will also include stem cell-derived NPCs, studies with which have often been built upon the knowledge gained from spinal cord-derived cells. With a growing appreciation for the range of neuronal and glial phenotypes that exist within the normal and developing spinal cord, those seeking to transplant NPCs have begun assessing donor cell phenotype more rigorously. These experiments began by using tissue obtained directly from the developing embryonic spinal cord. While often referred to as “fetal” tissue or cells, the term is typically used to describe cells derived from developmental tissue beyond the blastocyst stage  without distinction between embryonic and fetal stages of development. This may be a misnomer, especially when applied to rodent systems that have a relatively short fetal stage (embryonic day (E) 17–21 in rats).5 demonstrated that donor cells harvested directly from the developing spinal cord  provided a vastly heterogeneous population of cells for transplantation into the injured adult spinal cord. This has since been replicated independently by our research team8 and others9. They also had the capacity to retain their long-term phenotype, yielding mature spinal cord morphology11, and they become integrated with host neurons1214. These cells were also capable of modifying the internal milieu of the surrounding injured spinal cord, making it more permissive for repair1517. So, who are each of the donor cells that contribute to this repair?Early studies by Reier et al.18. Advances in molecular genetics and developmental biology have elucidated specific SpIN subtypes via their transcriptional factor profiles19, which are present at the age identified to result in optimal cell survival after transplantation . As a result, we have a better understanding of the development of specific SpIN precursors and their roles in motor and sensory neural circuits. These circuits contain an intricate balance of excitatory, inhibitory, and neuromodulatory SpINs. Understanding this balance in the normal spinal cord, and how neuroplasticity after injury may change this balance, will help predict which donor cell populations should be used for repair. It should be noted that spinal tissues dissected at this developmental stage  cut the axons of spinal (lower) motoneurons that have developed already, resulting in retrograde cell death. Accordingly, examples of spinal motoneurons within tissues isolated at this time are rare20.Neuronal precursors can be identified by molecular markers such as cadherins (ENCAM), neurofilaments, and microtubules . A vast range of transcription factors have also been characterized, enabling the histological identification of specific neuronal subtypes19. White et al.6 demonstrated differences between transplantation of dorsally and ventrally derived developing spinal cord tissues, when transplanted to repair phrenic (diaphragm) motor networks after cervical SCI. This study revealed that while ventrally derived tissue can be functionally beneficial, dorsally derived tissues may in fact limit the potential for motor recovery. With this in mind, recent studies have begun to focus on subsets of these SpINs for transplantation21, to assess which cells may be most effective for repair. The V2a SpINs have been a strong candidate for repair of motor networks2124. In the uninjured spinal cord, it is a pre-motor, excitatory SpIN that projects ipsilaterally. Thus, if transplanted on the side of the injury, they should increase activity within otherwise denervated motor neurons ipsilateral to injury. The V2a SpINs have also been associated with spontaneous neuroplasticity, further supporting their potential as a therapeutic target26. In contrast, quite different cell types may be more effective at treating hyperreflexia, spasticity, and/or pain28. With advances in cellular engineering, work is underway to purify several populations of distinct SpINs for transplantation2932.While ventrally derived tissues comprise primarily glial progenitors and motor or pre-motor interneuronal precursors, dorsally derived tissues comprise mostly interneuronal precursors with sensory functions13335 and Fischer3643 teams have revealed a great deal about the effects of culturing E13.5–14 spinal cord tissue prior to transplantation, and the refined the populations of neuronal and glial restricted progenitors  that result from the process. For example, the E14 rat spinal cord comprises approximately 5–10% of multipotent neuroepithelial cells (NEPs), 30% GRPs, and 60% NRPs1. Isolation and culture of these cells refines the donor populations to neuronal and glial progenitors 1 that have a capacity for self-renewal but restricted differentiation fate 38. However, less is known about the neuronal subtype of these cell populations with culture and how this may change over time.Studies initiated three decades ago by the Rao44. While early tissue transplant studies used developing brain and spinal cord sources, the latter was found to be most effective for spinal cord repair. However, brainstem-derived neurons with modulatory functions have been shown to be effective for improving function after SCI4547. Transplanting embryonically derived neuromodulators  at the lumbar level may facilitate recovery of locomotor circuits by activating preserved components of the central pattern generator. Brain-derived neural stem cell populations have also been used to treat the injured spinal cord4852. These studies also confirmed that the surrounding host environment influences the fate of transplanted stem cells, which become both neuronal and glial populations.While this discussion has centered on transplantation of spinal neuron progenitors, brain and brainstem neurons have also been tested for repair of the injured spinal cord54, or derived from stem cells. Donor motoneuron candidates survive transplantation into the adult spinal cord, and retain neuronal morphology, but growth and connectivity to peripheral targets seems to be a much greater challenge. In contrast, donor motoneuron candidates transplanted into peripheral nerve survived and served as a relay between surviving host motoneurons and their peripheral targets5557. Ongoing work in this area will better ascertain how to work with this population of donor cells.While spinal motoneurons are not often identified in transplants of embryonically derived spinal tissues, it is possible to attain large diameter, cholinergic, putative motoneurons from spinal tissues obtained earlier22. Alternatively, stem cell-derived neuronal populations can be driven toward specific phenotypic fates, but whether these fates are retained after transplantation, or whether they achieve the appropriate long-term function, is a subject of ongoing investigation. With a growing use of biomaterials to support transplanted cells, another consideration is how the biomaterial may affect which neuronal phenotypes survive pre- or post-transplantation into the injured spinal cord. These considerations are not unique to donor neurons, as they may also influence survival and differentiation of transplanted glia.At present, there is a general understanding of the types of precursors that exist within the developing nervous system at ages used to source donor tissue. However, the effects of isolation and cell culture on these phenotypes, and how they may be affected by the injured adult spinal cord once transplanted, is less clearly defined. We recently showed that just two days of 2D or 3D-cell culture altered transcription factor expression2B5, platelet-derived growth factor receptor alpha), intermediate filaments and cytoskeletal proteins , transcriptional markers (oligodendrocyte lineage transcription factors), and other binding proteins . The developing rat spinal cord at E13–14 comprises astrocytes, oligodendrocytes (and their precursors), and microglia. Astrocytes during these development stages are supportive of neural growth and development, and can facilitate endogenous axonal regeneration5860. However, transplantation of GRPs cultured from E13–14 rat spinal cord, into the injured adult spinal cord, has been shown to attenuate inhibitory aspects of the injury environment and enhance host axon growth6163. Immunohistochemistry of transplanted GRPs in vivo suggests that most donor cells become both astrocytes and oligodendrocytes62. While both Type 1  and Type 2  astrocytes have been reported2, additional studies are required to assess A1 versus A2 phenotype of these cells64. Transplantation of mature astrocytes derived from GRPs in vitro also survive, migrate into the injured spinal cord, and improve sensory function post-SCI62. With a focus on respiratory networks after cervical SCI, Li et al.65 demonstrated improved functional outcome following transplantation of induced pluripotent stem cell (iPSC)-derived astrocytes.Glial precursors and subtypes can be identified by molecular markers such as surface gangliosides and receptors , while the numbers of astrocytes and oligodendrocytes more distant from the lesion site become more even. The migration of oligodendrocytes away from the lesion and toward host axons could be an indication of these donor cells migrating to myelinate axons. This regional difference in donor glia may reflect important influences that the injured host spinal cord has on differentiation and/or migration of donor cells, and raises the importance of defining where cells should be transplanted (see below). In contrast, Lu et al.9 found limited migration of donor glia away from the transplant epicenter when delivered with neuronal progenitors, and a larger proportion of donor oligodendrocytes .GRPs can also give rise to oligodendrocytes, but the extent may be dependent on cell preparation. Jin et al.6670 and others7174 found that donor cells promote repair post-SCI, contribute to myelination, and improve functional outcome. These initial experiments led to the translational investigation of OPCs for treatment of SCI74, with clinical trials initiated by Geron, and more recently by Asterias.Another cell source that has been used both pre-clinically and clinically is selected populations of oligodendrocyte precursor cells (OPCs). Using stem cell-derived OPCs, Keirstead et al.While technically not of a neural lineage, donor microglia are found in transplants of developing spinal cord tissue. However, the contribution of these donor microglia to inflammation, survival, or development within donor tissue remains poorly defined. Chemically dissociating and culturing this donor tissue source, however, selects for astrocytic and oligodendroglial precursors and removes microglia. This is an example of the greater range of cell types that can be present in non-cultured donor tissue.1), developing neural tissues used for transplantation (not cultured) contain many other elements that may also contribute to neural repair. In addition to microglia, this donor tissue includes extracellular matrix and vascular endothelial cells, which support cell survival and growth through the expression of growth-supportive proteins . Donor vascular cells may support growth by recapitulating neural development and providing a growth-supportive surface for axon growth cones. The presence of these components may also contribute to improved vascular repair seen with tissue transplantation, restoring its metabolic capacity75. With only limited effort made to assess their potential as donor substrates76, the focus has remained on neuronal and glial elements.While cultured donor neural precursors are composed primarily of NRPs and GRPs (at a ratio of approximately 2:1what the target system is for treatment becomes an important consideration (see below).We now have the tools to identify, screen, and enrich for specific cell phenotypes destined for transplantation. With this in mind, the question of what the intended target for repair is. Within the injured spinal cord, which neural network is the intended focus? While it would be ideal to transplant cells that are effective at repairing all circuits, donor neurons will have specific functions and may be effective for some circuits more than others . While lower  motoneurons clearly target motor systems, there is a wide range of SpIN phenotypes with equally variable contributions to motor and sensory functions. As described above, White et al.6 reported differences when transplanting tissue derived from the dorsal versus ventral developing spinal cord . With some evidence for cells of defined neuronal fate retaining the capacity to synaptically integrate with appropriate host circuitry77, a logical goal for network repair will be to harness neuronal cells that are not only found within the network being treated, but are also capable of driving recovery . Thus, identifying the target network and the normal components of that network are essential for optimal treatment with transplanted cells.As the phenotype of donor cells becomes more clearly defined, there is a need to reconsider 79. SpINs are known to not only contribute to control and modulation of function, but are also key neural elements in plasticity after SCI7981. Recent pre-clinical studies are beginning to identify specific subsets of SpINs that play restorative roles after SCI. Within the phrenic motor circuit—which controls the diaphragm—a subset of excitatory cells known as “V2a” INs have now been shown to contribute to plasticity in pre-clinical models of amyotrophic lateral sclerosis82 and SCI25. Capitalizing on this finding, we recently demonstrated that transplantation of NPCs that were enriched with V2a cells resulted in improved phrenic motor recovery after cervical SCI83. In contrast, transplantation of inhibitory neurons may be better suited for treating pain and spasticity. Fandel et al.27 demonstrated improved recovery of bladder function and neuropathic pain in a mouse model of SCI, following transplantation of inhibitory neurons. Thus, it is possible that each system being treated will benefit from unique donor phenotype combinations.One cell that is of increasing interest as a target for SCI is the SpIN84. In either case, the system being treated and the temporal, anatomical, biochemical, and functional changes within the compromised network, then raises the question: when is the optimal time for cell transplantation?However, these strategies assume that efficacy is best achieved either via donor cell–host circuit integration, or that donor cells can elicit necessary effects without synaptic integration . Thus, the intended goal is to either “replace” relevant cells that are lost following injury, or provide new populations of cells that elicit pro-neuroplastic properties and enhance recovery. Alternatively, “by-stander” effects of donor cells  may be sufficient to achieve some recovery, as evident in work focused on transplanting donor cells that maintain their stemness even after transplantation85. Cell therapies have been used to neuroprotect the injured nervous system and limit tissue damage , enhance spontaneous neuroplastic mechanisms, restore tissue continuity and provide a growth permissive substrate for axonal growth and repair, and replace lost neurochemical input . In general terms, treatments can be divided into those applied acutely, sub-acutely, and chronically. As outlined in Timing of treatment following injury depends primarily on treatment goal (treating the acute vs. chronic pathophysiology), which also influences which donor cells would be optimal for repair. It is also a crucial consideration for cell transplantation strategies in general, as temporal changes in the host environment may affect donor cell survival, proliferation, and differentiation97.While many pre-clinical studies first test treatment efficacy in acute or sub-acute models of SCI, there has been a pre-clinical and clinical push toward developing treatments for more chronic time-points, which will then benefit a much larger population. Pre-clinical studies have even begun assessing treatment efficacy in aged rats, more than a year post-injuryClinical trials using cell therapies are also expanding their treatment window to target a wide population of people with SCI. As our understanding of the temporal changes within the injured spinal cord improves—at and distant from the injury site—the question becomes: where donor cells can and/or should be delivered to optimally improve outcome?98, which likely impacts functional outcomes.When deciding where to transplant cells to treat the injured spinal cord, one must consider the goal of transplantation and accordingly also the cells being used. For example, while oligodendrocytes might be transplanted into regions of primary demyelination, or those containing newly growing (unmyelinated) fibers, donor neurons capable of replacing damaged or dead neurons should be delivered into the lesion cavity. In contrast, donor neurons intended to provide neuromodulatory functions  may need to be delivered to denervated networks distant from the injury site. Once the location is established, the cytoarchitecture at that site needs to be defined. The location where donor cells are implanted can also affect their phenotypeWhile cell transplantation by its very nature is invasive, the goal remains to be minimally invasive. Thus, delivery of cells to distant locations must take into account that the tissue—while perhaps denervated—is relatively intact. In contrast, delivery to the lesion epicenter is easier to justify, but then has different caveats. Yet, with most cell transplants designed to promote neural repair, the lesion site and/or the peri-lesional area is the most commonly used site for transplantation.99101, has addressed this issue. Closed lesion sites associated with contusion or compression injuries result in cavitation in most species, providing an enclosed site for transplantation. However, the second issue associated with transplants into the lesion site is that it represents both a molecular and physical barrier to repair. Wound-healing processes post-injury result in scar formation that can prevent donor cell integration to some extent. Despite this, transplantation of neuronal and glial progenitors into the lesion epicenter has been shown to alleviate this, restoring tissue continuity and providing a bridge for axonal repair. There has been some suggestion that it is the donor glial progenitors that provide this modulatory effect on the scar17.If the lesion is penetrating , there must be a mechanism to keep transplanted cells at the lesion site. Use of either donor tissue pieces, or combined delivery with a biomaterial102 and respiration47. Intravenous injection of other donor cell populations  has also been used to elicit by-stander effects that promote some functional improvement.While many studies are focused on transplantation at the injury site, therapeutic effects can be achieved away from the injury site as well, especially if the intended goal is “by-stander” effects . Accordingly, donor cells can be transplanted wherever such effects are more warranted. Neuromodulation of motor output  can also be achieved with transplantation of these neuron types in the vicinity of target lower motoneurons that may be several spinal segments away from the injury. For example, the delivery of cells below the level of injury after a cervical or thoracic injury can still modulate function of the target cells for locomotion103 as well as bone marrow stromal cells104107. In fact, previous work has demonstrated that both endogenous108 and transplanted NPCs109 can migrate to sites of pathology and contribute to anatomical repair of nervous tissue. The chemotaxis driving this migration can also be engineered. For instance, viral vectors can be used to induce trophic factor expression and promote migration of donor cells to relevant targets, as has been done with directing growth of donor axons87.While the vast majority of neural cell transplantation strategies  have utilized intraparenchymal injection of cells directly into the lesion site or immediately surrounding spared tissue, there are studies that have employed less invasive approaches such as intrathecal delivery of donor cells. Parenchymal injection of donor cells, albeit an efficient delivery method, is considered to be an invasive technique risking further damage to the injured spinal cord. Delivery of donor cells into the cerebrospinal fluid is a potential alternative and has been demonstrated as a feasible technique in pre-clinical studies using neural progenitorsWith an ever-expanding number of approaches being developed for treatment of the injured spinal cord, what is the benefit of using cell transplantation? First, most cell therapies in testing are a natural mix of cell types. For example, those derived from neural precursors contain neuronal and glial progenitors (at the very least). In that way, they can be seen as an endogenous  combinatorial strategy.Second, cells are capable of a vast range of functions. Cells are biological elements capable of sensing, adapting, integrating with—and even modifying—their surrounding environment. Transplanted donor neurons are capable of synaptically integrating with host circuitry, and functionally contribute to restoring the communication once broken by a SCI. Donor glia  respond to the surrounding environment, but unlike host astrocytes, donor astrocytes appear to maintain a growth-supportive phenotype. These donor astrocytes not only modify the existing glial scar at an injury site, they also appear to guide host axons into the injury site and transplant. Like the endogenously proliferating host oligodendrocytes, donor oligodendrocytes not only support neurite myelination, but there is some suggestion that they also regulate inflammatory cascades. Lastly, donor endothelial cells serve as self-assembling biological scaffolds, coming together with host endothelial cells to restore tissue vascularity, while also supporting neurite outgrowth as seen in the developing nervous system.While we begin to appreciate the vast capacity of cells available for transplantation and repair of the injured nervous system, the optimal approach will most likely be built on multidisciplinary strategies. For example, expertise in genetic, anatomical and molecular neural development, and neural network electrophysiology are crucial in identifying optimal cellular components for repair. Cellular engineering is critical to the generation of specific cell subtypes tailored for repair. Pre-clinical and clinical expertise in activity-based therapies  and neuromodulation  are essential in designing combinatorial strategies to help optimize transplant integration with host injured circuitry. Finally, communication between scientists, clinicians and patients/patient advocates is important for translational success: (i) therapies need to be developed to best meet medical needs, (ii) pre-clinical studies need to be conducted under consultation with neurosurgeons and clinicians that will eventually coordinate clinical trials, (iii) ongoing trials need to be conducted in parallel with pre-clinical research to continually refine and improve treatments, and (iv) translated treatments need to be reverse translated to re-assess treatment goals and ensure they continue to meet the needs of a changing patient population.who are the ideal cells for transplantation and what is the target for repair, (ii) what are the strengths and weaknesses of these cells for the target, (iii) how and when best to harness their strengths, and (iv) when and where to use them. Yet pre-clinical studies are now becoming more focused on these issues.Cells are likely capable of far more than we currently appreciate. Tailoring cell therapies for individuals is becoming a commonly sought goal. Once we establish the patient and neural network to be treated, and the intended post-injury time for treatment, then the appropriate donor cell can be engineered and transplanted into the injured spinal cord. One of the biggest limitations we currently face is that we are still trying to understand (i) As appropriate donor cells are identified, logistical and ethical considerations become critical in then translating cell therapies. What is the original source of donor cell types used? Have they been obtained, prepared, and preserved adhering to established guidelines and legislature for global safety and ethics? Even if the optimal donor cell type(s) are identified, and are obtained safely and ethically, how are clinical trials conducted ? For that matter, how often are cell therapies used to treat patients without rigorous pre-clinical and clinical testing ? As new strategies develop for designing novel donor cell types, the regulations on clinical translation must be routinely re-evaluated to promote the safe and ethical use of these break-through technologies.With an improved understanding of cell biology and neural development, neural phenotypes are becoming better classified and studies have begun focusing on use of more specific cell types for transplantation. Existing cellular engineering and stem cell biology methods now enable the development of purified populations of donor cells that can be genetically modified to alter phenotype and function. As we better understand the neural repair process, the temporal use of cell therapies will become more refined, and new cell types may be included in donor populations. As the techniques available to us improve and we better understand the donor cell populations, the coming years will bring exciting advances in cell therapies for spinal cord repair.