Risk factors for clinically important traumatic brain injury in minor head injury in older people.

BACKGROUND AND OBJECTIVES: The incidence of traumatic brain injury (TBI) in older individuals is increasing with an increase in the older population. For older people, the required medical interventions and hospitalization following minor head injury have negative impacts, which have not been reported in literature up till now. We aimed to investigate the risk factors for clinically important traumatic brain injury (ciTBI) in older patients with minor head injury. METHODS: This is a retrospective single-center cohort study. Older patients aged ≥65 years presenting with head injury and a Glasgow Coma Scale (GCS) score of ≥13 upon arrival at the hospital between January 1, 2018, and October 31, 2021, were included. Patients with an injury duration of ≥24 h were excluded. The primary outcome was defined as ciTBI (including death, surgery, intubation, medical interventions, and hospital stays of ≥2 nights). Multiple logistic regression analysis was conducted to identify the risk factors. RESULTS: A total of 296 patients were included initially, and 6 of them were excluded subsequently. ciTBI was identified in 62 cases. According to the results of the multiple logistic regression analysis, GCS scores of ≤14 (OR 3.72, 95% CI 1.89-7.30), high-risk mechanisms of injury (OR 2.80, 95% CI 1.39-5.64), vomiting (OR 5.01, 95% CI 1.19-21.1), and retrograde amnesia (OR 6.90, 95% CI 3.37-14.1) were identified as risk factors. CONCLUSION: In older patients with minor head injury, GCS ≤14, high-risk mechanisms of injury, vomiting, and retrograde amnesia are risk factors for ciTBI.

Pharmacokinetics, pharmacodynamics and safety profile of the dual orexin receptor antagonist vornorexant/TS-142 in healthy Japanese participants following single/multiple dosing: Randomized, double-blind, placebo-controlled phase-1 studies.

The pharmacokinetics, pharmacodynamics and safety profile of vornorexant were investigated in healthy Japanese participants in three double-blind studies: a single ascending dose of 1-30 mg (Study 101; n = 6) and multiple ascending doses of 10-30 mg (Study 102; n = 6). Study 202 consisted of two steps: an open-label, 20 mg repeated-dose in non-elderly individuals (Step 1; n = 12) and a double-blind, 20 mg repeated-dose in elderly individuals (Step 2; n = 8/3 for vornorexant/placebo). Vornorexant was rapidly absorbed and eliminated under fasting conditions, with a time to maximum plasma concentration of 0.500-3.00 h (range) and elimination half-life of 1.32-3.25 h. The area under the plasma concentration-time curve (AUC) of vornorexant increased proportionally with dose increments. Sleepiness-related pharmacodynamic outcome changes (Karolinska sleepiness scale, digit symbol substitution test and psychomotor vigilance task) were generally increased with dose increments at 1 and 4 h post-dose, whereas no consistent dose-related changes were detected the next morning. Food intake did not affect the maximum observed plasma concentration of vornorexant but increased the AUC0-inf . Exposure in elderly individuals was generally comparable to that in non-elderly individuals. Altogether, vornorexant may have a favourable profile for insomnia treatment, including rapid onset of action and minimal next-day residual effects.

Behavioral and neural correlates of pareidolic illusions in dementia with Lewy bodies.

INTRODUCTION: Pareidolia, a form of visual illusions phenomenologically similar to complex visual hallucinations, is a phenomenon that is associated with visual hallucinations in dementia with Lewy bodies (DLB). This study aimed to identify commonalities and differences in behavioral and neural correlates between pareidolic illusions and visual hallucinations in DLB. METHODS: Forty-three patients with DLB underwent the scene pareidolia test, which evokes and measures pareidolic illusions, and standardized neuropsychological and behavioral assessments. Regional cerebral blood flow (rCBF) was measured by single-photon emission computed tomography. Factor analysis was performed to assess the relationships among pareidolic illusions, cognitive functions, and behavioral symptoms. Partial least squares correlation analysis was used to investigate the relationship between these symptoms and rCBF. RESULTS: Factor analysis yielded three behavior factors: the first factor (hallucinations/fluctuations) consisted of pareidolic illusions, visual hallucinations, and fluctuating cognition; the second factor (general cognitive function) consisted of general cognitive function and working memory; and the third factor (visual processing) consisted of visual processing and pareidolic illusions. Partial least squares correlation analysis identified two brain-behavior correlation patterns: (1) rCBF reduction in the frontal and perisylvian/periventricular regions was associated with lower general cognitive function and lower visual processing; and (2) rCBF reduction in the bilateral occipitotemporal cortex was associated with more severe hallucinations/fluctuations and lower visual processing. CONCLUSIONS: At the behavioral level, pareidolic illusions are associated with visual hallucinations, fluctuating cognition, and visual processing in DLB. At the neural level, pareidolic illusions may arise from the synergistic effects of global neuropathological changes and occipitotemporal cortical dysfunctions.

Transdiagnostic association between subjective insomnia and depressive symptoms in major psychiatric disorders.

In psychiatric disorders, comorbid depressive symptoms are associated with clinically important issues such as reduced quality of life, a poor prognosis, and increased suicide risk. Previous studies have found a close relationship between insomnia and depressive symptoms in major depressive disorder (MDD), and that actively improving insomnia heightens the improvement of depressive symptoms. This study aimed to investigate whether the association between insomnia and depressive symptoms is also found in other psychiatric disorders besides MDD. The subjects were 144 patients with MDD (n = 71), schizophrenia (n = 25), bipolar disorder (n = 22), or anxiety disorders (n = 26). Sleep status was assessed subjectively and objectively using the Athens Insomnia Scale (AIS) and sleep electroencephalography (EEG), respectively. Sleep EEG was performed using a portable EEG device. Depressive symptoms were assessed using the Beck Depression Inventory. Subjective insomnia, as defined by the AIS, was associated with depressive symptoms in all disorders. Moreover, in schizophrenia, a relation between depressive symptoms and insomnia was also found by objective sleep assessment methods using sleep EEG. Our findings suggest that the association between subjective insomnia and depressive symptoms is a transdiagnostic feature in major psychiatric disorders. Further studies are needed to clarify whether therapeutic interventions for comorbid insomnia can improve depressive symptoms in major psychiatric disorders, similar to MDD.

Comprehensive circulating microRNA profile as a supersensitive biomarker for early-stage lung cancer screening.

PURPOSE:  Less-invasive early diagnosis of lung cancer is essential for improving patient survival rates. The purpose of this study is to demonstrate that serum comprehensive miRNA profile is high sensitive biomarker to early-stage lung cancer in direct comparison to the conventional blood biomarker using next-generation sequencing (NGS) technology combined with automated machine learning (AutoML). METHODS: We first evaluated the reproducibility of our measurement system using Pearson's correlation coefficients between samples derived from a single pooled RNA sample. To generate comprehensive miRNA profile, we performed NGS analysis of miRNAs in 262 serum samples. Among the discovery set (57 patients with lung cancer and 57 healthy controls), 1123 miRNA-based diagnostic models for lung cancer detection were constructed and screened using AutoML technology. The diagnostic faculty of the best performance model was evaluated by inspecting the validation samples (74 patients with lung cancer and 74 healthy controls). RESULTS: The Pearson's correlation coefficients between samples derived from the pooled RNA sample ≥ 0.98. In the validation analysis, the best model showed a high AUC score (0.98) and a high sensitivity for early stage lung cancer (85.7%, n = 28). Furthermore, in comparison to carcinoembryonic antigen (CEA), a conventional blood biomarker for adenocarcinoma, the miRNA-based model showed higher sensitivity for early-stage lung adenocarcinoma (CEA, 27.8%, n = 18; miRNA-based model, 77.8%, n = 18). CONCLUSION: The miRNA-based diagnostic model showed a high sensitivity for lung cancer, including early-stage disease. Our study provides the experimental evidence that serum comprehensive miRNA profile can be a highly sensitive blood biomarker for early-stage lung cancer.

Differences in psychosocial factors and sleep study findings between delayed sleep-wake phase disorder and hypersomnia in teenagers.

Central hypersomnia (HS) and delayed sleep-wake phase disorder (DSWPD) appear commonly in adolescents, and they severely reduce quality of life and have an enormous impact on academic performance and other aspects of development. Although these disorders are thought to be considerably different in etiology, it is sometimes difficult to distinguish them because of their similar clinical features. This study aimed to compare psychosocial factors and sleep study findings between HS and DSWPD in teenagers. The clinical data of 89 teenagers who visited the psychiatric section of the Sleep Medicine Center of Nihon University Itabashi Hospital from January 2013 to December 2019 were analyzed. Psychosocial factors were evaluated at the first visit, and polysomnography (PSG) and the multiple sleep latency test (MSLT) were performed for patients deemed to require definitive diagnosis. Compared with patients with HS, those with DSWPD had a higher rate of mother's employment, introversion, adjustment problems, events that triggered the disorder, concurrent mental disorders, habitual lateness, and difficulty attending school or work. PSG did not show any differences in sleep parameters between the two disorders, except for sleep latency. On the MSLT, sleep latency was shorter in those with HS on the second, third, and fourth tests. The present results suggest that focusing on psychosocial factors could be useful for differential diagnosis of the two disorders that appear commonly in adolescents.

Adiponectin regulates the circadian rhythm of glucose and lipid metabolism.

Adiponectin is a cytokine secreted from adipocytes and regulates metabolism. Although serum adiponectin levels show diurnal variations, it is not clear if the effects of adiponectin are time-dependent. Therefore, this study conducted locomotor activity analyses and various metabolic studies using the adiponectin knockout (APN (-/-)) and the APN (+/+) mice to understand whether adiponectin regulates the circadian rhythm of glucose and lipid metabolism. We observed that the adiponectin gene deficiency does not affect the rhythmicity of core circadian clock genes expression in several peripheral tissues. In contrast, the adiponectin gene deficiency alters the circadian rhythms of liver and serum lipid levels and results in the loss of the time dependency of very-low-density lipoprotein-triglyceride secretion from the liver. In addition, the whole-body glucose tolerance of the APN (-/-) mice was normal at CT10 but reduced at CT22, compared to the APN (+/+) mice. The decreased glucose tolerance at CT22 was associated with insulin hyposecretion in vivo. In contrast, the gluconeogenesis activity was higher in the APN (-/-) mice than in the APN (+/+) mice throughout the day. These results indicate that adiponectin regulates part of the circadian rhythm of metabolism in the liver.

Effects of TS-142, a novel dual orexin receptor antagonist, on sleep in patients with insomnia: a randomized, double-blind, placebo-controlled phase 2 study.

RATIONALE: Novel compound with potent antagonistic activity against orexin receptors may be new treatment option for patients with insomnia. OBJECTIVE: The aim was to investigate the efficacy and safety of single oral doses of the dual orexin receptor antagonist TS-142 in patients with insomnia. METHODS: This multicenter, double-blind, crossover randomized clinical trial included non-elderly patients with insomnia. Patients were randomized to receive single doses of placebo and TS-142 at doses of 5, 10, and 30 mg in one of four different sequences, with a 7-day washout period between treatments. Primary efficacy endpoints were latency to persistent sleep (LPS) and wake time after sleep onset (WASO) measured by polysomnography. RESULTS: Twenty-four patients were included (mean age 50.3 ± 10.5 years; mean duration of insomnia 5.71 ± 8.68 years). Least-squares mean differences (95% confidence interval) from placebo in LPS with 5, 10, and 30 mg TS-142 were - 42.38 (- 60.13, - 24.63), - 42.10 (- 60.02, - 24.17), and - 44.68 (- 62.41, - 26.95) minutes, respectively (all p < 0.001). Least-squares mean differences (95% confidence interval) from placebo in WASO with 5, 10, and 30 mg TS-142 were - 27.52 (- 46.90, - 8.14), - 35.44 (- 55.02, - 15.87), and - 54.69 (- 74.16, - 35.23) minutes, respectively (all p < 0.01). Self-reported aspects of sleep initiation and sleep quality, determined using the Leeds Sleep Evaluation Questionnaire (LSEQ), were also improved with TS-142 administration versus placebo. TS-142 was well tolerated; all adverse events were mild or moderate and none were serious. CONCLUSION: Single-dose TS-142 was well tolerated and had clinically relevant effects on objective and subjective sleep parameters in patients with insomnia. CLINICAL TRIAL REGISTRATION: JapicCTI173570 (www. CLINICALTRIALS: jp); NCT04573725 (www. CLINICALTRIALS: gov).

Medical Costs Associated with Insomnia Treatment with Suvorexant Monotherapy in Japan: Results from a Retrospective Cohort Study Using a Large-Scale Claims Database.

BACKGROUND: The association of insomnia treatment with medical costs is not well characterized in Japan, despite the high economic burden of insomnia. OBJECTIVE: The aim of this study was to investigate the impact of suvorexant, the first dual orexin receptor antagonist, on direct medical costs in insomnia patients. PATIENTS AND METHODS: This retrospective cohort study, conducted using a large-scale claims database, included Japanese patients with diagnosed insomnia receiving suvorexant who were treatment naïve or treatment switchers (pre-treated with a different hypnotic and switched to suvorexant). Total medical costs were estimated for 1 year before and after suvorexant initiation; p-values were calculated for the difference in costs. RESULTS: Of the 1730 patients included, 1116 were treatment naïve and 614 were treatment switchers. Switching to suvorexant did not change the total treatment cost (US$4693-US$4692; p = 0.9964). Although treatment-naïve patients on average incurred US$3259 after suvorexant initiation, much of the additional cost was attributed to drugs other than hypnotics in the outpatient setting (US$332; p < 0.0001). While ~ 10% of the additional medical costs in the outpatient setting were attributable to hypnotics in both groups (treatment naïve: US$106, p < 0.0001; treatment switchers: US$115, p < 0.0001), no difference was observed in the inpatient setting. CONCLUSION: Suvorexant as an initial insomnia treatment was associated with higher total medical costs, given the additional burden of initiating treatment and monitoring costs associated with a new insomnia diagnosis. However, despite a switch from another hypnotic, suvorexant did not increase the incremental economic burden. The hypnotic cost remained proportionately low, demonstrating that suvorexant initiation did not raise the cost of insomnia treatment.

Optimal dose determination of enerisant (TS-091) for patients with narcolepsy: two randomized, double-blind, placebo-controlled trials.

BACKGROUND: The histamine H3 receptor has emerged as one of the most promising targets of novel pharmacotherapy for narcolepsy. Studies now aim to investigate the optimal dose of enerisant, a novel H3 antagonist/inverse agonist, for the treatment of excessive daytime sleepiness in patients with narcolepsy. METHODS: We conducted two phase 2, fixed-dose, double-blind, randomized, placebo-controlled trials in patients with narcolepsy. The first phase 2 study (Study 1) was conducted to investigate the efficacy and safety of enerisant at dosages of 25, 50, and 100 mg/day administered for 3 weeks based on the results of a phase 1 study conducted on healthy volunteers. The primary endpoint was mean sleep latency in maintenance of wakefulness test (MWT), and the secondary endpoint was the total score on the Epworth Sleepiness Scale (ESS). The dosages of enerisant in the second phase 2 study (Study 2) were set at 5 and 10 mg/day based on the simulation of receptor occupancy results from positron emission tomography study. RESULTS: Forty-six and fifty-three patients were randomized in Study 1 and Study 2, respectively. The efficacy of enerisant was partially confirmed in Study 1 with ESS; however, the doses were not tolerated, and there were many withdrawals due to adverse events (mainly insomnia, headache, and nausea). The doses in Study 2 were well tolerated, with a lower incidence of adverse events in Study 2 than in Study 1, although the efficacy could not be confirmed with MWT and ESS in Study 2. CONCLUSIONS: The optimal dose of enerisant could not be determined in these two studies. Although enerisant has a favorable pharmacokinetic profile, it is thought to have large interindividual variabilities in terms of efficacy and safety, suggesting the necessity of tailored dosage adjustments. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03267303 ; Registered 30 August 2017 (Study 2). Japic identifier: JapicCTI-142529 ; Registered 7 May 2014 (Study 1) and JapicCTI-173689 ; Registered 30 August 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?clinicalTrialId=29277 (Study 2).

Sleep Apnea Syndrome (SAS) Clinical Practice Guidelines 2020.

The prevalence of sleep disordered breathing (SDB) is reportedly very high. Among SDBs, the incidence of obstructive sleep apnea (OSA) is higher than previously believed, with patients having moderate-to-severe OSA accounting for approximately 20% of adult males and 10% of postmenopausal women not only in Western countries but also in Eastern countries, including Japan. Since 1998, when health insurance coverage became available, the number of patients using continuous positive airway pressure (CPAP) therapy for sleep apnea has increased sharply, with the number of patients about to exceed 500,000 in Japan. Although the "Guidelines for Diagnosis and Treatment of Sleep Apnea Syndrome (SAS) in Adults" was published in 2005, a new guideline was prepared in order to indicate the standard medical care based on the latest trends, as supervised by and in cooperation with the Japanese Respiratory Society and the "Survey and Research on Refractory Respiratory Diseases and Pulmonary Hypertension" Group, of Ministry of Health, Labor and Welfare and other related academic societies, including the Japanese Society of Sleep Research, in addition to referring to the previous guidelines. Because sleep apnea is an interdisciplinary field covering many areas, this guideline was prepared including 36 clinical questions (CQs). In the English version, therapies and managements for SAS, which were written from CQ16 to 36, were shown. The Japanese version was published in July 2020 and permitted as well as published as one of the Medical Information Network Distribution Service (Minds) clinical practice guidelines in Japan in July 2021.

Sleep Apnea Syndrome (SAS) Clinical Practice Guidelines 2020.

The prevalence of sleep-disordered breathing (SDB) is reportedly very high. Among SDBs, the incidence of obstructive sleep apnea (OSA) is higher than previously believed, with patients having moderate-to-severe OSA accounting for approximately 20% of adult males and 10% of postmenopausal women not only in Western countries but also in Eastern countries, including Japan. Since 1998, when health insurance coverage became available, the number of patients using continuous positive airway pressure (CPAP) therapy for sleep apnea has increased sharply, with the number of patients about to exceed 500,000 in Japan. Although the "Guidelines for Diagnosis and Treatment of Sleep Apnea Syndrome (SAS) in Adults" was published in 2005, a new guideline was prepared to indicate the standard medical care based on the latest trends, as supervised by and in cooperation with the Japanese Respiratory Society and the "Survey and Research on Refractory Respiratory Diseases and Pulmonary Hypertension" Group, of Ministry of Health, Labor and Welfare and other related academic societies, including the Japanese Society of Sleep Research, in addition to referring to the previous guidelines. Since sleep apnea is an interdisciplinary field covering many areas, this guideline was prepared including 36 clinical questions (CQs). In the English version, therapies and managements for SAS, which were written from CQ16 to 36, were shown. The Japanese version was published in July 2020 and permitted as well as published as one of the Medical Information Network Distribution Service (Minds) clinical practice guidelines in Japan in July 2021.

Association of insomnia symptoms and non-restorative sleep with Typus melancholicus: a Japanese general population survey.

This study aimed to investigate the association between insomnia symptoms and non-restorative sleep (NRS) in individuals with Typus melancholicus, a personality trait linked to depression, in the general population. We analyzed data from a Japanese cross-sectional survey of 2519 randomly sampled adults. Typus melancholicus was evaluated using a modified version of Kasahara's Typus melancholicus inventory (modified-KTM). Logistic regression analysis was used to examine the associations of insomnia symptoms and NRS with modified-KTM scores. We demonstrated that insomnia symptoms and NRS were both positively associated with modified-KTM scores. Our results provide evidence for an association between Typus melancholicus and insomnia.

Differential effects of aging and cognitive decline on visual exploration behavior in the elderly.

Visual exploration disturbance has been examined in the elderly, mainly from the perspective of associations with cognitive function. However, it remains unknown whether this is a consequence of cognitive decline, age-related changes independent of cognitive decline, or both. In this study, 15 healthy elderly individuals were evaluated using two figure-matching tasks representing visual information processing (clock-matching and inverted clock-matching tasks). Cognitive functions were evaluated for each subject using the Mini-Mental State Examination (MMSE). Infrared eye-movement assessments were used to analyze eye movements during task performance. Behavioral analyses showed that age was associated with longer reaction time, while MMSE score was associated with higher accuracy on the inverted clock-matching task. Analyses of eye-movement parameters showed that MMSE score was negatively associated with a parameter indicating difficulty in the efficiency of visual exploration planning, while age was tended to be positively associated with the sum of saccade times in each trial, both predominantly on the inverted clock-matching task. Our approaches highlighted that age and cognitive decline are separately associated with eye-movement characteristics: cognitive decline is associated with difficulty in visual exploration planning, particularly in situations that require substantial visual working memory resources, whereas aging may be associated with oculomotor dysfunction.

A Case of High Altitude Cerebral Edema With a Prolonged Motivational Deficit.

We report a case of prolonged motivational deficit as a sequela of high altitude cerebral edema (HACE), the most severe form of neuropsychiatric dysfunction arising from traveling to high altitude. Magnetic resonance imaging of the brain showed hyperintense lesions in the globi pallidi bilaterally on T2-weighted images. Single-photon emission computed tomography showed hypoperfusion in dorsolateral and orbital prefrontal cortices bilaterally and in the anterior cingulate cortex. This case suggests that a prolonged motivational deficit can occur in patients with HACE. The case may also suggest that HACE can cause network disturbances between the prefrontal cortex and the globi pallidi.

Periocular skin warming promotes body heat loss and sleep onset: a randomized placebo-controlled study.

Periocular skin warming was reported to have favorable effects on subjective and objective sleep quality. We hypothesized that enhancing body heat loss by periocular skin warming would reduce sleep onset and improve sleep quality. Eighteen healthy volunteers were asked to maintain wakefulness with their eyes closed for 60 min after applying either a warming or sham eye mask, followed by a 60-min sleep period. Compared to the sham, periocular warming increased the distal skin temperature and distal-proximal skin temperature gradient only during the 30-min thermal manipulation period. In the subsequent sleep period, periocular warming facilitated sleep onset, increased stage 2 sleep and electroencephalographic delta activity during the first half of the sleep period relative to the sham. These results suggest that periocular skin warming may accelerate and deepen sleep by enhancing physiological heat loss via the distal skin, mimicking physiological conditions preceding habitual sleep.

Severe fatigue due to valproate-induced hypothyroidism in a case of bipolar disorder.

BACKGROUND: Valproate-induced hypothyroidism is a rare condition and has been considered asymptomatic. Here, we report a case of bipolar I disorder who developed symptomatic valproate-induced hypothyroidism. CASE PRESENTATION: A 44-year-old woman with bipolar I disorder complained of severe fatigue after starting valproate. She showed a hormonal pattern of central hypothyroidism. Thyroid autoantibodies were negative, and no pituitary abnormality was seen on magnetic resonance imaging. After stopping valproate, her severe fatigue rapidly improved with normalizing thyroid function. CONCLUSIONS: Our case suggests that valproate-induced hypothyroidism should be considered when patients complain of excessive fatigue under treatment with valproate.