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

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

Extracts of Prunella vulgaris Enhanced Pentobarbital-Induced Sleeping Behavior in Mice Potentially via Adenosine A2A Receptor Activity.

The increasing prevalence of sleep dysregulation cases has prompted the search for effective and safe sleep-enhancing agents. Numerous medications used in the treatment of sleep disorders function by enhancing γ-aminobutyric acid neurotransmitter activity. Unfortunately, these substances may induce significant adverse effects in chronic users, such as dependence and motor behavior impairments. Consequently, there is a growing interest in exploring therapeutic sleep-enhancing agents derived from natural sources, with the anticipation of causing less severe side effects. Prunella vulgaris (PV), a perennial plant indigenous to South Korea, exhibits various pharmacological effects, likely attributed to its chemical composition. Rosmarinic acid, one of its components, has previously demonstrated sleep-potentiating properties, suggesting the potential for PV to exhibit similar pharmacological effects. This study aims to investigate the potential effects of repeated administration of PV extract on the sleep behavior, brainwave activity, sleep-wake cycle, and physiological behavior of mice. Findings indicate that PV extracts exhibit sleep-enhancing effects in mice, characterized by prolonged sleep duration and a reduced onset time of pentobarbital-induced sleep. However, PV extracts only reduced alpha wave powers, with minor alterations in wakefulness and rapid-eye-movement sleep duration. In contrast to diazepam, PV extracts lack adverse effects on locomotor activity, motor coordination, or anxiety in mice. Receptor-binding assay and caffeine treatment support the potential involvement of adenosine A2A receptors in the effects of PV, suggesting distinct mechanisms of action compared to diazepam, despite both exhibiting sleep-altering effects. Overall, our results suggest that PV holds promise as a potential source of sleep-aiding agents.

Interventions for insomnia in cancer patients and survivors-a comprehensive systematic review and meta-analysis.

BACKGROUND: Considering the persistent nature and higher prevalence of insomnia in cancer patients and survivors compared with the general population, there is a need for effective management strategies. This systematic review and meta-analysis aimed to comprehensively evaluate the available evidence for the efficacy of pharmacological and nonpharmacological interventions for insomnia in adult cancer patients and survivors. METHODS: Following the PRISMA guidelines, we analyzed data from 61 randomized controlled trials involving 6528 participants. Interventions included pharmacological, physical, and psychological treatments, with a focus on insomnia severity and secondary sleep and non-sleep outcomes. Frequentist and Bayesian analytical strategies were employed for data synthesis and interpretation. RESULTS: Cognitive-Behavioral Therapy for Insomnia (CBT-I) emerged as the most efficacious intervention for reducing insomnia severity in cancer survivors and further demonstrated significant improvements in fatigue, depressive symptoms, and anxiety. CBT-I showed a large postintervention effect (g = 0.86; 95% confidence interval [CI] = 0.57 to 1.15) and a medium effect at follow-up (g = 0.55; 95% CI = 0.18 to 0.92). Other interventions such as bright white light therapy, sleep medication, melatonin, exercise, mind-body therapies, and mindfulness-based therapies showed benefits, but the evidence for their efficacy was less convincing compared with CBT-I. Brief Behavioral Therapy for Insomnia showed promise as a less burdensome alternative for patients in active cancer treatment. CONCLUSIONS: CBT-I is supported as a first-line treatment for insomnia in cancer survivors, with significant benefits observed across sleep and non-sleep outcomes. The findings also highlight the potential of less intensive alternatives. The research contributes valuable insights for clinical practice and underscores the need for further exploration into the complexities of sleep disturbances in cancer patients and survivors.

A Cross Sectional Survey of Factors Related to Cannabis Use as a Sleep Aid Among Canadian Cancer Survivors.

OBJECTIVES: Poor sleep is a common side effect of cancer. Cannabis is increasingly used to manage cancer treatment-related symptoms, including sleep. This study investigated factors related to cannabis use for sleep among Canadian cancer survivors. METHOD: Adult Canadian cancer survivors (N = 940) were recruited via the Angus Reid Institute and completed an online, cross-sectional survey. Univariate and multiple binomial logistic regression models identified factors associated with cannabis use for sleep. RESULTS: Of the participants (Mage = 64.5 yrs; Women = 51.1%; White = 92.9%), 25.1% (n = 236) currently use cannabis for sleep. Participants were at greater odds of using cannabis for sleep if they identified as a gender other than man or woman (AOR = 11.132), were diagnosed with multiple medical conditions (2:AOR = 1.988; 3+:AOR = 1.902), two psychological conditions (AOR = 2.171), multiple sleep disorders (AOR = 2.338), insomnia (AOR = 1.942), bone (AOR = 6.535), gastrointestinal (AOR = 4.307), genitourinary (AOR = 2.586), hematological (AOR = 4.739), or an unlisted cancer (AOR = 3.470), received hormone therapy only (AOR = 3.054), drink heavily (AOR = 2.748), or had mild insomnia (AOR = 1.828). Older participants (AOR=.972) and those with sleep apnea were less likely to use cannabis for sleep (AOR=.560). CONCLUSION: Given its prevalence, research is needed to understand how factors associated with cannabis use as a sleep aid among Canadian cancer survivors may influence its use and effectiveness and whether these factors are barriers to accessing evidence-based treatments.

Risk factors and a nomogram model for postoperative delirium in elderly gastric cancer patients after laparoscopic gastrectomy.

BACKGROUND: To evaluate the risk factors of postoperative delirium (POD) in elderly gastric cancer (GC) patients after laparoscopic gastrectomy and construct a predictive model. METHODS: Elderly GC patients undergoing laparoscopic gastrectomy were enrolled and grouped based on the status of POD development within postoperative 7 days. Independent risk factors were selected out by univariate and multivariate logistic regression analyses and then enrolled in the nomogram prediction model. RESULTS: A total of 270 elderly GC patients were enrolled, and POD occurred in 74 (27.4%) patients within postoperative 7 days. The results of multivariate regression analysis indicated that age (OR: 3.30, 95% CI: 1.41-6.85, P < 0.001), sleeping pills (OR: 1.87, 95% CI: 1.12-3.09, P = 0.012), duration of ICU stay (OR: 1.55, 95% CI: 1.02-2.37, P = 0.029), albumin/fibrinogen ratio (AFR) (OR: 1.74, 95% CI: 1.03-2.76, P = 0.019), and neutrophils/lymphocytes ratio (NLR) (OR: 2.12, 95% CI: 1.11-4.01, P = 0.016) were five independent risk factors for POD in elderly GC patients. The AUC of the constructed nomogram model based on these five factors was 0.807. CONCLUSIONS: This study highlighted that age, AFR, NLR, sleeping pills taking, and duration of ICU stay were independent risk factors for POD, and the nomogram model based on these factors could effectively predict POD in elderly GC patients.

Nationwide database analysis of insomnia, depression, and sleeping pill prescriptions in hepatocellular carcinoma patients.

OBJECTIVE: To clarify the status of insomnia and depression and the prescription of sleeping pills in hepatocellular carcinoma (HCC) patients before and after HCC diagnosis and treatment. METHODS: Patients' data from a Japanese health insurance claims database were analyzed retrospectively to determine the incidence of insomnia and depression and their association with sleeping pill prescriptions during the 6 months before and after HCC diagnosis and treatment. RESULTS: A total of 9,109 HCC patients (median age at diagnosis = 71.5 years, 68.1% male) were analyzed. The incidences of insomnia and depression increased significantly after HCC diagnosis. Insomnia was reported in 15.0% of patients before diagnosis, and it increased to 27.6% after diagnosis. Similarly, depression was reported in 6.3% and 11.3% before and after diagnosis, respectively. The incidences of insomnia and depression before diagnosis were higher in patients with concomitant liver diseases including hepatitis, cirrhosis, and hepatic encephalopathy. However, the rate of sleeping pill prescription was significantly lower in patients with concomitant liver diseases after diagnosis. The incidence of fracture was higher in insomnia or depression patients than others and in patients treated with sleeping pills than without before and after diagnosis. CONCLUSIONS: HCC patients had increased risks of insomnia and depression after diagnosis. The high risk of fracture in HCC patients with insomnia and depression and treated with sleeping pills suggests that it is difficult to optimize the management of HCC patients, especially those with concomitant liver diseases.

Is Yoga Associated With Improved Sleep Amongst Breast Cancer Survivors?

BACKGROUND: Breast cancer survivors may experience sleep disturbances that can affect their physical and mental well-being. We sought to determine the association, if any, between yoga and sleep among breast cancer survivors in a population-based cohort. METHODS: The National Health Interview Survey is designed to be representative of the US civilian non-institutionalized population. We evaluated breast cancer survivors in the 2017 cohort to determine the association between yoga and self-reported quality of sleep. RESULTS: Of the 25,905 people surveyed, representing 238,738,039 in the population, 1.59% reported a previous history of breast cancer. Breast cancer survivors were less likely to report having practiced yoga in the preceding 12 months, compared to those without a history of breast cancer (9.98% vs 13.78%, P = .011). In addition, they were more likely to report having had trouble falling asleep (44.64% vs 36.32%, P = .002), staying asleep (53.72% vs 39.43%, P < .001), and using sleep medication on at least 1 day within the previous week (23.80% vs 13.49%, P < .001) than those without breast cancer. Among breast cancer survivors, there were no significant differences in difficulty falling asleep (39.16% vs 44.98%, P = .482), difficulty staying asleep (61.17% vs 52.70%, P = .305), and needing sleep medication (19.03% vs 24.53%, P = .395) between those who practiced yoga and those who did not. Controlling for sociodemographic factors, there remained no association between yoga and difficulty falling or staying asleep among breast cancer survivors. CONCLUSION: There is no direct association between yoga and sleep quality in breast cancer survivors.

Association of preterm birth with medications: machine learning analysis using national health insurance data.

PURPOSE: To use machine learning and population data for testing the associations of preterm birth with socioeconomic status, gastroesophageal reflux disease (GERD) and medication history including proton pump inhibitors, sleeping pills and antidepressants. METHODS: Population-based retrospective cohort data came from Korea National Health Insurance Service claims data for all women who aged 25-40 years and gave births for the first time as singleton pregnancy during 2015-2017 (405,586 women). The dependent variable was preterm birth during 2015-2017 and 65 independent variables were included (demographic/socioeconomic determinants, disease information, medication history, obstetric information). Random forest variable importance (outcome measure) was used for identifying major determinants of preterm birth and testing its associations with socioeconomic status, GERD and medication history including proton pump inhibitors, sleeping pills and antidepressants. RESULTS: Based on random forest variable importance, major determinants of preterm birth during 2015-2017 were socioeconomic status (645.34), age (556.86), proton pump inhibitors (107.61), GERD for the years 2014, 2012 and 2013 (106.78, 105.87 and 104.96), sleeping pills (97.23), GERD for the years 2010, 2011 and 2009 (95.56, 94.84 and 93.81), and antidepressants (90.13). CONCLUSION: Preterm birth has strong associations with low socioeconomic status, GERD and medication history such as proton pump inhibitors, sleeping pills and antidepressants. For preventing preterm birth, appropriate medication would be needed alongside preventive measures for GERD and the promotion of socioeconomic status for pregnant women.

Effect of Hibiscus syriacus Linnaeus extract and its active constituent, saponarin, in animal models of stress-induced sleep disturbances and pentobarbital-induced sleep.

Treatment of sleep disorders promotes the long-term use of commercially available sleep inducers that have several adverse effects, including addiction, systemic fatigue, weakness, loss of concentration, headache, and digestive problems. Therefore, we aimed to limit these adverse effects by investigating a natural product, the extract of the Hibiscus syriacus Linnaeus flower (HSF), as an alternative treatment. In the electric footshock model, we measured anxiety and assessed the degree of sleep improvement after administering HSF extract. In the restraint model, we studied the sleep rate using PiezoSleep, a noninvasive assessment system. In the pentobarbital model, we measured sleep improvement and changes in sleep-related factors. Our first model confirmed the desirable effects of HSF extract and its active constituent, saponarin, on anxiolysis and Wake times. HSF extract also increased REM sleep time. Furthermore, HSF extract and saponarin increased the expression of cortical GABAA receptor α1 (GABAAR α1) and c-Fos in the ventrolateral preoptic nucleus (VLPO). In the second model, HSF extract and saponarin restored the sleep rate and the sleep bout duration. In the third model, HSF extract and saponarin increased sleep maintenance time. Moreover, HSF extract and saponarin increased cortical cholecystokinin (CCK) mRNA levels and the expression of VLPO c-Fos. HSF extract also increased GABAAR α1 mRNA level. Our results suggest that HSF extract and saponarin are effective in maintaining sleep and may be used as a novel treatment for sleep disorder. Eventually, we hope to introduce HSF and saponarin as a clinical treatment for sleep disorders in humans.

Prevalência e fatores associados ao uso de medicamento indutor do sono entre mulheres assistidas na Atenção Primária à Saúde: estudo transversal em Vitória, Espírito Santo, 2014 / Prevalencia y factores asociados al uso de medicamentos inductores del sueño en mujeres atendidas en Atención Primaria de Salud: estudio transversal en Vitória, Espírito Santo, Brasil, 2014 / Prevalence and factors associated with the use of sleep-inducing medication among women receiving Primary Health Care: a cross-sectional study in Vitória, Espírito Santo, Brazil, 2014

Objetivo: Verificar a prevalência e fatores associados ao uso de medicamento indutor do sono entre mulheres assistidas na Atenção Primária à Saúde (APS), Vitória, ES, Brasil. Métodos: Estudo transversal com mulheres de 20-59 anos, realizado em 2014. Analisou-se a associação do uso de indutor do sono com fatores socioeconômicos e experiências de violência (regressão de Poisson). Resultados: Entre 991 participantes, 18,5% usavam medicamento indutor do sono e 45,9% usaram-no alguma vez na vida. Seu uso, atualmente e ao longo da vida, associou-se a idade, escolaridade e violências psicológica, física e sexual no último ano (p-valor<0,05). Menor renda familiar (RP=1,30; IC95% 1,03;1,64) e parceiro controlador (RP=1,35; IC95% 1,08;1,69) associaram-se ao uso atual, enquanto experiência de violência sexual na infância (RP=1,33; IC95% 1,13;1,56) associou-se ao uso alguma vez na vida. Conclusão: O uso de medicamento indutor do sono foi frequente entre usuárias da APS, associando-se a fatores socioeconômicos e experiências de violência.

Objetivo: Verificar la prevalencia y los factores asociados al uso de medicamentos inductores del sueño en mujeres en la Atención Primaria de Salud (APS) de Vitória, ES, Brasil. Métodos: Estudio transversal con mujeres de 20 a 59 años realizado en 2014. Se analizó la asociación del uso de inductores del sueño con factores socioeconómicos y violencia (regresión de Poisson). Resultados: Entre las 991 participantes, 18,5% usó medicamentos inductores y 45,9% los había usado en algún momento. El uso, actual y en la vida, de estos medicamentos se asoció con la edad, años de educación, violencia psicológica, física y sexual en el último año (p-valor<0,05). Ingresos familiares bajos (RP=1,30; IC95% 1,03;1,64) y pareja controladora (RP=1,35; IC95% 1,08;1,69) se asociaron con el uso actual, mientras que la experiencia de violencia en la infancia (RP=1,33; IC95% 1,13;1,56) se asoció con el uso alguna vez en la vida. Conclusión: El uso de inductores del sueño fue frecuente entre usuarias de la APS, asociado a factores socioeconómicos y violencia.

Objective: To verify prevalence and factors associated with the use of sleep-inducing medication among women receiving primary health care (PHC) in Vitória, ES, Brazil. Methods: This was a cross-sectional study conducted in 2014 with women aged 20-59. We analyzed association of sleep-inducing medication use with socioeconomic factors and experiences of violence (Poisson regression). Results: Out of 991 participants, 18.5% were using sleep-inducing medication and 45.9% had used it at some point in their lives. Current and lifetime use of these medications was associated with age, years of education, as well as psychological, physical and sexual violence in the last year (p-valor<0,05). Lower family income (PR=1.30; 95%CI 1.03;1.64) and controlling partner (PR=1.35; 95%CI 1.08;1.69) were associated with current use, while experience of sexual violence in childhood (PR=1.33; 95%CI 1.13;1.56) was associated with lifetime use. Conclusion: Use of sleep-inducing medication was frequent among PHC service users, and was associated with socioeconomic factors and experiences of violence.

Application of Chaihu-Guizhi-Longgu-Muli decoction combined with Liuwei Dihuang Pills in the treatment of menopausal insomnia and its effect on sleep quality.

To explore the application of Chaihu-Guizhi-Longgu-Muli decoction (CGLM) combined with Liuwei Dihuang Pills in the treatment of menopausal insomnia and its effect on sleep quality. The data of 120 menopausal insomnia patients admitted to our hospital from February 2019 to February 2020 were retrospectively analyzed and they were equally divided into the experimental group (n=60) and the control group (n=60) according to the order of admission. All patients were treated with Liuwei Dihuang Pills, and the experimental group was additionally given CGLM. The Pittsburgh Sleep Quality Index (PSQI), estrogen level, negative emotion score, quality of life score, serum ß-endorphin (ß-EP) level, serotonin level (5-HT) and treatment effective rate were compared between the two groups of patients. After treatment, the experimental group obtained markedly lower PSQI scores and negative emotion scores than the control group (P<0.001). The estrogen levels, ß-EP levels and 5-HT levels of the experimental group after treatment were significantly better than those of the control group (P<0.001). Higher quality of life scores and treatment effective rates were observed in the experimental group after treatment than the control group (P<0.001). CGLM combined with Liuwei Dihuang Pills can regulate the serum hormone levels of patients with menopausal insomnia, reduce negative emotions and improve sleep quality and quality of life, which merits clinical promotion.

Uso de hipnóticos, qualidade do sono e síndrome de Burnout em estudantes de medicina / Use of hypnotics, sleep quality and Burnout syndrome in medical students / Uso de hipnóticos, calidad del sueño y síndrome de Burnout en estudiantes de medicina

OBJETIVO: o objetivo deste estudo foi investigar possíveis associações entre Burnout, uso de hipnóticos e qualidade do sono em estudantes de medicina. MÉTODO: foi realizado um estudo transversal quantitativo com estudantes de medicina de um centro universitário do nordeste do Brasil, com metodologia de Aprendizagem Baseada em Problemas (ABP). O Maslach Burnout Inventory-Student Survey, o Pittsburgh Sleep Quality Index (PSQI) e um questionário sociodemográfico foram aplicados entre os alunos do pré-internato do curso. RESULTADOS: o estudo incluiu 523 alunos e encontrou 48 (9,2%) com critérios de diagnóstico tridimensional para Síndrome de Burnout (SB). A má qualidade do sono e o uso de hipnóticos para dormir foram associados à SB (p < 0,001 e p = 0,003, respectivamente). Não houve diferenças estatísticas quanto à idade, sexo, religião, estado civil, financiamento escolar e realização de trabalho remunerado, entre indivíduos com e sem SB. CONCLUSÃO: houve associação entre SB, uso de hipnóticos e má qualidade do sono em estudantes de medicina pré-internato.

OBJECTIVE: the aim of this study was to investigate possible associations between Burnout, use of hypnotics and sleep quality among medical students. METHOD: a cross-sectional quantitative study was conducted among medical students of a university center of northeastern Brazil, with the problem-based learning (PBL) methodology. The Maslach Burnout Inventory-Student Survey, the Pittsburgh Sleep Quality Index (PSQI) and a sociodemographic questionnaire were applied among pre-clerkship students of the course. RESULTS: the study included 523 students and found 48 (9.2%) with tridimensional diagnosis criteria for Burnout syndrome (BS). Poor sleep quality and use of hypnotic drugs for sleep were associated with BS (p < 0.001 and p = 0.003, respectively). There were no statistical differences in age, gender, religion, marital status, student financing and performing paid work, between individuals with and without BS. CONCLUSION: there was an association between BS, use of hypnotics and poor sleep quality among pre-clerkship medical students.

OBJETIVO: el objetivo de este estudio fue investigar las posibles asociaciones entre el síndrome de Burnout, el uso de hipnóticos y la calidad del sueño entre estudiantes de medicina. MÉTODOS: se realizó un estudio cuantitativo transversal entre estudiantes de medicina de un centro universitario del noreste de Brasil, con metodología de aprendizaje basado en problemas (ABP). Se aplicó el Maslach Burnout Inventory-Student Survey, el Pittsburgh Sleep Quality Index (PSQI) y un cuestionario sociodemográfico entre los estudiantes de pre-administrativo del curso. RESULTADOS: el estudio incluyó a 523 estudiantes y encontró 48 (9,2%) con criterios de diagnóstico tridimensional de síndrome de Burnout (SB). La mala calidad del sueño y el uso de fármacos hipnóticos para dormir se asociaron con SB (p <0,001 y p = 0,003, respectivamente). No hubo diferencias estadísticas en edad, sexo, religión, estado civil, financiamiento de los estudiantes y realización de trabajo remunerado, entre individuos con y sin SB. CONCLUSIÓN: hubo asociación entre SB, uso de hipnóticos y mala calidad del sueño entre los estudiantes de medicina antes de la rotación clínica.

Use of Melatonin Is Associated With Lower Risk of Colorectal Cancer in Older Adults.

INTRODUCTION: Preclinical evidence suggests that melatonin may affect cellular pathways involved in colorectal cancer (CRC). We sought to test whether melatonin use was associated with decreased risk of CRC using population-based data. METHODS: We performed a nationwide cohort study using a new-user study design. We identified a total of 58,657 incident melatonin users aged 50 years and older from the Prescribed Drug Register, and matched them with 175,971 comparisons who did not use melatonin, on the ratio of 1:3. The Cox regression model was used to calculate hazard ratios and 95% confidence intervals. RESULTS: The incidence rate of CRC was 10.40 per 10,000 person-years for melatonin users, whereas the rate was 12.82 per 10,000 person-years in the nonusers. We found a significant negative association between melatonin use and risk of CRC (adjusted hazard ratio, 0.82; 95% confidence interval, 0.72-0.92). A test for trend showed a significant dose-response correlation (P < 0.001). The decrease of CRC risk was independent of tumor location and stage at diagnosis. When stratified by age groups, the inverse association was significant only among individuals aged 60 years and older. DISCUSSION: This population-based cohort study suggests that the use of melatonin was associated with a reduced risk of CRC. Further studies are needed to confirm the observed association and to explore the underlying mechanisms.

Macroscopic identification of visceral titanium pigment in an intravenous drug user.

Autopsy findings in intravenous drug addicts are quite variable and may involve a number of organ systems. Reports of the macroscopic identification at autopsy of components of tablets that have been crushed and injected are, however, exceedingly rare. The case of 34-year-old man who died of zolpidem toxicity on a background of pulmonary hypertension attributed to intravenous injections of crushed tablets is described. A very unusual finding was very fine white stippling on the cut surfaces of both the liver and spleen which was shown on energy-dispersive x-ray spectroscopy (EDS) to be titanium dioxide most likely from the coating of the zolpidem tablets. This case is significant in demonstrating titanium dioxide accumulation within organs at both macroscopic and microscopic levels, with confirmation of exposure by EDS analysis. The clinical significance of exposure to such high levels of titanium dioxide is unclear.

Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation.

Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX2R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX2R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX2R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.

Prevalence and differences in habitual sleep efficiency, sleep disturbances, and using sleep medication: a national study of university students in Jordan.

BACKGROUND: Sleep quality has a significant impact on the physical and mental health of the young population. STUDY AIM: To evaluate sleep efficiency, sleep disturbances, and use of sleep medication among university students in Jordan and to examine differences in these problems in relation to selected demographic and health-risk behaviors. METHODS: The study used a cross-sectional design and a multi-stage sampling technique. Three public universities were randomly selected from three major governorates in Jordan. The Arabic version of the Pittsburgh Sleep Quality Index was used to measure sleep efficiency, sleep disturbances, and the use of sleep medication. Descriptive statistics and Kruskal-Wallis tests were used to analyze the data. RESULTS: Of 1308 students who participated in the study, 27% reported sleep efficiency less than 85%, 45% of the students reported nocturnal awakening, 30% reported getting up to use the bathroom, and 9% reported using medication to help sleep. Differences in sleep efficiency, sleep disturbances, and use of sleep medication were found in relation to students' gender, income, marital status, smoking status, and academic achievement. CONCLUSIONS: Poor sleep efficiency, sleep disturbances, and the use of sleep medications are significant problems affecting sleep quality among university students. Students' gender, marital status, income, smoking status, and academic achievement are important factors associated with sleep quality. IMPLICATIONS: Sleep screening among university students is required to identify and provide treatment for sleep problems. Furthermore, educating university students about the effects of smoking on health in general and on sleep in particular should be mandated.

Melatonin ameliorates the sleep disorder induced by surgery under sevoflurane anaesthesia in aged mice.

Post-operative sleep disorders induce adverse effects on patients, especially the elderly, which may be associated with surgery and inhalational anaesthetics. Melatonin is a neuroendocrine regulator of the sleep-wake cycle. In this study, we analysed the alterations of post-operative sleep in aged melatonin-deficient (C57BL/6J) mice, and investigated if exogenous melatonin could facilitate entrainment of circadian rhythm after laparotomy under sevoflurane anaesthesia. The results showed that laparotomy under sevoflurane anaesthesia had a greater influence on post-operative sleep than sevoflurane alone. Laparotomy under anaesthesia led to circadian rhythm shifting forward, altered EEG power density and delta power of NREM sleep, and lengthened REM and NREM sleep latencies. In the light phase, the number of waking episodes tended to decline, and wake episode duration elevated. However, these indicators presented the opposite tendency during the dark phase. Melatonin showed significant efficacy for ameliorating the sleep disorder and restoring physiological sleep, and most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist.

Stress-induced sleep-like inactivity modulates stress susceptibility in mice.

Severe environmental and social stress induces dysregulation of sleep along with mood and cognitive disturbances. However, the role and mechanism of this sleep dysregulation remain elusive. Here we evaluated sleep-like inactivity measured by voluntary movements and its relationship to social behaviors in mice without or with social defeat stress as well as the stressed mice with subsequent sleep deprivation. Social defeat stress immediately induced sleep-like inactivity with decreased body temperature. In the social interaction test, the control mice showed high social interest and its correlation with social sniffing intensity, the latter of which indicates positive valence of social sniffing. After the stress, these social characteristics were maintained in stress-resilient mice, but disrupted in stress-susceptible mice, leading to social avoidance. Sleep deprivation after the stress decreased social sniffing intensity along with reduced social interest, but enhanced the exploratory activity with the positive valence of social sniffing. We also found by c-Fos immunohistochemistry that the stress activated sleep-related brain regions, the dorsomedial hypothalamus and ventrolateral periaqueductal gray. Collectively, these findings show that stress activates sleep-related brain regions and induces sleep-like inactivity, contributing to multiple roles of stress-induced sleep for social behaviors.

Improvement of sleep quality after treatment in patients with lumbar spinal stenosis: a prospective comparative study between conservative versus surgical treatment.

Despite the importance of sleep and the evidence on its relationship with various chronic diseases, quality of sleep is not considered in patients with lumbar spinal stenosis (LSS). This prospective comparative study aimed to investigate the changes in sleep disturbance after treatment in patients with LSS. Patients with LSS and sleep disturbance (n = 201; 147 conservatively treated and 54 patients with surgical treatment) were included. The Pittsburgh sleep quality index (PSQI) was used to evaluate sleep quality. Propensity score matching was used to attenuate the potential bias. Clinical outcome of surgery, as determined by the Oswestry disability index, and the PSQI was compared between the two groups at 6 weeks, 3 months, and 6 months after enrollment. Multivariate logistic analysis was performed to adjust for possible confounders within the matched cohorts. Among the 201 patients, 96 (47.7%) patients were finally matched (48 patients in each group). Sleep quality was initially improved after treatment, regardless of the treatment method. Sleep quality in the surgical group was improved by 6 weeks after surgery and consistently improved during the 6-month follow-up period, despite less use of pain killer. Conversely, the improvement in sleep quality at 6-weeks following conservative treatment was not maintained during the follow-up, although the treatment outcome for LSS measured by ODI was continuously improved. After multivariate logistic regression analysis within propensity score matched cohorts, surgical treatment had a significantly greater chance to improve sleep quality compared to conservative treatment. The failure of sleep improvement in conservative group was significantly associated with depression presented by worse score in Hamilton depression rating scale, and more severe degree of foraminal-type stenosis, which should be carefully considered for conservative treatment of LSS patients with sleep disturbance.

Development and Validation of an LC-MS-MS Method for the Detection of 40 Benzodiazepines and Three Z-Drugs in Blood and Urine by Solid-Phase Extraction.

An analytical method for the detection of 40 benzodiazepines, (±)-zopiclone, zaleplon and zolpidem in blood and urine by solid-phase extraction liquid chromatography-tandem mass spectrometry was developed and validated. Twenty-nine of 43 analytes were quantified in 0.5 mL whole blood for investigating postmortem, drug-facilitated sexual assault (DFSA) and driving under the influence of drugs cases (DUID). The four different dynamic ranges of the seven-point, linear, 1/x weighted calibration curves with lower limits of quantification of 2, 5, 10 and 20 µg/L across the analytes encompassed the majority of our casework encountered in postmortem, DFSA and DUID samples. Reference materials were available for all analytes except α-hydroxyflualprazolam, a hydroxylated metabolite of flualprazolam. The fragmentation of α-hydroxyflualprazolam was predicted from the fragmentation pattern of α-hydroxyalprazolam, and the appropriate transitions were added to the method to enable monitoring for this analyte. Urine samples were hydrolyzed at 55°C for 30 min with a genetically modified ß-glucuronidase enzyme, which resulted in >95% efficiency measured by oxazepam glucuronide. Extensive sample preparation included combining osmotic lysing and protein precipitation with methanol/acetonitrile mixture followed by freezing and centrifugation resulted in exceptionally high signal-to-noise ratios. Bias and between-and within-day imprecision for quality controls (QCs) were all within ±15%, except for clonazolam and etizolam that were within ±20%. All 29 of the 43 analytes tested for QC performance met quantitative reporting criteria within the dynamic ranges of the calibration curves, and 14 analytes, present only in the calibrator solution, were qualitatively reported. Twenty-five analytes met all quantitative reporting criteria including dilution integrity. The ability to analyze quantitative blood and qualitative urine samples in the same batch is one of the most useful elements of this procedure. This sensitive, specific and robust analytical method was routinely employed in the analysis of >300 samples in our laboratory over the last 6 months.