Factors affecting psychiatrist hesitation towards epilepsy care and care for patients with epilepsy transitioning from pediatric to adult care: A survey by the Japanese Society of General Hospital Psychiatry.

OBJECTIVE: This study was undertaken by the Epilepsy Subcommittee of the Japanese Society of General Hospital Psychiatry (JSGHP) to explore the challenges faced by psychiatrists in treating epilepsy and the difficulties encountered during the transition of patients with epilepsy (PWE) from pediatric to adult care. METHODS: An online survey targeting 1,980 JSGHP-affiliated psychiatrists was conducted from May to July 2022. The participants were asked to complete a questionnaire on epilepsy care. We analyzed the factors associated with participant hesitancy to treat epilepsy and their professional characteristics. RESULTS: Responses were obtained from 545 of the 1,980 solicited psychiatrists (response rate: 27.5 %). The mean number of years of clinical experience in psychiatry was 20.9 ± 10.3 years. A majority of the psychiatrists were hesitant toward treating epilepsy (89.2 %) and managing the transition of PWE from pediatric services to adult care (83.3 %). Logistic regression analysis showed that the absence of hesitation toward epilepsy treatment was significantly associated with years of clinical experience in psychiatry (OR: 1.05, p = 0.002), being a board-certified epileptologist (OR: 4.36, p = 0.037), having colleagues who are specialists in epilepsy care that may be consulted in the workplace (OR: 2.12, p = 0.027), and general confidence in managing PWE transition from pediatric to adult care (OR 3.54, p < 0.001). Confidence in managing the transition was positively correlated with being a board-certified psychiatrist of the Japanese Society of Psychiatry and Neurology (OR: 4.55, p = 0.048), being a board-certified psychiatrist of the JSGHP (OR: 1.75, p = 0.034), treating six or more PWE per month (OR: 3.54; 95 % CI, p < 0.001), and overall confidence in treating epilepsy (OR: 3.38, p < 0.001). CONCLUSIONS: Alleviation of reluctance to providing epilepsy care and managing the process of transition are correlated; however, the factors influencing each are distinct. To reduce resistance to epilepsy treatment, enhancing the knowledge of epilepsy and creating an environment conducive to consultations are essential. Improving transition-related outcomes, having substantial psychiatric expertise, and increasing opportunities to treat PWE are of great significance. The integration of these approaches may enable psychiatrists to alleviate hesitancy towards epilepsy care and enhance both treatment and transitional care modalities.

Generation of transmitochondrial cybrids using a microfluidic device.

Mitochondrial cloning is a promising approach to achieve homoplasmic mitochondrial DNA (mtDNA) mutations. We previously developed a microfluidic device that performs single mitochondrion transfer from a mtDNA-intact cell to a mtDNA-less (ρ0) cell by promoting cytoplasmic connection through a microtunnel between them. In the present study, we described a method for generating transmitochondrial cybrids using the microfluidic device. After achieving mitochondrial transfer between HeLa cells and thymidine kinase-deficient ρ0143B cells using the microfluidic device, selective culture was carried out using a pyruvate and uridine (PU)-absent and 5-bromo-2'-deoxyuridine-supplemented culture medium. The resulting cells contained HeLa mtDNA and 143B nuclei, but both 143B mtDNA and HeLa nuclei were absent in these cells. Additionally, these cells showed lower lactate production than parent ρ0143B cells and disappearance of PU auxotrophy for cell growth. These results suggest successful generation of transmitochondrial cybrids using the microfluidic device. Furthermore, we succeeded in selective harvest of generated transmitochondrial cybrids under a PU-supplemented condition by removing unfused ρ0 cells with puromycin-based selection in the microfluidic device.

Suppression of joint destruction with subcutaneous tocilizumab for Japanese patients with rheumatoid arthritis in clinical practice.

Objectives: To investigate the efficacy of suppressing joint destruction with subcutaneous tocilizumab (TCZ-SC) for Japanese rheumatoid arthritis (RA) patients in the real-world clinical setting.Methods: This 1-year prospective, multicenter study included 110 RA patients in whom TCZ-SC was newly initiated. Primary endpoint was the change from baseline in vdH-modified total Sharp score (mTSS) at week 52. Structural remission was defined as yearly mTSS of 0.5 or less. Disease activity was evaluated using the disease activity score (DAS28-ESR) and clinical disease activity index (CDAI).Results: At baseline, the patients' mean age was 58.6 years, and the mean disease duration was 10.6 years. The proportion of patients who were naïve for biologics was 44.5%, and 64.5% concomitantly received methotrexate. The yearly mTSS showed significant improvement from 9.41 before TCZ-SC initiation to -0.15 after 52 weeks. The structural remission rate was 76.1%. After 52 weeks, the DAS28-ESR and CDAI remission rates were 52% and 21%, respectively. Although the previous usage of biologics and baseline disease activity significantly affected the clinical remission, no factors with significant effects on structural remission were identified.Conclusion: These findings support the efficacy of TCZ-SC in suppressing disease activity as well as joint destruction over a 1-year period.

Cytoplasmic fusion between an enlarged embryonic stem cell and a somatic cell using a microtunnel device.

Based on a previous finding that fusion of a somatic cell with an embryonic stem (ES) cell reprogrammed the somatic cell, genes for reprogramming transcription factors were selected and induced pluripotent stem (iPS) cell technology was developed. The cell fusion itself produced a tetraploid cell. To avoid nuclear fusion, a method for cytoplasmic fusion using a microtunnel device was developed. However, the ES cell was too small for cell pairing at the device. Therefore, in the present study, ES cell enlargement was carried out with the colchicine derivative demecolcine (DC). DC induced enlargement of ES cells without loss of their stemness. When an enlarged ES cell was paired with a somatic cell in the microtunnel device, cytoplasmic fusion was observed. The present method may be useful for further development of reprogramming techniques for iPS cell preparation without gene transfection.

Cryopreservation of adhered mammalian cells on a microfluidic device: Toward ready-to-use cell-based experimental platforms.

In this paper, we describe cryopreservation of mammalian cells in the adhered state on a microfluidic device (microdevice) for the first time. HeLa, NIH3T3, MCF-7, and PC12 cells were cultured on a microdevice in which a commercial polystyrene dish surface was used as the cell adhesion surface. Without cell-detaching treatment, the microdevice was stored in a freezer at -80°C. After thawing, we observed a greater number of live cells on the microdevice than those on a control culture dish. Although the effectiveness of the microdevice varied depending on the cell type and surface coating, the trend was consistent. We confirmed that the phenotype of the PC12 cells to differentiate into neuron-like cells was kept after the on-chip cryopreservation, and that the results of cytotoxicity test of cisplatin against the HeLa cells were essentially unchanged by the on-chip cryopreservation. These findings will open up a new possibility of ready-to-use cell-based experimental platforms.

Expert opinions on the first-line pharmacological treatment for delirium in Japan: a conjoint analysis.

BACKGROUND: There is little expert consensus as to which drugs should comprise the first-line pharmacological treatment for delirium. We sought to assess experts' opinions on the first-line oral and injection drugs for delirium associated with a diverse range of clinical features using a rating-based conjoint analysis. METHODS: We conducted a cross-sectional study. We mailed a questionnaire to all consultation-liaison psychiatrists/educators certified by the Japanese Society of General Hospital Psychiatry. RESULTS: Of 136 experts (response rate: 27.5%), more than 68% recommended the use of risperidone or quetiapine administered orally for hyperactive delirium, except in patients with comorbid diabetes and renal dysfunction. More than 67% recommended the use of haloperidol administered intravenously for hyperactive delirium if an intravenous line has been placed. No oral or injection drugs were recommended by over half of experts for treatment of hypoactive delirium with any clinical features. CONCLUSIONS: In the absence of a definitive treatment trial, there are both areas of agreement and a lack of consensus regarding the first-line drug. Efforts are needed to routinely collect information that would allow a comparison of the effectiveness and safety of various drugs in real-world clinical practice.

Modulating F-actin organization induces organ growth by affecting the Hippo pathway.

The Hippo tumour suppressor pathway is a conserved signalling pathway that controls organ size. The core of the Hpo pathway is a kinase cascade, which in Drosophila involves the Hpo and Warts kinases that negatively regulate the activity of the transcriptional coactivator Yorkie. Although several additional components of the Hippo pathway have been discovered, the inputs that regulate Hippo signalling are not fully understood. Here, we report that induction of extra F-actin formation, by loss of Capping proteins A or B, or caused by overexpression of an activated version of the formin Diaphanous, induced strong overgrowth in Drosophila imaginal discs through modulating the activity of the Hippo pathway. Importantly, loss of Capping proteins and Diaphanous overexpression did not significantly affect cell polarity and other signalling pathways, including Hedgehog and Decapentaplegic signalling. The interaction between F-actin and Hpo signalling is evolutionarily conserved, as the activity of the mammalian Yorkie-orthologue Yap is modulated by changes in F-actin. Thus, regulators of F-actin, and in particular Capping proteins, are essential for proper growth control by affecting Hippo signalling.

Effects of ROCK inhibitor Y-27632 on cell fusion through a microslit.

We previously reported a direct cytoplasmic transfer method using a microfluidic device, in which cell fusion was induced through a microslit (slit-through-fusion) by the Sendai virus envelope (HVJ-E) to prevent nuclear mixing. However, the method was impractical due to low efficiency of slit-through-fusion formation and insufficient prevention of nuclear mixing. The purpose of this study was to establish an efficient method for inducing slit-through-fusion without nuclear mixing. We hypothesized that modulation of cytoskeletal component can decrease nuclear migration through the microslit considering its functions. Here we report that supplementation with Y-27632, a specific ROCK inhibitor, significantly enhances cell fusion induction and prevention of nuclear mixing. Supplementation with Y-27632 increased the formation of slit-through-fusion efficiency by more than twofold. Disruption of F-actin by Y-27632 prevented nuclear migration between fused cells through the microslit. These two effects of Y-27632 led to promotion of the slit-through-fusion without nuclear mixing with a 16.5-fold higher frequency compared to our previous method (i.e., cell fusion induction by HVJ-E without supplementation with Y-27632). We also confirmed that mitochondria were successfully transferred to the fusion partner under conditions of Y-27632 supplementation. These findings demonstrate the practicality of our cell fusion system in producing direct cytoplasmic transfer between live cells.

Hippo pathway regulation by cell morphology and stress fibers.

The Hippo signaling pathway plays an important role in regulation of cell proliferation. Cell density regulates the Hippo pathway in cultured cells; however, the mechanism by which cells detect density remains unclear. In this study, we demonstrated that changes in cell morphology are a key factor. Morphological manipulation of single cells without cell-cell contact resulted in flat spread or round compact cells with nuclear or cytoplasmic Yap, respectively. Stress fibers increased in response to expanded cell areas, and F-actin regulated Yap downstream of cell morphology. Cell morphology- and F-actin-regulated phosphorylation of Yap, and the effects of F-actin were suppressed by modulation of Lats. Our results suggest that cell morphology is an important factor in the regulation of the Hippo pathway, which is mediated by stress fibers consisting of F-actin acting upstream of, or on Lats, and that cells can detect density through their resulting morphology. This cell morphology (stress-fiber)-mediated mechanism probably cooperates with a cell-cell contact (adhesion)-mediated mechanism involving the Hippo pathway to achieve density-dependent control of cell proliferation.

Cell fusion through a microslit between adhered cells and observation of their nuclear behavior.

This paper describes a novel cell fusion method which induces cell fusion between adhered cells through a microslit for preventing nuclear mixing. For this purpose, a microfluidic device which had ∼ 100 cell pairing structures (CPSs) making cell pairs through microslits with 2.1 ± 0.3 µm width was fabricated. After trapping NIH3T3 cells with hydrodynamic forces at the CPSs, the cells were fused through the microslit by the Sendai virus envelope method. With following timelapse observation, we discovered that the spread cells were much less susceptible to nuclear migration passing through the microslit compared with round cells, and that cytoplasmic fraction containing mitochondria was transferred through the microslit without nuclear mixing. These findings will provide an effective method for cell fusion without nuclear mixing, and will lead to an efficient method for reprograming and transdifferentiation of target cells toward regenerative medicine.

Antipsychotics for delirium in the general hospital setting in consecutive 2453 inpatients: a prospective observational study.

OBJECTIVE: Attention to risk of antipsychotics for older patients with delirium has been paid. A clinical question was whether risk of antipsychotics for older patients with delirium would exceed efficacy of those even in the general hospital setting. METHODS: A prospective observational study proceeded over a 1-year period at 33 general hospitals, where at least one psychiatrist worked full time. Subjects were patients who developed delirium during their admission due to acute somatic diseases or surgery, and who received antipsychotics for delirium. The primary outcome was rates and kinds of serious adverse events. RESULTS: Among 2834 patients who developed delirium, 2453 patients received antipsychotics, such as risperidone (34%), quetiapine (32%), and parenteral haloperidol (20%), for delirium. Out of 2453 patients, 22 serious adverse events (0.9%) were reported. Aspiration pneumonia was the most frequent (17 patients, 0.7%), followed by cardiovascular events (4 patients, 0.2%) and venous thromboembolism (1 patient, 0.0%). There was no patient with a fracture or intracranial injury due to a fall. No one died because of antipsychotic side effects. The mean Clinical Global Impressions-Improvement Scale score was 2.02 (SD 1.09). Delirium was resolved within 1 week in more than half of the patients (54%). CONCLUSIONS: In the general hospital setting under management including fine dosage adjustment and early detection of side effects, risk of antipsychotics for older patients with delirium might be low, in contrast to antipsychotics for dementia in the nursing home or outpatient settings. A point may be not how to avoid using antipsychotics but how to monitor their risk.

Remission in patients with active rheumatoid arthritis by tocilizumab treatment in routine clinical practice: results from 3 years of prospectively registered data.

OBJECTIVES: This study aimed to evaluate the remission in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ), based on prospectively registered data in clinical practice. METHODS: We studied 114 consecutive RA patients treated with TCZ for an average of 3.5 years. Remission was evaluated by using the EULAR criteria and the new ACR/EULAR Boolean-based criteria. RESULTS: Among 114 patients (average age 52.2 years; average disease duration 10.6 years), 76 (67 %) had previously received anti-TNF biologics. Mean baseline DAS28-ESR of 5.4 and improved to 2.4 at 36 months. Overall, DAS28-ESR <2.6 was attained by 66.7 %, while ACR/EULAR remission was attained by 35.1 %. ACR/EULAR remission rate was significantly higher in the patients who were biologics-naïve and had good response at the first month. Among 23 patients who completed the treatment for 3 years and had ACR/EULAR remission at 1 year, 15 (65 %) remained in the remission and 16 (70 %) had a DAS28-ESR <2.6 at the final follow-up. The retention rate at 36 months was 68.2 %. CONCLUSIONS: In patients with RA, TCZ is highly effective for both biologics-naïve patients and patients previously exposed to biologics, achieving a high remission rate and drug continuation rate (68.2 %) in clinical practice.

Suvorexant for Reduction of Delirium in Older Adults After Hospitalization: A Randomized Clinical Trial.

Importance: Delirium is common among older hospitalized adults. In addition to presenting immediate management issues, delirium can increase the long-term risk of dementia, institutionalization, and mortality. Delirium is associated with disrupted sleep, and prior studies suggest that some specific sleep-promoting agents may reduce delirium. Objective: To evaluate the orexin receptor antagonist suvorexant for reducing delirium in older adults at high risk for delirium after hospitalization. Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial was conducted at 50 hospitals in Japan between October 22, 2020, and December 23, 2022. The study population included Japanese adults aged 65 to 90 years who were at high risk for delirium (mild cognitive impairment or mild dementia, history of delirium at prior hospitalization, or both) and had been hospitalized for acute disease or elective surgery. Data analysis was performed between January 23 and March 13, 2023. Intervention: Participants were randomized 1:1 to suvorexant (15 mg) or placebo taken at bedtime for up to 7 days while in the hospital. Main Outcomes and Measures: Delirium, the primary end point, was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria while participants were hospitalized. The treatment difference in the proportion of participants with delirium was analyzed. Results: This study included 203 participants: 101 were treated with suvorexant (mean [SD] age, 81.5 [4.5]; years; 52 men [51.5%] and 49 women [48.5%]) and 102 received placebo (mean [SD] age, 82.0 [4.9] years; 45 men [44.1%] and 57 women [55.9%]). There were 17 participants with delirium (16.8%) in the suvorexant group compared with 27 (26.5%) in the placebo group (difference, -8.7% [95% CI, -20.1% to 2.6%]; P = .13). Adverse events were similar between the 2 groups. Conclusions and Relevance: In this randomized clinical trial of suvorexant in older adults at high risk for delirium after hospitalization, fewer participants taking suvorexant had delirium compared with placebo, but the difference was not statistically significant. Further studies are needed to determine whether suvorexant may be useful for reducing delirium, particularly delirium with a hyperactive component, in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT04571944.

One-year outcomes of unipolar depression patients with manic or hypomanic switch during acute antidepressant treatment.

OBJECTIVE: The aim of the study was to investigate one-year outcomes of unipolar depression patients with manic or hypomanic switch during acute antidepressant treatment. METHODS: A review of medical records revealed 37 consecutive patients admitted from 1997 to 2002 who underwent an antidepressant-induced manic or hypomanic switch fulfilling DSM-IV criteria. Their clinical courses were retrospectively investigated after discharge. RESULTS: Of the 37 patients, 33 (89.2%) were followed up for 1 year after discharge. None developed a manic episode, while seven developed a hypomanic episode, including 1 patient who was lost after emerging from a hypomanic episode within 6 months after discharge. Only one of those seven patients developed hypomania during acute antidepressant treatment for a recurrent depressive episode under maintenance mood stabilizer treatment. Furthermore, bipolar conversion occurred in four patients within the first 6 months and in another two patients, including 1 with rapid cycling, over the subsequent 6 months after discharge. Of these 33 patients, 28 received continuous maintenance treatment with mood stabilizers for the one-year period after discharge. CONCLUSIONS: The subjects were considered to have a bipolar nature according to the prevalence rate of bipolar conversion over a one-year period. Longer follow-up studies appear warranted determine the diagnostic issues of antidepressant-induced switch in unipolar depression.

The valproate serum level in maintenance therapy for bipolar disorder in Japan.

The appropriate therapeutic serum valproate level in maintenance therapy for bipolar disorder is not well known. We studied the serum valproate levels in seventeen bipolar I and twenty-four bipolar II disorder outpatients who had been treated with stable doses of valproate successfully for at least 12 months as prophylactic therapy. The trough serum valproate levels were 52.2 +/- 20.4 microg/ml in bipolar I, and 41.0 +/- 18.3 microg/ml in bipolar II disorder patients, respectively. A greater trend towards a higher trough level (p = 0.07) was indicated in the bipolar I disorder group. We speculate that these valproate levels may be an approximation to the appropriate valproate levels in maintenance therapy and that there may be a correlation between the level of valproate required for stabilization and the subtype of the bipolar disorder. However, when interpreting these findings, certain limitations to this study? Need to be taken into account as follows. The sample size was small. We could not look at a group on valproate that had relapsed and a group that had dropped out of maintenance therapy. Further studies are needed.

Remission in patients with active rheumatoid arthritis by tocilizumab treatment in routine clinical practice: results from 3 years of prospectively registered data.

OBJECTIVES: This study aimed to evaluate the remission in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ), based on prospectively registered data in clinical practice. METHODS: We studied 114 consecutive RA patients treated with TCZ for an average of 3.5 years. Remission was evaluated by using the EULAR criteria and the new ACR/EULAR Boolean-based criteria. RESULTS: Among 114 patients (average age 52.2 years; average disease duration 10.6 years), 76 (67 %) had previously received anti-TNF biologics. Mean baseline DAS28-ESR of 5.4 and improved to 2.4 at 36 months. Overall, DAS28-ESR <2.6 was attained by 66.7 %, while ACR/EULAR remission was attained by 35.1 %. ACR/EULAR remission rate was significantly higher in the patients who were biologics-naïve and had good response at the first month. Among 23 patients who completed the treatment for 3 years and had ACR/EULAR remission at 1 year, 15 (65 %) remained in the remission and 16 (70 %) had a DAS28-ESR <2.6 at the final follow-up. The retention rate at 36 months was 68.2 %. CONCLUSIONS: In patients with RA, TCZ is highly effective for both biologics-naïve patients and patients previously exposed to biologics, achieving a high remission rate and drug continuation rate (68.2 %) in clinical practice.

[Mood stabilizers].

Mood stabilizers available in Japan include lithium, valproate, carbamazepine, and lamotrigine. These are prescribed for manic or hypomanic episodes of bipolar disorder, organic mania, and drug-induced mania. Careful dose titration is needed in consideration for serum drug level and clinical symptoms. Lithium frequently develops neurological toxicity because of its narrow therapeutic serum level. Valproate has the most favorable adverse effect profile among mood stabilizers, but gastrointestinal symptoms and weight gain can appear with a dose dependent fashion. Hyperammonemia is occasionally induced early after initiation of valproate and tends to be overlooked. Carbamazepine sometimes develops liver dysfunction and skin disorders associated with allergic mechanisms. Lamotrigine should be slowly titrated to avoid severe skin disorders such as Stevens-Johnson syndrome.

[Clinical issues on prescribing psychotropics for elderly patients].

Psychopharmaologic intervention for elderly patients requires careful considerations for physical characteristics, comorbid medical illness, and interaction between drugs for psychotropic and somatic diseases drugs. Elderly patients often suffer from depression, delirium, and dementia, which occasionally coexist with each other. Antidepressants, antipsychotics, anxiolytics and hypnotics are prescribed according to the targeted psychiatric symptoms. Drug effect tens to be strengthened and prolonged pharmacodynamically in elderly patients because of decline of drug clearance in liver and kidney, prolongation of elimination half life of lipophilic drug resulted from reduced muscle tissue, and elevated free serum drug level induced by low albuminemia. Elderly patients pharmacokinetically develop adverse effects in relatively lower serum drug level. Lower initial dose and slow titration should be strongly recommended. Cerebrovascular disease and neurodegerative disease are frequently observed among elderly patients. Significant number of patients with cerebrovascular disease are complicated with depression, delirium, and in lower prevalence, dementia. Although drugs used in acute phase stroke have no pharmacodynamic interaction with psychotropics, many patients be carefully titrated with continuous monitoring of PT-INR during concurrent use of tricyclic antidepressants and selective serotonin reuptake inhibitors. Alzheimer's disease and Parkinson's disease are highly prevalent and clinically important neurodegerative disease in elderly population. Patients with Alzheimer's disease frequently exhibit delirium soon after hospitalization, which necessitates appropriate pharmacotherapy with psychotropics. After Food and Drug Foundation warned against antipsychotic use for patients with dementia, this off-label use are considered to be avoided but disease frequently coincide with depression and receive antidepressant treatment. If selegiline id prescribed, antidepressants cannot be initiated without discontinuation of selegiline. When delirium develops in patients with Parkinson's disease, second generation antipsychotics such as quetiapine are firstly administered with caution for deterioration of motor symptoms.

Oral theophylline augmentation for patients with missed or inadequate seizures with electroconvulsive therapy.

AIM: An inadequate seizure occasionally occurs during a course of acute electroconvulsive therapy (ECT) under the maximum approved electrical stimulation in Japan of 504 mC. This retrospective study was conducted to determine the effectiveness and adverse reactions of an oral theophylline augmentation technique. METHODS: A retrospective review of medical records was conducted of patients admitted to the Department of Psychiatry, Hiroshima Citizens Hospital, who received acute phase ECT from October 2014 to March 2017. RESULTS: A theophylline augmentation technique was instituted in 13 patients (7 males, 6 females; 56-79 years old). The total number of ECT sessions per patient ranged from 9 to 20 and the number of those with theophylline augmentation per patient ranged from 1 to 17. An augmentation effect was noted in all patients and each finished the scheduled ECT course, except for 1 who developed memory disturbance. The maximum dose of theophylline ranged from 200 to 700 mg/day, and the serum level at 06:00 on the day of the ECT session ranged from 5.3 to 23.6 mg/L in 12 patients, as 1 missed the examination. CONCLUSION: Oral theophylline augmentation can be considered as an effective treatment option for patients undergoing ECT with inadequate seizures.