Volume Reduction of the Dorsal Lateral Prefrontal Cortex Prior to the Onset of Frank Psychosis in Individuals with an At-Risk Mental State.

Although some individuals with at-risk mental states (ARMS) develop overt psychosis, surrogate markers which can reliably predict a future onset of psychosis are not well established. The dorsal lateral prefrontal cortex (DLPFC) is thought to be involved in psychotic disorders such as schizophrenia. In this study, 73 ARMS patients and 74 healthy controls underwent 1.5-T 3D magnetic resonance imaging scans at three sites. Using labeled cortical distance mapping, cortical thickness, gray matter (GM) volume, and surface area of DLPFC were estimated. These measures were compared across the diagnostic groups. We also evaluated cognitive function among 36 ARMS subjects to clarify the relationships between the DLPFC morphology and cognitive performance. The GM volume of the right DLPFC was significantly reduced in ARMS subjects who later developed frank psychosis (ARMS-P) relative to those who did not (P = 0.042). There was a positive relationship between the right DLPFC volume and the duration prior to the onset of frank psychosis in ARMS-P subjects (r = 0.58, P = 0.018). Our data may suggest that GM reduction of the DLPFC might be a potential marker of future onset of psychosis in individuals with ARMS.

Reduced cortical thickness of the paracentral lobule in at-risk mental state individuals with poor 1-year functional outcomes.

Although widespread cortical thinning centered on the fronto-temporal regions in schizophrenia has been reported, the findings in at-risk mental state (ARMS) patients have been inconsistent. In addition, it remains unclear whether abnormalities of cortical thickness (CT) in ARMS individuals, if present, are related to their functional decline irrespective of future psychosis onset. In this multicenter study in Japan, T1-weighted magnetic resonance imaging was performed at baseline in 107 individuals with ARMS, who were subdivided into resilient (77, good functional outcome) and non-resilient (13, poor functional outcome) groups based on the change in Global Assessment of Functioning scores during 1-year follow-up, and 104 age- and sex-matched healthy controls recruited at four scanning sites. We measured the CT of the entire cortex and performed group comparisons using FreeSurfer software. The relationship between the CT and cognitive functioning was examined in an ARMS subsample (n = 70). ARMS individuals as a whole relative to healthy controls exhibited a significantly reduced CT, predominantly in the fronto-temporal regions, which was partly associated with cognitive impairments, and an increased CT in the left parietal and right occipital regions. Compared with resilient ARMS individuals, non-resilient ARMS individuals exhibited a significantly reduced CT of the right paracentral lobule. These findings suggest that ARMS individuals partly share CT abnormalities with patients with overt schizophrenia, potentially representing general vulnerability to psychopathology, and also support the role of cortical thinning in the paracentral lobule as a predictive biomarker for short-term functional decline in the ARMS population.

Structural MRI Study of the Planum Temporale in Individuals With an At-Risk Mental State Using Labeled Cortical Distance Mapping.

Background: Recent studies have demonstrated brain structural changes that predate or accompany the onset of frank psychosis, such as schizophrenia, among individuals with an at-risk mental state (ARMS). The planum temporale (PT) is a brain region involved in language processing. In schizophrenia patients, gray matter volume reduction and lack of normal asymmetry (left > right) of PT have repeatedly been reported. Some studies showed progressive gray matter reduction of PT in first-episode schizophrenia patients, and in ARMS subjects during their development of psychosis. Methods: MRI scans (1.5 T field strength) were obtained from 73 ARMS subjects and 74 gender- and age-matched healthy controls at three sites (University of Toyama, Toho University and Tohoku University). Participants with ARMS were clinically monitored for at least 2 years to confirm whether they subsequently developed frank psychosis. Cortical thickness, gray matter volume, and surface area of PT were estimated using FreeSurfer-initiated labeled cortical distance mapping (FSLCDM). PT measures were compared among healthy controls, ARMS subjects who later developed overt psychosis (ARMS-P), and those who did not (ARMS-NP). In each statistical model, age, sex, intracranial volume, and scanning sites were treated as nuisance covariates. Results: Of 73 ARMS subjects, 18 developed overt psychosis (12 schizophrenia and 6 other psychoses) within the follow-up period. There were no significant group differences of PT measures. In addition, significant asymmetries of PT volume and surface area (left > right) were found in all diagnostic groups. PT measures did not correlate with the neurocognitive performance of ARMS subjects. Discussion: Our results suggest that the previously-reported gray matter reduction and lack of normal anatomical asymmetry of PT in schizophrenia patients may not emerge during the prodromal stage of psychosis; taken together with previous longitudinal findings, such PT structural changes may occur just before or during the onset of psychosis.

Subcortical Brain Volume Abnormalities in Individuals With an At-risk Mental State.

Previous structural magnetic resonance imaging studies of psychotic disorders have demonstrated volumetric alterations in subcortical (ie, the basal ganglia, thalamus) and temporolimbic structures, which are involved in high-order cognition and emotional regulation. However, it remains unclear whether individuals at high risk for psychotic disorders with minimal confounding effects of medication exhibit volumetric changes in these regions. This multicenter magnetic resonance imaging study assessed regional volumes of the thalamus, caudate, putamen, nucleus accumbens, globus pallidus, hippocampus, and amygdala, as well as lateral ventricular volume using FreeSurfer software in 107 individuals with an at-risk mental state (ARMS) (of whom 21 [19.6%] later developed psychosis during clinical follow-up [mean = 4.9 years, SD = 2.6 years]) and 104 age- and gender-matched healthy controls recruited at 4 different sites. ARMS individuals as a whole demonstrated significantly larger volumes for the left caudate and bilateral lateral ventricles as well as a smaller volume for the right accumbens compared with controls. In male subjects only, the left globus pallidus was significantly larger in ARMS individuals. The ARMS group was also characterized by left-greater-than-right asymmetries of the lateral ventricle and caudate nucleus. There was no significant difference in the regional volumes between ARMS groups with and without later psychosis onset. The present study suggested that significant volume expansion of the lateral ventricle, caudate, and globus pallidus, as well as volume reduction of the accumbens, in ARMS subjects, which could not be explained only by medication effects, might be related to general vulnerability to psychopathology.

Individualized Prediction of Transition to Psychosis in 1,676 Individuals at Clinical High Risk: Development and Validation of a Multivariable Prediction Model Based on Individual Patient Data Meta-Analysis.

Background: The Clinical High Risk state for Psychosis (CHR-P) has become the cornerstone of modern preventive psychiatry. The next stage of clinical advancements rests on the ability to formulate a more accurate prognostic estimate at the individual subject level. Individual Participant Data Meta-Analyses (IPD-MA) are robust evidence synthesis methods that can also offer powerful approaches to the development and validation of personalized prognostic models. The aim of the study was to develop and validate an individualized, clinically based prognostic model for forecasting transition to psychosis from a CHR-P stage. Methods: A literature search was performed between January 30, 2016, and February 6, 2016, consulting PubMed, Psychinfo, Picarta, Embase, and ISI Web of Science, using search terms ("ultra high risk" OR "clinical high risk" OR "at risk mental state") AND [(conver* OR transition* OR onset OR emerg* OR develop*) AND psychosis] for both longitudinal and intervention CHR-P studies. Clinical knowledge was used to a priori select predictors: age, gender, CHR-P subgroup, the severity of attenuated positive psychotic symptoms, the severity of attenuated negative psychotic symptoms, and level of functioning at baseline. The model, thus, developed was validated with an extended form of internal validation. Results: Fifteen of the 43 studies identified agreed to share IPD, for a total sample size of 1,676. There was a high level of heterogeneity between the CHR-P studies with regard to inclusion criteria, type of assessment instruments, transition criteria, preventive treatment offered. The internally validated prognostic performance of the model was higher than chance but only moderate [Harrell's C-statistic 0.655, 95% confidence interval (CIs), 0.627-0.682]. Conclusion: This is the first IPD-MA conducted in the largest samples of CHR-P ever collected to date. An individualized prognostic model based on clinical predictors available in clinical routine was developed and internally validated, reaching only moderate prognostic performance. Although personalized risk prediction is of great value in the clinical practice, future developments are essential, including the refinement of the prognostic model and its external validation. However, because of the current high diagnostic, prognostic, and therapeutic heterogeneity of CHR-P studies, IPD-MAs in this population may have an limited intrinsic power to deliver robust prognostic models.

Open-label study of cognitive behavioural therapy for individuals with at-risk mental state: Feasibility in the Japanese clinical setting.

AIM: To date, most cognitive behavioural therapy (CBT) trials for individuals with at-risk metal state (ARMS) have been conducted in few Western countries and its feasibility in other regions, including Japan, has not been established. METHODS: We designed an open-label pilot study. Fourteen ARMS participants received CBT over 6 months and were followed-up for 6 months. RESULTS: Thirteen individuals completed the CBT intervention and assessments. The mean total score on the Positive and Negative Syndrome Scale improved from 60.2 to 46.0 after the intervention (Cohen's d = 1.1). The effects were maintained at the follow-up assessment. One participant transitioned to psychosis after the CBT intervention, and was the only patient who received antipsychotics. CONCLUSIONS: We confirmed the feasibility of the provision of CBT for ARMS in Japan. Since overprescription of antipsychotics is a matter of great concern in Japan, CBT could be a valuable alternative treatment strategy.

Federated multi-site longitudinal study of at-risk mental state for psychosis in Japan.

There has been recent accumulation of evidence and clinical guidance regarding the at-risk mental state (ARMS) for psychosis. However, most studies have been observational cohort and intervention studies of Western populations. To assess the validity of the ARMS concept and the transition rate to psychosis in a non-Western nation, we retrospectively combined and analyzed clinical data of individuals diagnosed with ARMS who were prospectively followed-up at three specialized clinical services for ARMS in Japan. In total, we included 309 individuals with ARMS, of whom 43 developed overt psychosis. We estimated cumulative transition rates to psychosis with the Kaplan-Meier method, obtaining rates of 12% at 12, 16% at 24, 19% at 36, and 20% at 48 months. Only two individuals reported past cannabis use. Despite several differences among the three sites, transition rates did not differ among them. Furthermore, the transition rate of children aged between 14 and 17 years did not differ from that of individuals aged 18 years or older. Regression analysis revealed that meeting the brief limited intermittent psychotic symptoms (BLIPS) criterion was associated with an increased risk of transition to psychosis, whereas genetic risk factors were not. Although antipsychotic prescription was relatively frequent in this cohort, there was no evidence supporting frequent use of antipsychotics for this population. In conclusion, our findings support the assertion that the current concept of ARMS is applicable in Japan. Development of local clinical guidelines and training for clinicians is necessary to disseminate this concept to more clinical settings.

No regional gray matter volume reduction observed in young Japanese people at ultra-high risk for psychosis: A voxel-based morphometry study.

OBJECTIVES: Structural brain magnetic resonance imaging studies of individuals at ultra-high risk (UHR) for psychosis have shown subtle but widespread reductions in baseline gray matter volume (GMV) in the frontal, temporal, and limbic regions compared with healthy controls (HC). These regions coincide with regions of reduced GMV in patients with established psychosis and have led to the consideration of structural changes in UHR as a potential biomarker for future transition to psychosis. However, most studies have been from Europe, North America, and Australia, with few reports from other regions, and two recent studies from Asian countries have failed to detect regional GMV reduction in UHR, suggesting the need for further analysis of an Asian sample. In this study, we investigated GMV reduction in Japanese UHR subjects. RESULTS: The study used voxel-based morphometry to compare magnetic resonance imaging brain scans between 45 UHR individuals recruited by a specialist and 33 HCs. This showed no significant GMV reduction in the UHR group compared with the healthy control group. This negative result may be attributable to characteristics of Asian samples, such as a low prevalence of illicit drug use, or to the heterogeneous nature of UHR subjects.

The relationship between cognitive insight and cognitive performance among individuals with at-risk mental state for developing psychosis.

Impairments in cognitive insight-the capacity to appraise and modify one's own distorted beliefs-are believed to be associated with the formation of psychosis. Nevertheless, the association between cognitive insight and cognitive function among people with at-risk mental state (ARMS) for developing psychotic illness has not been made clear. In this study, we used the Beck Cognitive Insight Scale (BCIS) to assess cognitive insight and the Brief Assessment of Cognition in Schizophrenia (BACS) and the Wisconsin Card Sorting Test (WCST) to assess cognitive functions. Fifty subjects with ARMS and 29 healthy volunteers were recruited as participants. The scores for the two groups on the BCIS, BACS, and WCST were compared and Spearman's rank correlations between the domains of the BCIS and cognitive performance were examined in each group. No significant differences were found in BCIS scores between these groups, whereas all of the cognitive function scores were poorer in the participants with ARMS. In the ARMS group, higher self-certainty on the BCIS was significantly correlated with lower performance in the mean number of categories achieved (ρ=-0.31, P=0.03) and perseverative errors of the Nelson type (ρ=0.29, P=0.04) on the WCST. This indicates that excessively high self-certainty might be linked with weaknesses in cognitive flexibility or set-shifting ability in people with ARMS.

The associations between quality of life and clinical symptoms in individuals with an at-risk mental state and first-episode psychosis.

Quality of life (QOL) is strongly associated with severity of clinical symptoms and is often compromised in patients with chronic or first-episode psychosis (FEP). However, it remains unclear whether baseline QOL in individuals with an at-risk mental state (ARMS) for psychosis is higher or lower than that in patients with FEP, or what specific clinical symptoms relate to a decreased QOL in individuals with ARMS and FEP. The World Health Organization's WHOQOL-BREF, an instrument assessing QOL, was administered to 104 individuals with ARMS and 53 with FEP. Clinical symptoms were assessed by the Positive and Negative Syndrome Scale and the Beck Depression Inventory-II. We compared the four domain scores of the WHOQOL-BREF between the two groups, and calculated Pearson correlations between each WHOQOL-BREF domain score and the clinical symptoms and compared these correlations between the groups. We observed significant correlations between poor QOL and severity of depressive symptoms in both the FEP and ARMS group. No between-group differences were found in any correlation coefficients between WHOQOL-BREF domains and clinical symptoms. Thus, depressive symptoms should be investigated as a key factor relating to poor QOL in both individuals with ARMS and those with FEP.

Deficits of cognitive theory of mind and its relationship with functioning in individuals with an at-risk mental state and first-episode psychosis.

Disturbance of theory of mind (ToM) and its relationship with functioning in schizophrenia is well documented; however, this is unclear in spectrum disorders like at-risk mental state (ARMS) and first-episode psychosis (FEP). To assess mental state reasoning ability, the total score of the Theory of Mind Picture Stories Task questionnaire was compared among 36 Japanese individuals with ARMS, 40 with FEP, and 25 healthy controls (HC). Pearson's correlations between ToM performance and global and social functioning indices were examined. ToM performance for FEP and ARMS subjects was significantly lower than that for HC, though the significance of the difference between the ARMS and HC disappeared when controlling for premorbid IQ. ToM deficits in ARMS subjects were confirmed only in the comprehension of higher-order false belief. Only among FEP subjects were ToM performance and global functioning significantly correlated, though the significance disappeared when controlling for neurocognitive performance or dose of antipsychotics. No significant correlation between ToM performance and social functioning was observed in the FEP and ARMS groups. The current findings suggest that ToM deficits emerge in ARMS subjects confined within a higher-order domain, and that the relationship between ToM impairment and functional deterioration might be established after psychosis onset.

Correction: Criticism and Depression among the Caregivers of At-Risk Mental State and First-Episode Psychosis Patients.

[This corrects the article DOI: 10.1371/journal.pone.0149875.].

Criticism and Depression among the Caregivers of At-Risk Mental State and First-Episode Psychosis Patients.

Expressed emotion (EE), especially criticism, is an important predictor of outcomes for the patient for a wide range of mental health problems. To understand complex links between EE and various relevant variables in early phase psychosis, this study examined criticism, distress of caregivers, other patients', and caregivers' variables, and links between criticism and these variables in those with at-risk mental state (ARMS) for psychosis and first-episode psychosis (FEP). The participants were 56 patients (mean age 18.8 ± 4.2 years) with ARMS and their caregivers (49.4 ± 5.8 years) and 43 patients (21.7 ± 5.2 years) with FEP and their caregivers (49.3 ± 7.4 years). We investigated criticisms made by caregivers using the Japanese version of the Family Attitude Scale and caregiver depressive symptoms via the self-report Beck Depression Inventory. We also assessed psychiatric symptoms and functioning of the patients. Approximately one-third of caregivers of patients with ARMS or FEP had depressive symptoms, predominately with mild-to-moderate symptom levels, whereas only a small portion exhibited high criticism. The level of criticism and depression were comparable between ARMS and FEP caregivers. The link between criticism, caregivers' depression, and patients' symptoms were observed in FEP but not in ARMS caregivers. These findings imply that the interaction between criticism and caregivers' and patients' mental states may develop during or after the onset of established psychosis and interventions for the caregivers should be tailored to the patient's specific stage of illness. Interventions for FEP caregivers should target their emotional distress and include education about patient's general symptoms.

Post-traumatic stress disorder and depression prevalence and associated risk factors among local disaster relief and reconstruction workers fourteen months after the Great East Japan Earthquake: a cross-sectional study.

BACKGROUND: Many local workers have been involved in rescue and reconstruction duties since the Great East Japan Earthquake (GEJE) on March 11, 2011. These workers continuously confront diverse stressors as both survivors and relief and reconstruction workers. However, little is known about the psychological sequelae among these workers. Thus, we assessed the prevalence of and personal/workplace risk factors for probable post-traumatic stress disorder (PTSD), probable depression, and high general psychological distress in this population. METHODS: Participants (N = 1294; overall response rate, 82.9%) were workers (firefighters, n = 327; local municipality workers, n = 610; hospital medical workers, n = 357) in coastal areas of Miyagi prefecture. The study was cross-sectional and conducted 14 months after the GEJE using a self-administered questionnaire which included the PTSD Checklist-Specific Version, the Patient Health Questionnaire-9, and the K6 scale. Significant risk factors from bivariate analysis, such as displacement, dead or missing family member(s), near-death experience, disaster related work, lack of communication, and lack of rest were considered potential factors in probable PTSD, probable depression, and high general psychological distress, and were entered into the multivariable logistic regression model. RESULTS: The prevalence of probable PTSD, probable depression, and high general psychological distress was higher among municipality (6.6%, 15.9%, and 14.9%, respectively) and medical (6.6%, 14.3%, and 14.5%, respectively) workers than among firefighters (1.6%, 3.8%, and 2.6%, respectively). Lack of rest was associated with increased risk of PTSD and depression in municipality and medical workers; lack of communication was linked to increased PTSD risk in medical workers and depression in municipality and medical workers; and involvement in disaster-related work was associated with increased PTSD and depression risk in municipality workers. CONCLUSIONS: The present results indicate that at 14 months after the GEJE, mental health consequences differed between occupations. High preparedness, early mental health interventions, and the return of ordinary working conditions might have contributed to the relative mental health resilience of the firefighters. Unlike the direct effects of disasters, workplace risk factors can be modified after disasters; thus, we should develop countermeasures to improve the working conditions of local disaster relief and reconstruction workers.

The association between cognitive deficits and depressive symptoms in at-risk mental state: a comparison with first-episode psychosis.

Cognitive deficits and a high prevalence of depressive symptoms have been reported in at-risk mental state (ARMS) for psychosis, but the relationships between these variables remain unclear. The Brief Assessment of Cognition in Schizophrenia (BACS) was administered to 50 individuals with ARMS, 50 with first-episode psychosis (FEP), and 30 healthy controls (HC). Clinical symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) and the Beck Depression Inventory-2nd edition (BDI-II). Composite z-scores in BACS were compared between the three groups. Pearson correlations between composite z-scores on the BACS and indices of clinical symptoms were compared in the ARMS and FEP groups. The mean composite z-scores on the BACS for the ARMS (-2.82) and FEP (-2.85) groups were significantly lower than the HC group (P<0.001); no differences between the ARMS and FEP groups emerged (P=0.995). Cognitive deficits and depressive symptoms were significantly correlated in the ARMS group (PANSS depression: r=-0.36, P=0.010; BDI-II: r=-0.34, P=0.02), while the correlation between cognitive deficits and negative symptoms was significant in the FEP group (r=-0.46, P=0.001) and approached significance in the ARMS group (r=-0.25, P=0.08). The correlation between cognitive deficits and depressive symptoms significantly differed between the ARMS and FEP groups (PANSS depression: Z=2.50, P=0.012; BDI-II: Z=1.96, P=0.0499). Thus, a relationship between cognitive deficits and depression appears to be specific to ARMS compared to FEP.

A naturalistic longitudinal study of at-risk mental state with a 2.4 year follow-up at a specialized clinic setting in Japan.

OBJECTIVE: The notion of at-risk mental state (ARMS) is valuable for identifying individuals in a putative prodromal state of psychosis and for reducing conversion risk by pharmacological and psychological interventions. However, further systematic study is required because 1) diagnostic reliability in various clinical settings is not yet established; 2) predictive ability is insufficient; 3) optimal interventions in diversified populations are elusive; and 4) little evidence from non-Western regions exists. METHODS: A naturalistic longitudinal study was conducted at a specialized clinic for early psychosis at a university hospital in Sendai, Japan. Individuals with ARMS (n=106) were recruited and followed up with case-by-case treatment. RESULTS: Two-thirds of the participants were psychiatrist referrals, and 83 were followed up for at-least 1 year (mean follow-up=2.4 years). Fourteen developed psychosis and the estimated (by Kaplan-Meier) cumulative transition rate was 11.1% at 12, 15.4% at 24, and 17.5% at 30 months. At the end-point, about 30% of the 83 followed-up participants including 11 converters received antipsychotic medication. Compared to non-converters, converters showed more severe attenuated psychotic symptoms, including ego-boundary disturbance, formal thought disorder, and emotional disturbance. CONCLUSIONS: The present study replicated previous major Western longitudinal studies, in terms of clinical characteristics, psychosis transition rate, and antipsychotic prescription rate. Our results emphasize the importance of phenomenological assessment of ARMS and intensive care in a clinical setting.

[Activity to prevent mental diseases after the Great East Japan Earthquake].

Following the Great East Japan Earthquake, we have been supporting psychiatric hospitals and mental health and welfare centers in Miyagi Prefecture. In October 2011, with a grant from Miyagi Prefecture, the Department of Preventive Psychiatry was established in Tohoku University Graduate School of Medicine. The institute aims to promote the prevention of and early intervention for mental diseases. As its members, we carry out our duties in collaboration with the Miyagi Disaster Mental Health Care Center. We refer to our activities as the Great East Japan Earthquake Mental Health Support and Research (GEMS) project. The GEMS project includes both practices and research in the affected areas in Miyagi Prefecture. The focus is on supporting those who provide services for survivors long-term, such as municipal employees, nurses, fire fighters, and staff of the social welfare council. We investigated how much the disaster impaired the functioning of psychiatric hospitals and clinics in Miyagi Prefecture. We also conduct mental health surveys in public organizations. Based on the results, we arrange workshops, consultation, or counseling. Moreover, we promote improvement of the mental health skills of mental health professionals, which are essential for mid and long-term support after the disaster. One of them is "Skills for Psychological Recovery". As members of the support organization in the region, we keep working toward the recovery and development of mental health systems in Miyagi Prefecture.

[Application of cognitive behavioral therapy to early phase of psychosis].

Attempts to apply cognitive-behavioral therapy (CBT) to treat patients in the early stage of psychosis, including those with First-Episode Psychosis (FEP) and those with an At-Risk Mental State (ARMS), have recently attracted considerable attention. Such CBT for FEP focuses on promoting the recovery process and relapse prevention, although evidence on its efficacy is currently limited. Further, studies on CBT for ARMS have not consistently demonstrated its effectiveness. Some reports affirm the effectiveness of CBT in FEP prevention, while others claim that the treatment leads to no compelling difference in comparison to nonspecific treatment such as supportive therapy and treatment as usual. It is evident that psychosocial interventions play a fundamental role in the treatment of early stages of psychosis. Therapeutic approaches based on CBT have been applied to various cases: however, further research is necessary in order to produce more concrete results and obtain the evidence needed to approve this method.

[Natori EI project: the early intervention project for psychiatric disorders by the Miyagi Psychiatric Center].

Attempts to promote early intervention (EI) for psychiatric disorders are becoming accepted worldwide. Although several attempts at EI have begun in Japan, this movement is still limited, and the development of concrete EI services suited to individual regions is required. At the Miyagi Psychiatric Center, the "Natori EI project" is being carried out with the aim of improving the mental health of young people. This project involves three activities: consultation and mental health promotion in high schools, specialized outpatient clinics for young people, and psychosocial intervention for first-episode psychosis. There are many difficulties in building a system to support this kind of EI within the framework of the conventional medical care system; it is necessary to sort out issues such as collaboration with government and educational institutions, sharing the basic principle of EI, medical economic problems, ensuring manpower, and staff training system.