New-onset schizophrenia in an adolescent after COVID-19.

Schizophrenia develops during adolescence. Maternal infections during the fetal period increase the incidence of schizophrenia in children, which suggests that the pathogenesis involves neuroinflammation. Here, we report a case of new-onset schizophrenia in a 16-year-old boy after COVID-19. After developing COVID-19, he entered a catatonic state 4 days later and was hospitalized. Benzodiazepines alleviated his catatonia, but hallucinations and delusions persisted. Encephalitis and epilepsy were excluded by magnetic resonance imaging (MRI), encephalography, and cerebrospinal fluid examination. Psychosis persisted after the virus titer declined and the inflammatory response subsided. Moreover, the patient exhibited delusions of control-a Schneider's first-rank symptom. Schizophrenia was diagnosed, and olanzapine improved his symptoms. He had a brief history of insomnia before COVID-19 but his symptoms did not satisfy the ultra-high-risk criteria. However, COVID-19 may have facilitated development of schizophrenia through neuroinflammation and volume reduction in the gray matter of the right medial temporal lobe. This case demonstrates that infectious diseases in adolescents should be carefully managed, to prevent schizophrenia.

Usefulness of Gabapentin as an Alternative/Adjunct Therapy for Delirium: A Retrospective Observational Study.

BACKGROUND: Antipsychotics are commonly used to treat delirium but can adversely affect the extrapyramidal and cardiac conduction systems. Antipsychotic use has also been reported to be associated with increased mortality in older adults. Therefore, alternative and adjunct medications for delirium are necessary. We retrospectively assessed the efficacy and safety of gabapentin (GBP) as an alternative and adjunct medication for delirium. METHODS: We retrospectively investigated the records of patients with delirium treated with GBP (71 patients; median age, 81 years; interquartile range, 76-87.5 years; 54.9% males) at a general hospital. We examined duration to delirium improvement, as assessed by the Intensive Care Delirium Screening Checklist (ICDSC) and DSM-5 criteria, as well as adverse events. RESULTS: The median (interquartile range) GBP dose was 200 mg (150-350 mg) /day. A total of 71.8% and 85.9% of the patients failed to meet the diagnostic criteria for delirium at 2 days and 5 days after initial administration, respectively (p<0.05). In subgroup analysis, patients with a history of epilepsy or cerebrovascular disease responded better to GBP than did those without such histories, suggesting that patients with abnormal/borderline neuronal activity respond to GBP even though they do not exhibit seizures. GBP did not induce extrapyramidal symptoms, cardiac conduction disturbances, hyperglycemia, or epilepsy but caused sleepiness and myoclonus. CONCLUSIONS: GBP may improve delirium with fewer adverse effects and may be a safe alternative or adjunct treatment for delirium. Dosage adjustment may be necessary to prevent sleepiness.

Dielectric Study on Supramolecular Gels by Fiber Structure Formation from Low-Molecular-Weight Gelator/Water Mixtures.

There are various types of gel materials used in a wide range of fields, and their gelation mechanisms are extremely diverse. Furthermore, in the case of hydrogels, there exist some difficulties in understanding complicated molecular mechanisms especially with water molecules interacting through hydrogen bonding as solvents. In the present work, the molecular mechanism of the structural formation of fibrous super-molecular gel by the low molecular weight gelator, N-oleyl lactobionamide/water mixture was elucidated using the broadband dielectric spectroscopy (BDS) method. The dynamic behaviors observed for the solute and water molecules indicated hierarchical structure formation processes in various time scales. The relaxation curves obtained at various temperatures in the cooling and heating processes showed relaxation processes respectively reflecting the dynamic behaviors of water molecules in the 10 GHz frequency region, solute molecules interacting with water in MHz region, and ion-reflecting structures of the sample and electrode in kHz region. These relaxation processes, characterized by the relaxation parameters, showed remarkable changes around the sol-gel transition temperature, 37.8 °C, determined by the falling ball method and over the temperature range, around 53 °C. The latter change suggested a structure formation of rod micelles appearing as precursors before cross-linking into the three-dimensional network of the supramolecular gels. These results clearly demonstrate how effective relaxation parameter analysis is for understanding the gelation mechanism in detail.

A revision of JPOS/JASCC clinical guidelines for delirium in adult cancer patients: a summary of recommendation statements.

OBJECTIVE: The Japanese Psycho-Oncology Society and the Japanese Association of Supportive Care in Cancer have recently revised the clinical practice guidelines for delirium in adult cancer patients. This article reports the process of developing the revised guidelines and summarizes the recommendations made. METHODS: The guidelines were developed in accordance with the Medical Information Network Distribution Service creation procedures. The guideline development group, consisting of multi-disciplinary members, created three new clinical questions: non-pharmacological intervention and antipsychotics for the prevention of delirium and trazodone for the management of delirium. In addition, systematic reviews of nine existing clinical questions have been updated. Two independent reviewers reviewed the proposed articles. The certainty of evidence and the strength of the recommendations were graded using the grading system developed by the Medical Information Network Distribution Service, following the concept of The Grading of Recommendations Assessment, Development, and Evaluation system. The modified Delphi method was used to validate the recommended statements. RESULTS: This article provides a compendium of the recommendations along with their rationales, as well as a short summary. CONCLUSIONS: These revised guidelines will be useful for the prevention, assessment and management of delirium in adult cancer patients in Japan.

Delusions and Hallucinations Are Associated With Greater Severity of Delirium.

BACKGROUND: The 3 core domains of delirium (cognitive, higher level thinking, circadian) do not include the less common noncore psychotic symptoms. However, psychosis might inform about perturbations of neural circuitry, outcomes, or suggest tailored clinical management. OBJECTIVE: We assessed relationships between psychosis and other characteristics of delirium in patients without dementia or antipsychotics treatment. METHODS: Cross-sectional analysis of 366 adults with delirium per the Delirium Rating Scale Revised-98, whose items distinguish hallucinations and delusions from other types of misperceptions and abnormal thought content, assessed during the preceding 24 hours to capture symptom severity fluctuation. The relationship of psychosis with other delirium characteristics was assessed using bivariate comparisons and analysis of variance as appropriate for groups with no psychosis and any psychosis (hallucinations and/or delusions), and subgroups with only hallucinations, only delusions, or both. A discriminant logistic model assessed variables associated with presence of any psychotic features versus none. RESULTS: Delirium with any psychotic features occurred in 44.5% (163 of 366). Of the 366, 119 (32.5%) had only hallucinations (Hall), 14 (3.8%) had only delusions (Del), and 30 (8.2%) had both (Both). In the psychotic group (n = 163), 73.0% were Hall, 8.6% Del, and 18.4% Both. All psychotic patient groupings had significantly greater delirium severity on the Delirium Rating Scale Revised-98. Delusions and hallucinations were discordant for occurring together. The discriminant model found increased odds of having psychosis as 3 symptom severities increased (visuospatial ability, thought process, and sleep-wake cycle) where these each represented a delirium core domain. The noncore symptom of lability of affect had high odds ratio for psychosis, while motor retardation reduced odds of psychosis in this model. CONCLUSIONS: Consistent with prior reports, psychosis occurred in less than half of delirious patients with delusions being infrequent, and an association with affective lability was found. Given that previous functional magnetic resonance imaging research found a correlation between neural network dysconnectivity with greater severity of delirium, psychotic symptoms might be a clinical marker for greater underlying cerebral cortical neural circuitry dysfunction.

Translation and Cross-Cultural Adaptation of the Japanese Version of the INTERMED Self-Assessment Questionnaire (IMSA) for Patient-Case Complexity Assessment.

Purpose: This study aims to translate and ensure cross-cultural adaptation of a Japanese version of the INTERMED Self-Assessment Questionnaire (IMSA). Methods: A family medicine physician, a medical education specialist, a psychiatrist who prepared the Japanese version of the INTERMED, and two members of the INTERMED consortium were selected as committee members. We used the standard forward and backward translation method to translate the IMSA into Japanese. After translating the original IMSA into Japanese, all committee members discussed and reached a consensus on the proposed translation. The back-translation was performed by an English native professional translator who did not know the original text. We contacted the INTERMED consortium and asked them to review the conceptual equivalence of the back-translated Japanese version with the original version; after two reviews, the members approved the Japanese version. Thereafter, we conducted cognitive debriefings with four patients and nine healthcare professionals to ensure cross-cultural adaptation. Results: The members of the INTERMED consortium approved the use of the Japanese version. We modified some expressions and words, while retaining the original meaning, to make it easier for Japanese patients to understand. Conclusion: We developed a Japanese version of the IMSA. A future study will investigate the construct criterion-related validity and the reliability of the scale.

Does scoring patient complexity using COMPRI predict the length of hospital stay? A multicentre case-control study in Japan.

OBJECTIVE: To clarify the factors associated with prolonged hospital stays, focusing on the COMplexity PRediction Instrument (COMPRI) score's accuracy in predicting the length of stay of newly hospitalised patients in general internal medicine wards. DESIGN: A case-control study. SETTING: Three general internal medicine wards in Chiba Prefecture, Japan. PARTICIPANTS: Thirty-four newly hospitalised patients were recruited between November 2017 and December 2019, with a final analytic sample of 33 patients. We included hospitals in different cities with general medicine outpatient and ward facilities, who agreed to participate. We excluded any patients who were re-hospitalised within 2 weeks of a prior discharge. PRIMARY AND SECONDARY OUTCOME MEASURES: Patients' COMPRI scores and their consequent lengths of hospital stay. RESULTS: The 17 patients (52%) allocated to the long-term hospitalisation group (those hospitalised ≥14 days) had a significantly higher average age, COMPRI score and percentage of participants with comorbid chronic illnesses than the short-term hospitalisation group (<14 days). A logistic regression model (model A, comprising only the COMPRI score as the explanatory variable) and a multiple logistic regression model (model B, comprising variables other than the COMPRI score as explanatory variables) were created as prediction models for the long-term hospitalisation group. When age ≥75 years, a COMPRI score ≥6 and a physician with 10 years' experience were set as explanatory variables, model A showed better predictive accuracy compared with model B (fivefold cross-validation, area under curve of 0.87 vs 0.78). The OR of a patient with a COMPRI score of ≥6 joining the long-term hospitalisation group was 4.25 (95% CI=1.43 to 12.63). CONCLUSIONS: Clinicians can use the COMPRI score when screening for complexity assessment to identify hospitalised patients at high risk of prolonged hospitalisation. Providing such patients with multifaceted and intensive care may shorten hospital stays.

Impact of Behavioral Health Comorbidities on Health Care Costs Among Japanese Patients With Cancer.

BACKGROUND: Little is known about how behavioral health (BH) conditions affect health care costs of patients with cancer in Japan. OBJECTIVE: The purpose of this study is to evaluate the magnitude of general medical claims expenditures for individuals with cancer who use or do not use BH services in Japan. METHODS: The study used a health insurance claims database for more than 3 million enrollees in Japan. All health plan enrollees (18 y or older) who had tumors without metastasis or metastatic solid tumors defined by the Charlson Comorbidity Index were included in the study (n = 20,260). Measurements included total claims expenditures for BH and medical services. RESULTS: The proportion of enrollees using BH services was 12.8%. BH service users accounted for 17.7% of total health service spending. Mean annual cost of total health care services were 1.5 times higher in BH users than those with no BH use, whereas the median was 1.8 times higher. Mean annual medical cost alone for BH users was 1.3 times higher than that for non-BH users, whereas the median was 1.5 times higher. CONCLUSIONS: The findings suggest the importance for the Japanese medical system to address BH needs of patients with cancer and introduce fiscal efficiencies to cancer care. Strategic implementation of effective integrated care services for patients with cancer should be considered in Japan.

General medical claims for behavioral health patients in Japan.

OBJECTIVES: To evaluate the magnitude of general medical claims expenditures (ie, medical service use) for individuals who use and do not use behavioral health (BH) services in the Japanese free-access medical insurance system to determine if BH patients use substantially more health services, as has consistently been reported in the United States. STUDY DESIGN: Retrospective comparison of Japanese occupation-based total health services use for enrollees with and without comorbid BH conditions. METHODS: The study used a health insurance claims database for more than 3 million enrollees in Japan. All health plan enrollees (18 years and older) who had at least 1 diagnosis of a chronic medical condition were included in the study (N = 192,613). Measurements were total claims expenditures for BH and medical services. RESULTS: The proportion of enrollees using BH services was 14.3%. BH service users accounted for 21.1% of total health service spending. Annual total costs of BH service users were 1.6 times higher than those of non-BH users. Annual medical costs of BH users were 1.3 times higher than those of non-BH users. CONCLUSIONS: The results of this Japanese cohort study show that patients with concurrent BH conditions and chronic medical illnesses have substantially lower total health care costs than numerous studies have demonstrated in US populations. This is perhaps in part due to the integration of medical and BH claims payment and care delivery in Japan, an approach that the US health system may wish to consider testing.

JPOS/JASCC clinical guidelines for delirium in adult cancer patients: a summary of recommendation statements.

BACKGROUND: The Japanese Psycho-Oncology Society and Japanese Association of Supportive Care in Cancer recently launched the clinical practice guidelines for delirium in adult cancer patients. The aim of the guidelines was to provide evidence-based recommendations for the clinical assessment and management of delirium in cancer patients. This article reports the process of developing the guideline and summarizes the recommendations made. METHODS: The guidelines were developed in accordance with the Medical Information Network Distribution Service creation procedures. The guideline development group, consisting of multidisciplinary members, formulated nine clinical questions. A systematic literature search was conducted to identify relevant articles published prior to through 31 May 2016. Each article was reviewed by two independent reviewers. The level of evidence and the strength of the recommendations were graded using the grading system developed by the Medical Information Network Distribution Service, following the concept of The Grading of Recommendations Assessment, Development and Evaluation system. The modified Delphi method was used to validate the recommendation statements. RESULTS: This article provides a summary of the recommendations with rationales for each, as well as a short summary. CONCLUSIONS: These guidelines will support the clinical assessment and management of delirium in cancer patients. However, additional clinical studies are warranted to further improve the management of delirium.

Real-World Effectiveness of Ramelteon and Suvorexant for Delirium Prevention in 948 Patients With Delirium Risk Factors.

OBJECTIVE: The aim of this study was to examine the effectiveness of ramelteon and suvorexant for delirium prevention in real-world practice. It explored whether ramelteon and/or suvorexant would affect delirium prevention among both patients at risk for but without delirium (patients at risk) and those with delirium the night before a consultation. METHODS: This multicenter, prospective, observational study was conducted by trained psychiatrists at consultation-liaison psychiatric services from October 1, 2017, to October 7, 2018. Patients who were aged 65 years or older and hospitalized because of acute diseases or elective surgery, had risk factors for delirium, and had insomnia or delirium on the night before the consultation were prescribed ramelteon and/or suvorexant. The decision to take medication was left to the discretion of each patient. The primary outcome was incidence of delirium based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, during the first 7 days. RESULTS: Among 526 patients at risk, those taking ramelteon and/or suvorexant developed delirium significantly less frequently than those who did not, after control for the effects of risk factors on the estimate of an independent association between the effects of ramelteon and/or suvorexant and the outcome of developing delirium (15.7% vs 24.0%; odds ratio [OR] = 0.48;, 95% CI, 0.29-0.80; P = .005). Similar results were found among 422 patients with delirium (39.9% vs 66.3%; OR = 0.36; 95% CI, 0.22-0.59; P < .0001). CONCLUSIONS: Ramelteon and suvorexant appear to be effective for delirium prevention in real-world practice.

Delirium Phenotype by Age and Sex in a Pooled Data Set of Adult Patients.

The authors aimed to evaluate whether the clinical phenotype of delirium differs if dichotomized either by sex or age (cutoff age, 65 years old) in a pooled sample of 406 nondemented adult patients with delirium as defined by DSM-IV criteria. Delirium characteristics were measured with the Delirium Rating Scale-Revised-98 (DRS-R-98). DRS-R-98 items were subgrouped to represent subscores representing the three core domains of delirium (cognitive, higher-order thinking, and circadian), noncore accessory symptoms (psychotic and affective), and diagnostic characteristics (temporal onset, fluctuation, and physical disorder). The authors compared means of the DRS-R-98 subscores and medians of individual items. Exploratory factor analyses evaluated delirium characteristics for each subgroup for each of the four groups-male, female, nongeriatric, and geriatric-while taking into account active medical diagnoses. Males had higher scores on motor agitation and affective lability (behavioral), whereas females had a higher frequency of hypoactive delirium. Delirium had a two-factor structure that emerged in all four study groups, and all its core domains loaded (i.e., correlated together) onto some of these two factors and with circadian domain correlating with accessory symptoms. Although the influence of a variety of active diagnoses on delirium was small and complex, traumatic brain injury had a clear influence on cognitive domain and abrupt onset. Age had a mild influence over delirium characteristics for both males and females. In conclusion, the authors confirmed a two-factor structure for delirium phenomenology, regardless of age and sex, with few significant differences between etiological groups.

Preventive Effects of Suvorexant on Delirium: A Randomized Placebo-Controlled Trial.

OBJECTIVE: No highly effective pharmacologic interventions to prevent delirium have been identified. We examined whether suvorexant, a potent and selective orexin receptor antagonist, is effective for the prevention of delirium. METHODS: We conducted a multicenter, rater-blinded, randomized, placebo-controlled clinical trial in intensive care units and regular acute wards between April 2015 and March 2016. Eligible patients were 65 to 89 years old, newly admitted due to emergency, and able to take medicine orally and had an expected stay or life expectancy of 48 hours or more. Seventy-two patients were randomly assigned using the sealed envelope method to receive suvorexant (15 mg/d; 36 patients) or placebo (36 patients) every night for 3 days. The primary outcome measure was incidence of delirium as determined by the DSM-5. Trained psychiatrists assessed for delirium. RESULTS: We found that delirium developed significantly less often among patients taking suvorexant than among those taking placebo (0% [n/N = 0/36] vs 17% [6/36], respectively, P = .025). Comparison by log-rank test also showed that delirium developed significantly less often among patients taking suvorexant than among those taking placebo (χ² = 6.46, P = .011). Analysis of variance revealed a tendency for main effect of treatment (F = 3.79, P = .053) on the sleep-wake cycle disturbance score (item 1) of the Japanese version of the Delirium Rating Scale-Revised-98 (DRS-R-98-J). There were no significant differences in adverse events. CONCLUSIONS: Suvorexant administered nightly to elderly patients admitted for acute care may provide protection against delirium. Larger studies are needed to show the potential of suvorexant to improve the circadian core domain of delirium. TRIAL REGISTRATION: UMIN Clinical Trials Registry identifier: UMIN000015681​.

Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity.

Th17 cells are key players in defense against pathogens and maintaining tissue homeostasis, but also act as critical drivers of autoimmune diseases. Based on single-cell RNA-seq profiling of pathogenic versus nonpathogenic Th17 cells, we identified protein C receptor (PROCR) as a cell surface molecule expressed in covariance with the regulatory module of Th17 cells. Although PROCR expression in T cells was controlled by the cooperative action of the Th17 lineage-specific transcription factors RORγt, IRF4, and STAT3, PROCR negatively regulated Th17 differentiation. CD4+ T cells from PROCR low expressor mutant mice readily differentiated into Th17 cells, whereas addition of the PROCR ligand, activated protein C, inhibited Th17 differentiation in vitro. In addition, PROCR acted as a negative regulator of Th17 pathogenicity in that it down-regulated expression of several pathogenic signature genes, including IL-1 and IL-23 receptors. Furthermore, T cell-specific deficiency of PROCR resulted in the exacerbation of experimental autoimmune encephalomyelitis (EAE) and higher frequencies of Th17 cell in vivo, indicating that PROCR also inhibits pathogenicity of Th17 cells in vivo. PROCR thus does not globally inhibit Th17 responses but could be targeted to selectively inhibit proinflammatory Th17 cells.

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.

A case of suicide by helium gas.

Helium is a colorless, tasteless, and odorless gas that is used as a lifting gas for air balloons and small airships due to its high level of safety. In recent years, it has become easy to search the Internet for methods to commit suicide, and the use of helium gas for this purpose has recently been garnering attention. We report a case of a male in his 30's in which helium gas was used to commit suicide. He was found unconscious on a bed with a plastic bag covering his head. When emergency personnel arrived at the scene, he was in cardiac arrest and remained in cardiac arrest at the time of his arrival at the hospital. Continued cardiopulmonary resuscitation resulted in a return of spontaneous circulation. Head computed tomography showed the corticomedullary border was indistinct. Fifteen hours at the hospital, the patient died. Recently, there has been an increasing trend for suicide being performed according to methods obtained through the Internet or mass media. Although there are only a few cases of suicide by helium gas in Japan, attention must be paid to this issue as the number of such cases may increase in the future.

CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity.

Th17 cells play a critical role in host defense against extracellular pathogens and tissue homeostasis but can induce autoimmunity. The mechanisms implicated in balancing "pathogenic" and "non-pathogenic" Th17 cell states remain largely unknown. We used single-cell RNA-seq to identify CD5L/AIM as a regulator expressed in non-pathogenic, but not in pathogenic Th17 cells. Although CD5L does not affect Th17 differentiation, it is a functional switch that regulates the pathogenicity of Th17 cells. Loss of CD5L converts non-pathogenic Th17 cells into pathogenic cells that induce autoimmunity. CD5L mediates this effect by modulating the intracellular lipidome, altering fatty acid composition and restricting cholesterol biosynthesis and, thus, ligand availability for Rorγt, the master transcription factor of Th17 cells. Our study identifies CD5L as a critical regulator of the Th17 cell functional state and highlights the importance of lipid metabolism in balancing immune protection and disease induced by T cells.

Confirmatory Factor Analysis of the Delirium Rating Scale Revised-98 (DRS-R98).

Principal components analysis applied to the Delirium Rating Scale-Revised-98 contributes to understanding the delirium construct. Using a multisite pooled international delirium database, the authors applied confirmatory factor analysis to Delirium Rating Scale-Revised-98 scores from 859 adult patients evaluated by delirium experts (delirium, N=516; nondelirium, N=343). Confirmatory factor analysis found all diagnostic features and core symptoms (cognitive, language, thought process, sleep-wake cycle, motor retardation), except motor agitation, loaded onto factor 1. Motor agitation loaded onto factor 2 with noncore symptoms (delusions, affective lability, and perceptual disturbances). Factor 1 loading supports delirium as a single construct, but when accompanied by psychosis, motor agitation's role may not be solely as a circadian activity indicator.

Using the INTERMED complexity instrument for a retrospective analysis of patients presenting with medical illness, substance use disorder, and other psychiatric illnesses.

BACKGROUND: The financial and treatment challenges of complex patients must be addressed with adequate assessment and evaluation. The INTERMED complexity instrument (INTERMED) has been developed for this purpose, but to date has not been used retrospectively. The current study represents a retrospective validity investigation of INTERMED with patients with substance use disorder comorbid with other psychiatric and medical conditions (triple diagnoses). Such patients were expected to generate high complexity scores on the INTERMED instrument. METHODS: Information on 66 patients with triple diagnoses was submitted to the INTERMED complexity grid. These data were subjected to cluster analysis and other analytic procedures. RESULTS: Total INTERMED scores reflected elevated complexity for patients with triple diagnoses. As a group, they represented a single cluster of complex patients. CONCLUSIONS: The validity of the INTERMED complexity assessment was corroborated in relation to retrospective data. In addition to elevations in the biological domain that hospital personnel typically confront, findings related to coping deficiencies and problems in living conditions were noteworthy in requiring comprehensive interventions.