Assessing the Real-World, Long-Term Impact of Lemborexant on Sleep Quality in a Home-Based Clinical Study.

Purpose: Both subjective and objective evaluations are essential for the treatment of insomnia. Lemborexant has been shown to be effective in the long-term based solely on a subjective basis, and no long-term objective measures have been evaluated under natural sleep conditions. Small, lightweight sleep electroencephalogram (EEG) monitor was used, instead of polysomnography, to objectively evaluate sleep at home 4 and 12 weeks after lemborexant treatment. Patients and Methods: Adults and elderly subjects with insomnia disorder, per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were enrolled in this open-label, single-arm, single-center trial. Objective and subjective measures of sleep were prospectively assessed. Sleep disturbance, excessive sleepiness, and depressive symptoms were assessed using questionnaires. Results: A total of 45 subjects were screened, of which 33 were enrolled. Paired t-tests were conducted to evaluate changes in sleep variables and compared with the baseline; subjects showed significant improvements in objective sleep efficiency (SE) and subjective sleep parameters at weeks 4 and 12 following treatment with lemborexant. When baseline values were taken into account, a repeated-multivariate analysis of variance (MANOVA) revealed statistically significant changes in the objective measures. Sleep disturbance, excessive sleepiness, and depressive symptoms improved after three months of lemborexant treatment. Conclusion: Furthermore, lemborexant therapy improved nocturnal sleep, when measured objectively using sleep EEG monitoring at home, and improved daytime sleepiness and depressive symptoms in older adults with insomnia disorder.

Impact of quality of life on future frailty status of rural Japanese community-dwelling older adults.

OBJECTIVES: We aimed to clarify the factors that contribute to the improvement or progression of frailty in rural Japanese community-dwelling older adults. METHODS: Of the 840 participants in the cohort study of independent older adults aged 65 years and older living in the Tamba-Sasayama area of Hyogo Prefecture (FESTA study) from September 2016 to December 2017, 551 participated in the 2-year follow-up survey from September 2018 to December 2019. METHODS: We evaluated clinical background, physical and cognitive function, total physical activity, daily protein intake, quality of life (QOL) using the WHOQOL-BREF (WHOQOL-26), and frailty status diagnosed using the Japanese version of the Cardiovascular Health Study. We compared the frailty status at the initial and follow-up examinations and classified the participants into three groups: improvement, unchanged, and worsening. Each parameter was compared among the three groups and the factors contributing to the improvement or worsening of frailty status were analyzed using a modified Poisson regression analysis. RESULTS: The median age at the first survey was 72 years (range: 68-76); 190 men and 361 women were enrolled. The improvement group consisted of individuals with a change in status from frail to prefrail/robust and from prefrail to robust (n = 114); the worsening group consisted of individuals with a change in status from robust to prefrail/frail and from prefrail to frail (n = 92). The physical domain of QOL was significantly associated with an improvement in frailty status independent of the frailty status at baseline. Contrastingly, any domains of QOL were not significantly associated with a worsening frailty status. CONCLUSIONS: This study demonstrated for the first time that QOL has a significant impact on the future improvement and progression of frailty status and that QOL conditions and frailty status affect older adults bidirectionally.

Estimation of Muscle Mass Using Creatinine/Cystatin C Ratio in Japanese Community-Dwelling Older People.

OBJECTIVES: Sarcopenia is defined as a combination of low skeletal muscle mass index (SMI), weak muscle strength, and reduced physical function. Recently, many studies have reported that the creatinine/cystatin C ratio (Cr/CysC) is useful for evaluating muscle mass. We designed a cross-sectional study with separate model development and validation groups to develop a prediction equation to estimate bioimpedance analysis (BIA)-measured SMI with Cr/CysC. DESIGN: The current study was a retrospective cross-sectional study. SETTING AND PARTICIPANTS: The model development group included 908 subjects (288 men and 620 women) from the Frail Elderly in the Sasayama-Tamba Area (FESTA) study, and the validation group included 263 subjects (112 men and 151 women) from participants in the medical checkup program at the Anti-Aging Center in Ehime Prefecture. MEASURES: Multivariate regression analysis indicated that age, hemoglobin (Hb), body weight (BW), and Cr/CysC were independently associated with SMI in both men and women. The SMI prediction equation was developed as follows: Men:4.17-0.012×Age+1.24×(Cr/CysC)-0.0513×Hb+0.0598×BW Women:3.55-0.00765×Age+0.852×(Cr/CysC)-0.0627×Hb+0.0614×BW RESULTS: The SMI prediction equation was applied to the validation group and strong correlations were observed between the BIA-measured and predicted SMI (pSMI) in men and women. According to the receiver operator characteristic (ROC) analysis, the areas under the curve were 0.93 (specificity 89.0%, sensitivity 87.2%) among men and 0.88 (specificity 83.6%, sensitivity 79.6%) among women for using pSMI to identify low SMI in the model development group. The pSMI also indicated high accuracy in ROC analysis for low SMI in the validation group. The Bland-Altman plot regression showed good agreement between BIA-measured and pSMI. CONCLUSIONS AND IMPLICATIONS: Our new prediction equation to estimate SMI is easy to calculate in daily clinical practice and would be useful for diagnosing sarcopenia.

FLUID study: study protocol for an open-label, single-centre pilot study to investigate the efFect of Lemborexant on sleep management in Japanese sUbjects aged 50 years and older with Insomnia Disorder.

INTRODUCTION: Bidirectional associations have been reported between sleep disturbance and both cognitive impairment, including Alzheimer's disease and amyloid beta-peptide (Aß) accumulation. These relationships can be explained by the glymphatic system, which acts as a garbage drainage system in the brain. As interstitial fluid dynamics are suggested to increase during sleep, clearance of Aß can be influenced by sleep disturbance or deprivation. We hypothesised that using lemborexant, an orexin receptor antagonist, to improve sleep quality would also improve the function of the glymphatic system. We plan to examine the effect of lemborexant on sleep quality and the glymphatic system among patients with insomnia disorder. METHODS AND ANALYSIS: This pilot study is designed as an open-label, single-arm, single-centre trial. Thirty patients aged 50 years and over with insomnia will be recruited. The participants will take lemborexant (5 mg) at bedtime for 12 weeks and undergo a home-based sleep study at baseline and weeks 4 and 12, as well as MRI examinations to evaluate the glymphatic system at baseline and week 12. The primary outcome will be changes in objective sleep parameters as evaluated using a sleep monitoring system. The secondary outcomes will be changes in subjective sleep parameters. The relationships between changes in sleep parameters and the glymphatic system will be evaluated using diffusion tensor image analysis along the perivascular space, which is called the ALPS-index. Sleep parameters and the ALPS-index will be analysed using a paired t-test or Pearson's correlation coefficient. ETHICS AND DISSEMINATION: The study protocol was approved by Nagoya University Certified Review Board. The findings from this research will be published in peer-reviewed journals and be presented at local, national and international conferences. TRIAL REGISTRATION NUMBER: jRCTs041210024.

Low back pain is closely associated with frailty but not with sarcopenia: Cross-sectional study of rural Japanese community-dwelling older adults.

AIM: We speculated that low back pain, which is the most common ailment in older adults, is associated with frailty and/or sarcopenia and contributes to the progression of either condition. Our objective was to evaluate the relationship between low back pain, sarcopenia and frailty in rural Japanese community-dwelling older adults. METHODS: We recruited 730 participants aged ≥65 years who underwent a comprehensive health examination between November 2016 and December 2018. The Oswestry Disability Index (ODI) was used to assess low back pain quantitatively, and scores were compared for the frail groups determined by the Japanese version of Cardiovascular Health Study, and the sarcopenia groups as determined by the Asian Working Group for Sarcopenia 2019. RESULTS: Among 730 participants, the prevalence of low back pain was 57.8%. There were significant differences in the ODI scores between the robust, prefrail and frail groups (P < 0.001). In contrast, there were no significant differences in the ODI scores among the robust, low appendicular skeletal muscle and sarcopenia groups. Logistic regression analysis showed that the prevalence of low back pain and the ODI scores were significantly associated with frailty after adjustment for age, sex and body mass index (odds ratio 3.41, 95% confidence interval 1.39-8.39, P = 0.008, and odds ratio 1.06, 95% confidence interval 1.04-1.09, P < 0.001, respectively). CONCLUSIONS: To the best of our knowledge, this study is the first to show the close association between low back pain and frailty, and suggests that not only the decline in physical function but also neuropsychiatric factors, including chronic pain, constitute a vicious cycle of frailty in community-dwelling older adults. Geriatr Gerontol Int 2021; 21: 54-59.

Relationships between cystatin C- and creatinine-based eGFR in Japanese rural community- dwelling older adults with sarcopenia.

BACKGROUND: Sarcopenia is prevalent in patients with chronic kidney disease (CKD). The indices of physical function, such as grip power and gait speed, decreased according to the decline in the estimated glomerular filtration rate (eGFR). METHODS: We examined the relationships between cystatin C-based GFR (eGFRcys), creatinine-based GFR (eGFRcre), their ratio (eGFRcys/eGFRcre) and sarcopenia in community-dwelling older adults in Japan. This cross-sectional study included 302 men aged 73.9 ± 6.2 years and 647 women aged 72.9 ± 5.8 years from a rural area in Hyogo Prefecture, Japan. eGFRcys and eGFRcre were simultaneously measured, and sarcopenia based on the Asia Working Group for Sarcopenia (AWGS) 2019 criteria was evaluated. RESULTS: eGFRcys and the eGFRcys/eGFRcre ratio were significantly correlated with grip power and gait speed (p < 0.001). The eGFRcys/eGFRcre ratio was also correlated with skeletal muscle mass index (SMI) (p < 0.01). Univariate logistic regression analysis showed eGFRcys and eGFRcys/eGFRcre ratio but not eGFRcre were associated with sarcopenia (p < 0.01). The presence of low eGFRcys (CKDcys) and low eGFRcys/eGFRcre ratio (< 1.0) but not that of low eGFRcre (CKDcre) were associated with sarcopenia (p < 0.01). In the multivariate logistic regression analysis, when the eGFRcys/eGFRcre ratio was added as a covariate to the basic model, it was significantly associated with sarcopenia in women (p < 0.05). Moreover, low eGFRcys/eGFRcre ratio (< 1.0) was associated with a higher risk of sarcopenia in men (p < 0.01). CONCLUSION: In conclusion, CKDcys but not CKDcre is associated with sarcopenia. A lower eGFRcys/eGFRcre ratio may be a practical screening marker of sarcopenia in community-dwelling older adults.

Physical frailty predicts the development of social frailty: a prospective cohort study.

BACKGROUND: It has not been clarified whether physical frailty symptoms predict social. frailty. The purpose of this study was to elucidate the effect of physical frailty on social frailty, and to determine which domains of physical frailty predict the development of social frailty. METHODS: We employed a two-year prospective cohort study. A total of 342 socially robust community-dwelling older adults were recruited. We used a modified social frailty screening index consisting of four social domains including financial difficulties, living alone, social activity, and contact with neighbors. Physical frailty status was also assessed at baseline. At the two-year follow-up, we assessed the development of social frailty. Social status was assessed using four social subdomains for the primary analysis. Social status was assessed using the two social subdomains of social activity and contact with neighbors, which would be affected by the physical frailty component, for the secondary analysis. The risk ratios (RR) of physical frailty for the development of social frailty were estimated. RESULTS: Although physical frailty symptoms were not a significant risk factor for future development of social frailty as assessed by four social subdomains (adjusted RR 1.39, 95% CI 0.95-2.15), it became significant when development of social frailty was assessed by the two social subdomains (adjusted RR 1.78, 95% CI 1.10-2.88). An analysis using the physical frailty subdomain showed that slow gait speed (adjusted RR 3.41, 95% CI 1.10-10.53) and weakness (adjusted RR 1.06, 95% CI 1.01-1.12) were independent risk factors for development of social frailty as assessed by two social subdomains. CONCLUSIONS: Physical frailty symptoms predict the development of social frailty. Among physical frailty subdomains, gait speed and muscle strength are critical independent risk factors for future decline in the social aspect. The prevention of physical frailty, especially by maintaining gait ability and muscle strength, may be effective for avoiding social frailty.

Comparison of Pregnane X Receptor Antagonists for Enhancing the Antitumor Effect of Cisplatin.

BACKGROUND: Cisplatin is a platinum compound capable of inducing apoptosis of cancer cells. However, cancer cells can become cisplatin-resistant. A recent study showed that a pregnane X receptor (PXR) antagonist, leflunomide, can enhance the antitumor activity of cisplatin and overcome such resistance. This study determined whether PXR antagonists ketoconazole and phenethyl isothiocyanate (PEITC) enhance the antitumor activity of platinum compounds and by which mechanism(s) of action. MATERIALS AND METHODS: Caspase-3 activity, intracellular platinum level, and expression of ATP-binding cassette subfamily C member 2 (ABCC2; previously named multidrug resistance-associated protein 2) were assessed in HepG2 human hepatocellular carcinoma cells exposed to carboplatin or cisplatin with and without PXR antagonist. RESULTS: In combination with platinum compounds, PEITC increased the intracellular platinum level, while ketoconazole induced higher caspase-3 activity. Additionally, PEITC suppressed ABCC2 protein expression. CONCLUSION: These results suggested that ketoconazole and PEITC enhance the antitumor activity of platinum compounds by different and complex mechanisms.

The Involvement of Pregnane X Receptor-regulated Pathways in the Antitumor Activity of Cisplatin.

BACKGROUND/AIM: Nuclear receptors regulate the expression of cellular transporters, which may be contributing factors for cisplatin (CDDP) resistance. This study aimed to clarify whether nuclear receptor ligands could be potentially used as drugs to overcome CDDP resistance. MATERIALS AND METHODS: Caspase-3 activity was measured using a fluorogenic substrate. mRNA levels were determined using real-time polymerase chain reaction. RESULTS: Pregnane X receptor (PXR) showed an expression level change dependent on caspase-3 activation by CDDP in HepG2. Rifampicin, a PXR agonist, reduced the accumulation of CDDP and suppressed growth inhibition and caspase-3 activation in HepG2 after CDDP exposure. Leflunomide, a PXR antagonist, significantly enhanced caspase-3 activation by CDDP in HepG2 and CDDP-resistant HepG2/R. CONCLUSION: These results suggest that PXR can modify the antitumor activity of CDDP, presumably through regulating the expression of transporters, which control intracellular CDDP concentration. Thus, PXR antagonists can be further investigated as potential drugs capable of overcoming CDDP resistance.

The Relationship between Dietary Habits and Frailty in Rural Japanese Community-Dwelling Older Adults: Cross-Sectional Observation Study Using a Brief Self-Administered Dietary History Questionnaire.

To develop effective nutritional interventions for preventing frailty, the specific problems associated with the dietary habits of individuals based on sex differences must be identified. The purpose of this study was to evaluate the association between dietary habits and frailty in rural Japanese community-dwelling older adults. We recruited 800 participants, aged 65 and older, who underwent a comprehensive health examination between November 2015 and December 2017. Dietary habits were assessed by a brief self-administered dietary history questionnaire. Frailty was determined using either the Kihon Checklist (KCL) or the Japanese version of the Cardiovascular Health Study (J-CHS). The percentage of frail older adults was 8.4% according to KCL and 4.0% according to J-CHS. Various kinds of nutrient intakes, including three major nutrients, minerals, and vitamins in frail men, according to KCL, were the lowest. By contrast, there were no differences in nutrient intake between the robust, prefrail, and frail female groups according to KCL. We found significant associations of the intakes of soluble dietary fiber, potassium, folate, and vitamin C with a frail status in men (p = 0.035, 0.023. 0.012, and 0.007, respectively), and an association of the intake of vitamin C with a frail status in women (p = 0.027) according to J-CHS. Attention should be paid to the diagnostic criteria of frailty and to sex differences, when nutritional interventions for the prevention of frailty are planned.

Isotemporal substitution of sedentary time with physical activity and its associations with frailty status.

OBJECTIVES: Recently, isotemporal substitution has been developed to substitute activity time for an equivalent amount of another activity. This study employed this method to demonstrate the effects of replacing sedentary behavior (SB) time with an equivalent amount of light-intensity physical activity (LPA) and moderate-to-vigorous intensity physical activity (MVPA) on the risk for different severities of frailty. METHODS: A total of 886 older adults (average age 73.6 years, female 70%) participated in this cross-sectional study. Frailty status was assessed according to the cardiovascular health study criteria. MAIN OUTCOME MEASURES: Wrist-worn accelerometers were used to measure SB, LPA, and MVPA. Isotemporal substitution models were applied to show the estimated effects of substituting 30 min of SB with an equal amount of time spent in LPA or MVPA on the risk for pre-frailty and frailty. RESULTS: The physical activity level and SB were not associated with the incidence of pre-frailty. However, a 16% (OR: 0.84; 95% CI: 0.78-0.90) and 42% (OR: 0.58; 95% CI: 0.37-0.92) decrease in frailty risk was noted when SB was substituted with LPA and MVPA, respectively, in the crude model. In the adjusted model, the significant effect was sustained for LPA (OR: 0.86; 95% CI: 0.80-0.92) but not for MVPA (OR: 0.74; 95% CI: 0.47-1.17). CONCLUSIONS: This study indicates that replacing 30 min of SB with an equivalent amount of LPA decreases the risk for frailty in older adults. Moreover, increasing LPA seems more feasible than increasing MVPA in older adults, with substantial benefit.

Administration of Kampo medicine through a tube at an advanced critical care center.

n emergency and critical care medical centers, tube administration is employed for patients who have difficulty swallowing oral drugs owing to decreased consciousness or mechanical ventilation. However, tube clogging due to drug injection is a concern. We compared the crushing method with the simple suspension method for the passage of amlodipine, an antihypertensive drug, in combination with rikkunshito, which has been used to treat upper gastrointestinal disorders such as functional dyspepsia and gastroesophageal reflux in emergency and critical care medical centers, to ascertain the effect of Kampo products on the passage of other drugs during tube administration. When the crushing method was employed, poorly water-soluble solid products were formed, while a uniformly dispersed suspension was obtained using the simple suspension method. In addition, the passage rate of amlodipine through the tube was 64% and 93% in the crushing and simple suspension methods, respectively, thereby indicating that the simple suspension method provided more favorable than the crushing method. The results of this study suggested that the passage rate of amlodipine for patients who received Kampo products concurrently was higher when the simple suspension method was used, and an appropriate drug amount might well be able to administered to patients using this method. J. Med. Invest. 65:32-36, February, 2018.

[Modification of the Insulin Pen Assistive Device to Improve the Usability and Its Evaluation].

　In this study, we prepared 4 assistive devices (A-D) for Miriopen® to improve the "ease of holding" and "ease of pushing" and compared their usability with that of a device provided by the pharmaceutical company (S). Fifty-five healthy volunteers in their 20s performed the self-injection maneuver using all 5 assistive devices and ranked them regarding 3 items, i.e., the "ease of holding", "ease of pushing", and "overall ease of administration". In all evaluation items, C was ranked first by the largest number of subjects, and the ranking by the subjects was shown by Kendall's coefficient of concordance to be consistent. In addition, comparison of the distance scale calculated from the ordinal scale showed significantly higher ranks of C and D compared with A, B, and S in all evaluation items. No significant difference was noted between C and D. Since C and D had shapes with concavities and convexities that fit the index, middle, and ring fingers (2nd-4th fingers), the fingers are considered to be better stabilized during the injection maneuver with consequent high ratings. Moreover, the 4 assistive devices prepared in this study were rated to be equal to or higher than S.

Effects of physical and psychological stress on 5-HT2A receptor-mediated wet-dog shake responses in streptozotocin-induced diabetic rats.

Several epidemiological and clinical studies have indicated that the prevalence of psychiatric disorders is higher in diabetic patients than in the general population. In the present studies, we examined the behavioral changes in streptozotocin-induced diabetic rats, and investigated the effects of physical and psychological stress on the hippocampal BDNF levels and on the serotonin 2A (5-HT(2A)) receptor-mediated wet-dog shake responses. The streptozotocin (60 mg/kg, i.p.)-induced diabetes had no significant effects on the immobility time in the forced swim test or on locomotor activity in the open-field test. Moreover, there was no significant difference in the wet-dog shake responses induced by DOI, a 5-HT(2A) receptor agonist, between nondiabetic and diabetic rats. Five-day exposure to physical (electric footshock) and psychological (non-footshock) stress had no significant effect on the hippocampal BDNF level in diabetic or nondiabetic rats. The 2 types of stress had no significant effect on the DOI-induced wet-dog shake responses in nondiabetic rats. In diabetic rats, the repeated exposure to physical stress markedly increased the DOI-induced wet-dog shake responses, but the repeated exposure to psychological stress had no effect. These results suggest that exposure to physical stress augmented the susceptibility to the wet-dog shake responses to 5-HT(2A) receptor stimulation in streptozotocin-induced diabetic rats.