Copy number variations in RNF216 and postsynaptic membrane-associated genes are associated with bipolar disorder: a case-control study in the Japanese population.

AIM: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population. METHODS: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%. RESULTS: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05). CONCLUSION: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.

Association of plasma arachidonic acid levels with a bipolar disorder and the effects of a FADS gene variant.

Recent genome-wide association studies (GWASs) have identified fatty acid desaturase (FADS) genes, which code key enzymes involved in polyunsaturated fatty acid (PUFA) desaturation as susceptibility genes for bipolar disorder (BD). Several quantitative changes in PUFAs suggest their involvement in BD pathogenesis. Therefore, this study aimed to clarify the relationship between BD and PUFAs by conducting lipidomics covariating with the FADS gene variant (rs174550), which is associated with PUFA levels and BD susceptibility. The concentrations of 23 fatty acids were measured using plasma samples from the BD group (n = 535) and the control group (n = 107). Differences in each PUFA concentration ratio were compared between the two groups. Also, differences in each PUFA concentration ratio were compared for each genotype in rs174550. Our results showed that the BD group had significantly lower concentrations of linoleic acid (LA) (ß = -0.36, p = 0.023) and arachidonic acid (AA) (ß = -0.18, p = 0.013) than the control group. Concerning the effect of FADS on the PUFA concentration ratio, carriers of C-allele at rs174550 had significantly decreased γ-linolenic acid and AA concentration ratios. A previous GWAS reported that the presence of a C-allele at rs174550 increased the BD risk. This direction is consistent with the lipidomic results of the present study. In conclusion, both the FADS and BD were considered to regulate the AA concentration. Thus, as the FADS gene variant is crucial for conducting lipidomics of BD we believe that the allele frequency of FADS must be analyzed.

External Validation of Updated Prediction Models for Neurological Outcomes at 90 Days in Patients With Out-of-Hospital Cardiac Arrest.

BACKGROUND: Few prediction models for individuals with early-stage out-of-hospital cardiac arrest (OHCA) have undergone external validation. This study aimed to externally validate updated prediction models for OHCA outcomes using a large nationwide dataset. METHODS AND RESULTS: We performed a secondary analysis of the JAAM-OHCA (Comprehensive Registry of In-Hospital Intensive Care for Out-of-Hospital Cardiac Arrest Survival and the Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest) registry. Previously developed prediction models for patients with cardiac arrest who achieved the return of spontaneous circulation were updated. External validation was conducted using data from 56 institutions from the JAAM-OHCA registry. The primary outcome was a dichotomized 90-day cerebral performance category score. Two models were updated using the derivation set (n=3337). Model 1 included patient demographics, prehospital information, and the initial rhythm upon hospital admission; Model 2 included information obtained in the hospital immediately after the return of spontaneous circulation. In the validation set (n=4250), Models 1 and 2 exhibited a C-statistic of 0.945 (95% CI, 0.935-0.955) and 0.958 (95% CI, 0.951-0.960), respectively. Both models were well-calibrated to the observed outcomes. The decision curve analysis showed that Model 2 demonstrated higher net benefits at all risk thresholds than Model 1. A web-based calculator was developed to estimate the probability of poor outcomes (https://pcas-prediction.shinyapps.io/90d_lasso/). CONCLUSIONS: The updated models offer valuable information to medical professionals in the prediction of long-term neurological outcomes for patients with OHCA, potentially playing a vital role in clinical decision-making processes.

Pharmacogenomic-guided clozapine administration based on HLA-DQB1, HLA-B and SLCO1B3-SLCO1B7 variants: an effectiveness and cost-effectiveness analysis.

The identification of pharmacogenetic factors that increase the susceptibility to clozapine-induced agranulocytosis or granulocytopenia (CIAG) has received increasing interest. The SLCO1B3-SCLO1B7 variant (rs149104283) and single amino acid changes in human leukocyte antigen (HLA) HLA-DQB1 (126Q) and HLA-B (158T) were associated with an increased risk of CIAG. In this study, we evaluated the effectiveness and cost-effectiveness of adding the SLCO1B3-SCLO1B7 to HLA variants as a new pharmacogenomic (PGx) approach and explored the evolution of a cohort of schizophrenic patients taking long-term clozapine as a third-line antipsychotic medication. The decision model included probabilistic and deterministic sensitivity analyses to assess the expected costs and quality-adjusted life-years (QALYs). The current monitoring scheme was compared with the PGx-guided strategy, where all patients underwent pre-emptively a genetic test before taking clozapine, over 10 years. By adding the SLCO1B3-SCLO1B7 variant into HLA variants, CIAG sensitivity increased from 36.0% to 43.0%, the specificity decreased from 89.0% to 86.9%, and the probability of cost-effectiveness improved from 74.1% to 87.8%. The incremental cost-effectiveness ratio was £16,215 per QALY and remained below the conventional decision threshold (£30,000 or US$50,000 per QALY). Therefore, the SLCO1B3-SCLO1B7 variant, as an additional risk allele to HLA variants, increases preemptive test sensitivity and improves the effectiveness and cost-effectiveness of PGx-guided clozapine administration.

Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder.

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

Shared genetic components between metabolic syndrome and schizophrenia: Genetic correlation using multipopulation data sets.

AIM: The genetic relationship between schizophrenia (SCZ) and other nonpsychiatric disorders remains largely unknown. We examined the shared genetic components between these disorders based on multipopulation data sets. METHODS: We used two data sets for East Asian (EAS) and European (EUR) samples. SCZ data was based on the Psychiatric Genomics Consortium Asia with our own genome-wide association study for EAS and Psychiatric Genomics Consortium for EUR. Nonpsychiatric data (20 binary traits [mainly nonpsychiatric complex disorders] and 34 quantitative traits [mainly laboratory examinations and physical characteristics]) were obtained from Biobank Japan and UK Biobank for EAS and EUR samples, respectively. To evaluate genetic correlation, linkage disequilibrium score regression analysis was utilized with further meta-analysis for each result from EAS and EUR samples to obtain robust evidence. Subsequent mendelian randomization analysis was also included to examine the causal effect. RESULTS: A significant genetic correlation between SCZ and several metabolic syndrome (MetS) traits was detected in the combined samples (meta-analysis between EAS and EUR data) (body mass index [rg  = -0.10, q-value = 1.0 × 10-9 ], high-density-lipoprotein cholesterol [rg  = 0.072, q-value = 2.9 × 10-3 ], blood sugar [rg  = -0.068, q-value = 1.4 × 10-2 ], triglycerides [rg  = -0.052, q-value = 2.4 × 10-2 ], systolic blood pressure [rg  = -0.054, q-value = 3.5 × 10-2 ], and C-reactive protein [rg  = -0.076, q-value = 7.8 × 10-5 ]. However, no causal relationship on SCZ susceptibility was detected for these traits based on the mendelian randomization analysis. CONCLUSION: Our results indicate shared genetic components between SCZ and MetS traits and C-reactive protein. Specifically, we found it interesting that the correlation between MetS traits and SCZ was the opposite of that expected from clinical studies: this genetic study suggests that SCZ susceptibility was associated with reduced MetS. This implied that MetS in patients with SCZ was not associated with genetic components but with environmental factors, including antipsychotics, lifestyle changes, poor diet, lack of exercise, and living conditions.

Cost effectiveness of pharmacogenetic-guided clozapine administration based on risk of HLA variants in Japan and the UK.

Pharmacogenetics/pharmacogenomics have enabled the detection of risk of human leukocyte antigen (HLA) variants for clozapine-induced agranulocytosis/granulocytopenia (CIAG). To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed "HLA-guided treatment schedule" and the "current schedule" being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500/mm3); in the "HLA-guided treatment schedules," we considered a situation wherein the HLA test performed before clozapine initiation could provide "a priori information" by detecting patients harboring risk of HLA variants (HLA-B*59:01 and "HLA-B 158T/HLA-DQB1 126Q" for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% "prevention rate"). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of "HLA-guided treatment schedule" and "current schedule" used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000/mm3 and 500/mm3) and plotted the cost/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the "HLA-guided treatment schedule" was more cost effective than the "current schedule"; the ICER was £20,995 and £21,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500/mm3 without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the "current schedule" of ANC cutoff at 1500/mm3. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.

Effect of a brief cognitive behavioral program on depressive symptoms among newly licensed registered nurses: An observational study.

Depressive symptoms are a serious problem in workplaces. Hospital staff members, such as newly licensed registered nurses (NLRNs), are at particularly increased risk of these symptoms owing to their limited experience. Previous studies have shown that a brief program-based cognitive behavioral therapy program (CBP) can offer effective treatment. Here, we conducted a longitudinal observational study of 683 NLRNs (CBP group, n = 522; no-CBP group, n = 181) over a period of 1 year (six times surveys were done during this period). Outcomes were assessed on the basis of surveys that covered the Beck Depression Inventory-I (BDI). The independent variables were CBP attendance (CBP was conducted 3 months after starting work), personality traits, personal stressful life events, workplace adversity, and pre-CBP change in BDI in the 3 months before CBP (ΔBDIpre-CBP). All factors were included in Cox proportional hazards models with time-dependent covariates for depressive symptoms (BDI ≥10), and we reported hazard ratios (HRs). Based on this analysis, we detected that CBP was significantly associated with benefit for depressive symptoms in all NLRNs (Puncorrected = 0.0137, HR = 0.902). To identify who benefitted most from CBP, we conducted a subgroup analysis based on the change in BDI before CBP (ΔBDIpre-CBP). The strongest association was when BDI scores were low after starting work and increased before CBP (Puncorrected = 0.00627, HR = 0.616). These results are consistent with previous findings, and indicate that CBP may benefit the mental health of NLRNs. Furthermore, selective prevention based on the pattern of BDI change over time may be important in identifying who should be offered CBP first. Although CBP is generally effective for all nurses, such a selective approach may be most appropriate where cost-effectiveness is a prominent concern.

Massive hemothorax due to bleeding from thoracic spinal fractures: a case series and systematic review.

BACKGROUND: Massive hemothorax secondary to thoracic spinal fractures is rare, and its clinical characteristics, treatment, and prognosis are unknown. We present two cases of thoracic spinal fracture-induced massive hemothorax and a systematic review of previously reported cases. METHODS: This study included patients with traumatic hemothorax from thoracic spinal fractures at a Japanese tertiary care hospital. A systematic review of published cases was undertaken through searches in PubMed, EMBASE, and ICHUSHI from inception to October 13, 2019. RESULTS: Case 1: An 81-year-old man developed hemodynamic instability from a right hemothorax with multiple rib fractures following a pedestrian-vehicle accident; > 1500 mL blood was evacuated through the intercostal drain. Thoracotomy showed hemorrhage from a T8-burst fracture, and gauze packing was used for hemostasis. Case 2: A 64-year-old man with right hemothorax and hypotension after a fall from height had hemorrhage from a T7-burst fracture, detected on thoracotomy, which was sealed with bone wax. Hypotension recurred during transfer; re-thoracotomy showed bleeding from a T7 fracture, which was packed with bone wax and gauze for hemostasis. The systematic review identified 10 similar cases and analyzed 12 cases, including the abovementioned cases. Inferior part of thoracic spines was prone to injury and induced right-sided hemothorax. Most patients developed hemodynamic instability, and some sustained intra-transfer hemorrhage; direct compression (gauze packing, bone wax, and hemostatic agents) was the commonest hemostatic procedure. The mortality rate was 33.3%. CONCLUSIONS: Hemothorax due to thoracic spinal fracture can be fatal. Thoracotomy with direct compression is necessary in hemodynamically unstable patients.

Topical application of ketamine to prevent postoperative sore throat in adults: A systematic review and meta-analysis.

BACKGROUND: Postoperative sore throat is a leading undesirable postoperative outcome. Ketamine is an N-methyl-d-aspartate receptor antagonist and its topical application is used for chronic pain and oral/throat indications. We conducted a systematic review to assess the efficacy of preoperative, topical ketamine application for preventing postoperative sore throat. METHODS: We searched MEDLINE, EMBASE, and CENTRAL through September 23, 2019 for randomized controlled trials in which at least one intervention was topical ketamine to prevent postoperative sore throat in adults undergoing endotracheal intubation. The primary outcome was the incidence of sore throat at 24 hours postoperatively. The comparators were non-analgesic controls (placebo, no treatment, or usual care) or active agents. We pooled the data using a random-effects model. RESULTS: We included 41 randomized controlled trials involving 3784 participants. Topical ketamine was associated with reduced incidence of sore throat at 24 hours postoperatively compared to non-analgesic methods (risk ratio, 0.45; 95% CI, 0.37-0.54; P < .001). We found significant publication bias, but the results remained unchanged with a trim-and-fill analysis. Trial sequential analysis (TSA) suggested that the efficacy of topical ketamine was adequate (TSA-adjusted 95% CI, 0.33-0.56). The GRADE quality for this evidence was moderate. Topical ketamine was inferior to a combination of nebulized ketamine and clonidine in preventing postoperative sore throat. CONCLUSIONS: Preoperative, topical ketamine application may be more effective than non-analgesic methods in preventing postoperative sore throat. The number of studies did not suffice to determine the place of topical ketamine among agents to prevent postoperative sore throat.

Polygenic risk scores in schizophrenia with clinically significant copy number variants.

AIMS: Recent studies have revealed that the interplay between polygenic risk scores (PRS) and large copy number variants (CNV; >500kb) is essential for the etiology of schizophrenia (SCZ). To replicate previous findings, including those for smaller CNV (>10kb), the PRS between SCZ patients with and without CNV were compared. METHODS: The PRS were calculated for 724 patients with SCZ and 1178 healthy controls (HC), genotyped using array-based comparative genomic hybridization and single nucleotide polymorphisms chips, and comparisons were made between cases and HC, or between subjects with and without 'clinically significant' CNV. RESULTS: First, we replicated the higher PRS in patients with SCZ compared to that in HC (without taking into account the CNV). For clinically significant CNV, as defined by the American College of Medical Genetics ('pathogenic' and 'uncertain clinical significance, likely pathogenic' CNV), 66 patients with SCZ carried clinically significant CNV, whereas 658 SCZ patients had no such CNV. In the comparison of PRS between cases with/without the CNV, despite no significant difference in PRS, significant enrichment of the well-established risk CNV (22q11.2 deletion and 47,XXY/47,XXX) was observed in the lowest decile of PRS in SCZ patients with the CNV. CONCLUSION: Although the present study failed to replicate the significant difference in PRS between SCZ patients with and without clinically significant CNV, SCZ patients with well-established risk CNV tended to have a lower PRS. Therefore, we speculate that the CNV in SCZ patients with lower PRS may contain 'genuine' risk; PRS is a possible tool for prioritizing clinically significant CNV because the power of the CNV association analysis is limited due to their rarity.

Suvorexant for insomnia in patients with psychiatric disorder: A 1-week, open-label study.

AIM: There have been no previous reports on the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders. METHODS: This one-week, prospective, single-arm, clinical trial of fixed dose of suvorexant (20 mg if ages 18-64 or 15 mg if age ≥ 65 years) for insomnia included 57 patients with psychiatric disorders who had experienced any of the following insomnia symptoms for four or more nights during the week prior to the start of the study: total sleep time (TST) <6 hours, time to sleep onset (TSO) ≥30 minutes, or two or more episodes of wake after sleep onset. RESULTS: The mean age of the patients was 49.4 ± 17.3 years; 54.4% were women, 49.1% had a major depressive disorder, and 77.2% completed the trial. Compared with the baseline scores (the mean scores for the two days before the start of the study), taking suvorexant was associated with significant improvements in TST, TSO, wake time after sleep onset, and the patients' sleep satisfaction level at week 1. Adverse events included at least one adverse event (43.9%), sleepiness (28.8%), fatigue (11.5%), nightmares (5.8%), headache (3.8%), dizziness (3.8%), and vomiting (1.9%). CONCLUSION: Suvorexant was beneficial for the treatment of insomnia in people with psychiatric disorders. However, this study was of short duration and included only a relatively small number of patients. A larger, long-term study is needed to investigate the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders.