Sleep Dysfunction Research Articles

Altered sleep and inflammation are related to outcomes in neonatal encephalopathy.

Immune dysregulation and delayed onset of sleep wake cycling (SWC) are associated with worse outcome in neonatal encephalopathy (NE), however the association between sleep and immune dysfunction in NE remains unclear. Aimed to evaluate association of sleep and systemic inflammation with outcomes in NE. Amplitude-integrated electroencephalography (aEEG) recordings were collected on infants undergoing therapeutic hypothermia (TH). Duration to onset of (SWC) and sleep quality (SQ) were examined. Blood samples collected during the first 2 days of life. Thirteen pro- and anti-inflammatory serum cytokines were quantified. Adverse outcome defined as death or abnormal MRI brain. Earlier onset of SWC and better SQ had less adverse outcomes. SQ provided better prognostic value and showed better interobserver agreement compared to duration to SWC. Better SQ associated with lower cytokines EPO and interleukin (IL)-1β. In infants with unfavourable outcome, shorter duration to SWC was associated with higher EPO and better SQ was associated with lower TNF-α. Earlier onset of SWC or better SQ showed less systemic inflammation and fewer adverse outcomes. SQ during TH provided better prognostic information than time of onset of SWC. Modulation of circadian rhythm in infants with NE may have an immunomodulatory role, leading to improved outcomes.

Sleep Abnormalities in SLC13A5 Citrate Transporter Disorder.

SLC13A5 Citrate Transporter Disorder is a rare pediatric neurodevelopmental disorder. Patients have epilepsy, developmental disability, and impaired mobility. While sleep disorders are common in children with neurodevelopmental disorders, sleep abnormalities have not been reported in SLC13A5 patients. Here, we assessed sleep disturbances in patients through caregiver reported surveys and in a transgenic mouse model of SLC13A5 deficiency. A total of 26 patients were evaluated with the Sleep Disturbance Scale for Children three times over a one-year span. Sleep and wake activities were assessed in the SLC13A5 knock-out (KO) mice using wireless telemetry devices. A high burden of clinically significant sleep disturbances were reported in the patients, with heterogeneous symptoms that remained stable across time. While sleep disturbances were common, less than 30% of patients were prescribed medications for sleep. Comparatively, in SLC13A5 KO mice using EEG recordings, significant alterations were found during light cycles, when rodents typically sleep. During the sleep period, SLC13A5 mice had increased activity, decreased paradoxical sleep, and changes in absolute power spectral density, indicating altered sleep architecture in the mouse model. Our results demonstrate a significant component of sleep disturbances in SLC13A5 patients and mice, highlighting a potential gap in patient care. Further investigation of sleep dysfunction and the underlying etiologies of sleep disturbances in SLC13A5 citrate transporter disorder is warranted.

Impact of Pemphigus on Sleep Quality: A Prospective Observational Single-Center Case-Control Study.

Pemphigus, an autoimmune disorder, significantly impacts the quality of life for those affected. This study examined the sleep quality in patients with pemphigus, a domain for which the existing literature provides limited data without a focused analysis. A total of 156 individuals, 52 in the case and 104 in the control group, completed several questionnaires (Pittsburgh Sleep Quality Index [PSQI], General Health Questionnaire-12 [GHQ-12], and ABQOL [Autoimmune Bullous Disease Quality of Life]). Disease severity was evaluated using the Pemphigus disease area index (PDAI index). The case group exhibited significantly higher levels of psychological distress, reflected in GHQ-12 scores (P = 0.00), and notably poorer sleep quality compared to controls across various parameters (sleep latency [SL], disturbances [SDi], medication [SM], daytime sleep dysfunction [DSD]), and the global PSQI score (GS)] (P = 0.00)). Significant correlations were observed between PDAI scores and sleep duration (SDu) (P = 0.01), SM (P=0.03), SL (P =0.03), and GS (P=0.00). An association was found between the equivalent steroid intake and SDu (P=0.00) as well as GS (P=0.02). No statistically significant correlation emerged between disease duration and PSQI scores. Our findings indicated a correlation between poor sleep quality and cutaneous rather than mucosal manifestations (p=0.01). Pemphigus affects sleep quality. Severe disease showed heightened SDi, correlating with higher steroid doses, and in the chronic phase, the impact seems to have been more influenced by the pro-inflammatory stage of the disease. Patients with cutaneous pemphigus exhibited reduced sleep quality compared to those with oral pemphigus. Understanding that pemphigus worsens sleep quality can be beneficial for the holistic management of individuals with this condition.

Integrating the Memory Support Intervention into the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C): can improving memory for treatment in midlife and older adults improve patient outcomes? Study protocol for a randomized controlled trial

BackgroundPoor memory for treatment is associated with poorer treatment adherence and poorer patient outcomes. The memory support intervention (MSI) was developed to improve patient memory for treatment with the goal of improving patient outcomes. The aim of this study protocol is to conduct a confirmatory efficacy trial to test whether a new, streamlined, and potent version of the MSI improves outcomes for midlife and older adults. This streamlined MSI is comprised of constructive memory supports that will be applied to a broader range of treatment content. The platform for this study is the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C). We will focus on midlife and older adults who are low income and experiencing mobility impairments.MethodsParticipants (N = 178) will be randomly allocated to TranS-C + MSI or TranS-C alone. Both intervention arms include eight 50-min weekly sessions. Assessments will be conducted at pre-treatment, post-treatment, 6-, and 12-month follow-up (6FU and 12FU). Aim 1 will compare the effects of TranS-C + MSI versus TranS-C alone on sleep and circadian functioning, daytime functioning, well-being, and patient memory. Aim 2 will test whether patient memory for treatment mediates the relationship between treatment condition and patient outcomes. Aim 3 will evaluate if previously reported poor treatment response subgroups will moderate the relationship between treatment condition and (a) patient memory for treatment and (b) treatment outcome. Exploratory analyses will compare treatment condition on (a) patient adherence, patient-rated treatment credibility, and patient utilization of treatment contents, and (b) provider-rated acceptability, appropriateness, and feasibility.DiscussionThis study has the potential to provide evidence for (a) the efficacy of a new simplified version of the MSI for maintaining health, well-being, and functioning, (b) the wider application of the MSI for midlife and older adults and to the treatment of sleep and circadian problems, and (c) the efficacy of the MSI for sub-groups who are likely to benefit from the intervention.Trial registrationClinicalTrials.gov NCT05986604. Registered on 2 August 2023.

Using augmented intelligence to improve long term outcomes.

For augmented intelligence (AI) tools to realize their potential, critical care clinicians must ensure they are designed to improve long-term outcomes. This overview is intended to align professionals with the state-of-the art of AI. Many AI tools are undergoing preliminary assessment of their ability to support the care of survivors and their caregivers at multiple time points after intensive care unit (ICU) discharge. The domains being studied include early identification of deterioration (physiological, mental), management of impaired physical functioning, pain, sleep and sexual dysfunction, improving nutrition and communication, and screening and treatment of cognitive impairment and mental health disorders.Several technologies are already being marketed and many more are in various stages of development. These technologies mostly still require clinical trials outcome testing. However, lacking a formal regulatory approval process, some are already in use. Plans for long-term management of ICU survivors must account for the development of a holistic follow-up system that incorporates AI across multiple platforms. A tiered post-ICU screening program may be established wherein AI tools managed by ICU follow-up clinics provide appropriate assistance without human intervention in cases with less pathology and refer severe cases to expert treatment.

Sleep Quality in High-Risk Pregnancies: Mixed Methods Results from a Randomized Controlled Trial of a Mindfulness Training Intervention.

Objectives: Sleep difficulties in pregnancy are common and increase the risk for obstetric complications. Past research shows that mindfulness training (MT) is helpful for improving sleep in non-pregnant adults and may improve sleep during pregnancy. However, it is unknown if MT improves sleep among pregnant people at risk for obstetric complications. We examined the effects of MT on sleep quality in individuals at risk of developing hypertensive disorders of pregnancy. Methods: Twenty-nine participants (mean age, 32 ± 4 years; mean gestational age, 16 ± 3weeks) at risk for hypertensive disorders in pregnancy (HDP) were randomized to an 8-week phone-delivered MT intervention (n = 15) or treatment as usual (TAU; n = 14), designed to test MT feasibility and acceptability. As part of the study, participants completed the Pittsburgh Sleep Quality Index and participated in a semi-structured individual qualitative interview which queried for sleep changes over pregnancy. Results: Participants randomized to MT reported less daytime sleep dysfunction compared to TAU (F = 5.79, p = 0.03, ηp2 = 0.28). Qualitative data illustrated the common experiences of sleep disturbance across both study groups; however, MT participants reported an improved ability to initiate sleep and return to sleep using mindfulness skills. About half of the participants in the MT condition reported an improvement in overall sleep quality due to less interference related to anxiety and restlessness, while other MT participants reported no change in sleep quality. Conclusions: Results from this study confirm that pregnant individuals frequently encounter sleep challenges. Findings also suggest that MT may be a helpful tool in improving sleep quality among pregnant people at risk for obstetric complications.

Cortisol and cortisone determination by disposable pipette extraction (DPX) and ultra-efficient liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) in urine and saliva samples from patients with Parkinson's disease.

Higher serum cortisol levels appear to be associated with stress that can overlap or manifest anxiety, fatigue, depression, and sleep dysfunction. These are common and intrusive non-motor symptoms of Parkinson's disease (PD). Thus, stress has been proposed to mediate Parkinson's disease development, and cortisol has been suggested as a biomarker for the generation of stress-related symptoms in Parkinson's disease. This study describes sensitive and robust disposable pipette extraction (DPX) and ultra-efficient liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method to determine cortisol and cortisone (as potential endocrine biomarkers for Parkinson's disease) in 24-h urine and saliva samples obtained from Parkinson's disease patients. Important parameters on DPX extraction were optimized to achieve the best extraction recovery and cleanup efficiency. The proposed method was linear from 0.5 (lower limit of quantification) to 500ngmL-1 for cortisol and from 3.0 (lower limit of quantification) to 500ngmL-1 for cortisone. To determine whether urinary cortisol and urinary cortisone are adequate as biomarkers to evaluate the level of anxiety in patients suffering from Parkinson's disease, twenty-nine Parkinson's disease patients (18 with anxiety and 11 without anxiety) were selected for urine analysis. Based on the obtained results, 24-h urine samples obtained from Parkinson's disease patients with anxiety had higher cortisone levels than samples obtained from healthy controls. Receiving operating curves (ROC) analysis, which presented the area under the ROC curve (AUC = 0.733), showed that urinary cortisone levels (µg/24-h urine) were sensitive (56.3%) and specific (93.3%) for distinguishing Parkinson's disease patients with anxiety from healthy controls. In terms of salivary results, PD patients' samples taken 30min after waking up had higher cortisol and cortisone levels than healthy controls, while their samples taken at night had lower cortisol and cortisone levels.

Sleep dysfunction and gut dysbiosis related amino acids metabolism disorders in cynomolgus monkeys after middle cerebral artery occlusion

IntroductionThis study aimed to explore the characteristics of post-stroke sleep dysfunction and verify their association with gut dysbiosis and the related amino acid metabolism disorders. This was achieved by using fecal microbiota transplantation (FMT) in a non-human primate stroke model. MethodsTwenty adult male cynomolgus monkeys were divided into the sham (n = 4), middle cerebral artery occlusion (MCAO, n = 5), MCAO + FMT (n = 3), and donor (n = 8) groups. The MCAO+FMT group received FMT at post-MCAO week 4. Sleep parameters, gut microbiota, gamma-aminobutyric acid (GABA), and glutamine (Gln) in the cerebrospinal fluid (CSF) were measured at baseline and postoperative weeks 4, 8, and 12. ResultsAt postoperative weeks 4, 8, and 12, the MCAO group showed decreased sleep efficiency, measured as the percentage of sleep during the whole night (82.3 ± 3.2 % vs 91.3 ± 2.5 %, 79.0 ± 3.75 % vs 90.8 ± 3.2 %, and 69.5 ± 4.8 % vs 90.5 ± 2.7 %; all P < 0.05), lower relative abundance of Lactobacillus (all P < 0.05), and reduced GABA concentrations in the CSF (317.3 ± 30.6 nmol/L vs 437.7 ± 25.6 nmol/L, 303.1 ± 48.9 nmol/L vs 4 40.9 ± 37.8 nmol/L, and 337.9 ± 49.4 nmol/L vs 457.4 ± 39.2 nmol/L; all P < 0.05) compared with the sham group. Sleep efficiency at post-FMT weeks 4 and 8 (84.7 ± 1.1 % vs 79.0 ± 3.75 %, and 84.1 ± 2.0 % vs 69.5 ± 4.8 %; both P < 0.05) and GABA concentration in the CSF at post-FMT week 4 (403.1 ± 25.4 nmol/L vs 303.1 ± 48.9 nmol/L, P < 0.05) was higher in the MCAO+FMT group than in the MCAO group. ConclusionsPost-stroke sleep dysfunction in monkeys is characterized by impaired sleep coherence, associated with decreased levels of probiotics such as Lactobacillus, GABA, and Gln in the CSF and can be ameliorated using FMT.

Evaluating the Spectrum of Sleep Abnormalities in Patients With Primary Hypothyroidism.

This cross-sectional study included 81 participants attending the endocrinology outpatient department. The participants included those with both overt and subclinical primary hypothyroidism who were drug-naive or had a thyroid-stimulating hormone (TSH) level >4.5 µIU/L while on treatment. The study subjects were assessed based on various validated questionnaires for sleep disturbance. The study predominantly comprised 64 (79%) female participants. Overall, poor sleepers in subclinical and overt hypothyroidism were 66.7 and 60.8%. The Berlin Risk Score Questionnaire showed the occurrence of sleep apnea to be 26.7% and 27.5% in subclinical and overt groups, respectively. However, the occurrence of sleep dysfunction did not correlate with TSH values alone. Our findings demonstrate that sleep dysfunction is prevalent in patients with both overt and subclinical primary hypothyroidism. Furthermore, the severity of sleep disruption appears independent of the degree of thyroid dysfunction.

Intravenous arachnoid granulation hypertrophy in patients with Parkinson disease

Intravenous arachnoid granulations (AGs) are protrusions of the arachnoid membrane into the venous lumen and function as contributors to the cerebrospinal fluid (CSF) flow circuit. Patients with Parkinson disease (PD) often present with accumulation of alpha synuclein. Previous works have provided evidence for neurofluid circulation dysfunction in neurodegenerative diseases associated with changes in CSF egress, which may have implications regarding AG morphology. The present study aims to investigate group differences in AG volumetrics between healthy and PD participants, as well as relationships between AG characteristics and clinical assessments. Generalized linear models revealed significant increases in AG volumetrics and number in PD compared to healthy controls. Partial Spearman-rank correlation analyses demonstrated significant relationships between AG metrics and motor and cognitive assessments. Finally, AG volumetrics were positively correlated with objective actigraphy measures of sleep dysfunction, but not self-report sleep symptoms.

Chronic sleep deprivation induces erectile dysfunction through increased oxidative stress, apoptosis, endothelial dysfunction, and corporal fibrosis in a rat model.

Sleep is foundational for nocturnal erections, facilitating nutrient exchange and waste removal, which has brought widespread attention to the relationship between sleep and erectile dysfunction (ED). However, there is currently a lack of basic research confirming whether chronic sleep deprivation (CSD) leads to erectile impairment and its underlying pathological mechanisms. The study sought to investigate whether CSD impairs erectile function in rats and the potential tissue damage it may cause in rats. The modified multiple platform method was employed to induce CSD in 14 rats, randomly divided into a platform control group and a CSD group. After 3 weeks, erectile function was evaluated by measuring intracavernosal pressure following cavernous nerve stimulation. Arterial blood samples were then analyzed for testosterone levels, and cavernous tissues were processed for advanced molecular biology assays, including Western blotting and immunofluorescence. After inducing CSD, rats exhibited a marked reduction in erectile function, yet their serum testosterone levels remained statistically unchanged when compared with the control group. More importantly, rats in the CSD group exhibited a significant increase in oxidative stress levels, accompanied by low expression of HO-1 and high expression of NOX1 and NOX4. Subsequently, elevated oxidative stress induced increased apoptosis in smooth muscle and endothelial cells, as evidenced by significant decreases in CD31 and α-smooth muscle actin expression in the CSD group, demonstrated through Western blotting and immunofluorescence assays. Endothelial cell apoptosis led to a significant decrease in endothelial nitric oxide synthase, resulting in lowered levels of nitric oxide and cyclic guanosine monophosphate, which severely impaired the erectile mechanism. Additionally, activation of the transforming growth factor β1 fibrotic pathway led to increased levels of tissue fibrosis, resulting in irreversible damage to the penile tissue in the CSD group. Our study lacks further exploration of the molecular mechanisms linking CSD and ED, representing a future research focus for potential targeted therapies. Our findings demonstrated that CSD significantly impairs erectile function in rats. CSD severely impairs erectile function in rats. When exposed to CSD, rats exhibit significantly elevated oxidative stress levels, which lead to increased tissue apoptosis, endothelial dysfunction, and ultimately irreversible fibrotic changes in the tissues. Further researches into the potential molecular mechanisms are needed to identify possible therapeutic targets for ED related to CSD.

Accelerated Resolution Therapy (ART) for the treatment of posttraumatic stress disorder in adults: A systematic review

Accelerated Resolution Therapy (ART), developed in 2008, uses techniques such as rapid eye movement, in vivo exposure, and image rescripting to recondition stressful memories, and reduce physical and emotional reactions to traumatic memories. There is considerable interest in evidence-based treatments for post-traumatic stress disorder (PTSD). This is the first systematic review examining the efficacy of ART for the treatment of PTSD among adults. We searched MEDLINE, PsycINFO, Embase, CINAHL, Scopus, trial registries, and government and private websites for citations published before October 2023. Studies that reported on the effect of ART for PTSD among adults were included. Meta-analyses could not be undertaken due to heterogeneity in study designs and an insufficient number of studies with a low risk of bias. Risk of bias was assessed, and findings synthesized following the synthesis without meta-analysis (SWiM) guidelines. Of the 112 records screened, five studies (Nenrolled = 337; Ncompleted = 250) and six reports of studies met criteria for inclusion. Included studies reported a significant reduction in symptoms of PTSD from pre- to post-intervention, d = 1.12 to 3.28. Significant reductions were also reported in symptoms of depression, mental distress, anxiety, and sleep dysfunction. ART shows some promise as a time-efficient clinical treatment for symptoms of PTSD in adults; however, more high-quality studies are needed.

"So Many Other Things Improve" with Transdiagnostic Treatment for Sleep and Circadian Problems: Interviews with Community Providers on Treating Clients with Serious Mental Illness.

Community mental health centers (CMHCs) offer invaluable, publicly-funded treatment for serious mental illness (SMI). Unfortunately, evidence-based psychological treatments are often not delivered at CMHCs, in part due to implementation barriers, such as limited time, high caseloads, and complex clinical presentations. Transdiagnostic treatments may help address these barriers, because they allow providers to treat symptoms across multiple disorders concurrently. However, little research has investigated CMHC providers' experiences of delivering transdiagnostic treatments "on the ground," particularly for adults with SMI. Thus, the aim of the present study was to assess CMHC providers' perspectives on delivering a transdiagnostic treatment - the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) - to adults diagnosed with SMI. In the context of a larger parent trial, providers were randomized to deliver a standard version of TranS-C (Standard TranS-C) or a version adapted to the CMHC context (Adapted TranS-C). Twenty-five providers from the parent trial participated in a semi-structured interview (n = 10 Standard TranS-C; n = 15 from Adapted TranS-C). Responses were deductively and inductively coded to identify themes related to Proctor's taxonomy of implementation outcomes. Four novel "transdiagnostic take homes" were identified: (1) transdiagnostic targets, such as sleep, can be perceived as motivating and appropriate when treating SMI, (2) strategies to bolster client motivation/adherence and address a wider range of symptom severity may improve transdiagnostic treatments, (3) balancing feasibility with offering in-depth resources is an important challenge for transdiagnostic treatment development, and (4) adapting transdiagnostic treatments to the CMHC context may improve provider perceptions of implementation outcomes.

TBICoE approach to concussion rehabilitation in service members and veterans.

Concussion, also known as mild traumatic brain injury (mTBI), is a condition with unique ties to military service. Service members (SMs) are inherently at a higher risk for concussive injuries due to the intense physical training environment and combat operational tempo required to serve. The Traumatic Brain Injury Center of Excellence (TBICoE) is the US Department of Defense authority on this condition and provides a thorough approach to management of concussion and associated symptom sequela. This article seeks to review the TBICoE approach to the management and rehabilitation of military SMs with mTBI, and highlight resources available to military medical providers. The authors reviewed evidence and TBICoE resources to provide this comprehensive overview of the TBICoE approach to management and rehabilitation of concussion in military SMs. A progressive return to activity protocol in conjunction with symptom-guided management of common post-concussive sequelae, including headache, vestibular and oculomotor issues, sleep dysfunction, cognitive rehabilitation, and behavioral health comorbidities are essential for concussion management in the acute, post-acute and chronic phases of injury. The TBICoE approach to the rehabilitation of military SMs is comprehensive, and includes initial management with a stepwise return to duty protocol and an objective return to duty screening. The mainstays of treatment for SMs with post-acute and chronic post-concussion symptoms are headache management, vestibular and oculomotor rehabilitation, sleep interventions, cognitive rehabilitation, and early intervention for behavioral health comorbidities. These evidence-based strategies may be applied in the treatment of SMs in the US and internationally.

Clinical characteristics and long-term outcome of CASPR2 antibody-associated autoimmune encephalitis in children

BackgroundContactin-associated protein-2(CASPR2) antibody-associated autoimmune encephalitis(AE) is rare in children. This study aimed to report the clinical characteristics and long-term outcome of CASPR2 autoimmunity in children to expand the disease spectrum.MethodsChildren who were hospitalized in our hospital with clinically suspected AE from May 2015 to April 2022 and underwent neuronal surface antibodies detections were retrospectively analyzed. Clinical data of patients with CASPR2 autoimmunity were collected.ResultsPatients who were positive for NMDAR-IgG, CASPR2-IgG, LGI1-IgG and IgLON5-IgG occupied 95.2%(119/125),3.2%(4/125),0.8%(1/125) and 0.8%(1/125), respectively.The median onset age of the 4 patients with CASPR2-IgG was 5.6 years. The most common symptoms were psychiatric symptoms/abnormal behavior(3/4) and sleep dysfunction(3/4). One patient developed a phenotype of Rasmussen encephalitis(RE). Tumor was absent in our patients. Two patients showed abnormal findings on initial brain magnetic resonance imaging(MRI) scans. All the patients showed favorable response to immunotherapy except the patient with RE experienced recurrent symptoms who finally achieved remission after surgery. All the patients had a favorable long-term outcome at the last follow-up(33-58months).ConclusionsCASPR2 autoimmunity may be the second most common anti-neuronal surface antibodies associated neurological disease in children. Psychiatric symptoms/abnormal behavior and sleep disorder were common in children with CASPR2-associated AE. Tumor was rare in those patients. Most pediatric patients had a favorable long-term outcome.

Sleep, Diet, and Exercise: How Much Dementia Caregivers Are Affected?

The current descriptive study reports the sleep, diet, and exercise patterns among 114 dementia caregivers, whose mean age was 55.7 (SD: 10.4) years, with 83 (72.8%) being women. The results indicate significant sleep dysfunction: 37.2% of caregivers reported rarely or never feeling rested upon waking, and 46.5% did not get enough sleep, with 45.6% sleeping only 5 to 5.5 h on average. Sleep latency was also prevalent, as 33.3% required 16 to 30 min to fall asleep. Dietary habits showed reliance on coffee, with 69.4% consuming it daily. Meat consumption was reported by 75%, and 60.9% ate pasta, indicating common dietary preferences. While 86.2% had one to three meals per day, 100% of the caregivers supplemented their diets with vitamins. The physical activity level was low, with 62.3% of respondents reporting no exercise in the past week. These findings underscore significant health concerns among dementia caregivers, including sleep deprivation, inadequate nutrition, and physical inactivity. The report emphasizes the need for targeted interventions to promote self-care practices that can enhance caregivers' health, including better sleep hygiene, balanced nutrition, and regular exercise.

A pharmacist's guide to mitigating sleep dysfunction and promoting good sleep in the intensive care unit.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. To review causes, risk factors, and consequences of sleep disruption in critically ill patients; evaluate the role of nonpharmacological and pharmacological therapies for management of sleep in the intensive care unit (ICU); and discuss the role of pharmacists in implementation of sleep bundles. Critically ill patients often have disrupted sleep and circadian rhythm alterations that cause anxiety, stress, and traumatic memories. This can be caused by factors such as critical illness, environmental factors, mechanical ventilation, and medications. Methods to evaluate sleep, including polysomnography and questionnaires, have limitations that should be considered. Multicomponent sleep bundles with a focus on nonpharmacological therapy aiming to reduce nocturnal noise, light, and unnecessary patient care may improve sleep disorders in critically ill patients. While pharmacological agents are often used to facilitate sleep in critically ill patients, evidence supporting their use is often of low quality, which limits use to patients who have sleep disruption refractory to nonpharmacological therapy. Dedicated interprofessional teams are needed for implementation of sleep bundles in the ICU. Extensive pharmacotherapeutic training and participation in daily patient care rounds make pharmacists vital members of the team who can help with all components of the bundle. This narrative review discusses evidence for elements of the multicomponent sleep bundle and provides guidance on how pharmacists can help with implementation of nonpharmacological therapies and management of neuroactive medications to facilitate sleep. Sleep bundles are necessary for patients in the ICU, and dedicated interprofessional teams that include pharmacists are vital for their successful creation and implementation.

Usp14 down-regulation corrects sleep and circadian dysfunction of a Drosophila model of Parkinson's disease.

PD is a complex, multifactorial neurodegenerative disease, which occurs sporadically in aged population, with some genetically linked cases. Patients develop a very obvious locomotor phenotype, with symptoms such as bradykinesia, resting tremor, muscular rigidity, and postural instability. At the cellular level, PD pathology is characterized by the presence of intracytoplasmic neurotoxic aggregates of misfolded proteins and dysfunctional organelles, resulting from failure in mechanisms of proteostasis. Nonmotor symptoms, such as constipation and olfactory deficits, are also very common in PD. They include alteration in the circadian clock, and defects in the sleep-wake cycle, which is controlled by the clock. These non-motor symptoms precede the onset of the motor symptoms by many years, offering a window of therapeutic intervention that could delay-or even prevent-the progression of the disease. The mechanistic link between aberrant circadian rhythms and neurodegeneration in PD is not fully understood, although proposed underlying mechanisms include alterations in protein homeostasis (proteostasis), which can impact protein levels of core components of the clock. Loss of proteostasis depends on the progressive pathological decline in the proteolytic activity of two major degradative systems, the ubiquitin-proteasome and the lysosome-autophagy systems, which is exacerbated in age-dependent neurodegenerative conditions like PD. Accordingly, it is known that promoting proteasome or autophagy activity increases lifespan, and rescues the pathological phenotype of animal models of neurodegeneration, presumably by enhancing the degradation of misfolded proteins and dysfunctional organelles, which are known to accumulate in these models, and to induce intracellular damage. We can enhance proteostasis by pharmacologically inhibiting or down-regulating Usp14, a proteasome-associated deubiquitinating enzyme (DUB). In a previous work, we showed that inhibition of Usp14 enhances the activity of the ubiquitin-proteasome system (UPS), autophagy and mitophagy, and abolishes motor symptoms of two well-established fly models of PD that accumulate dysfunctional mitochondria. In this work we extended the evidence on the protective effect of Usp14 down-regulation, and investigated the beneficial effect of down-regulating Usp14 in a Pink1 Drosophila model of PD that develop circadian and sleep dysfunction. We show that down-regulation of Usp14 ameliorates sleep disturbances and circadian defects that are associated to Pink1 KO flies.

Efficacy of cannabinoids compared to the current standard treatments on symptom relief in persons with multiple sclerosis (CANSEP trial): study protocol for a randomized clinical trial.

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system. More than 90,000 Canadians are affected; a cure is yet to be found. Available treatments to manage the disease course are only partially effective. For many years, persons with MS (PwMS) have used cannabis to relax, to reduce pain and spasticity, or to improve sleep and daily functioning, despite the lack of scientific evidence on the efficacy of specific cannabinoids [i.e., tetrahydrocannabinol (THC) and cannabidiol (CBD)] on these MS symptoms. The purpose of this clinical trial is to assess the effectiveness of different doses of these cannabinoids, alone or combined, on spasticity relief, compared to placebo. Moreover, we aim to determine which treatment is best effective to address other key MS conditions. A double-blinded, randomized, factorial, placebo-controlled trial will be performed. We intend to include up to 250 PwMS aged over 21 recruited from the Centre hospitalier de l'Université de Montréal MS Clinic. PwMS will be randomly assigned on a 1:1:1:1 ratio to one of the trial arms: THC alone, CBD alone, THC/CBD combination, or placebo, using stratified blocked randomization, with random blocks within each stratum. The primary outcome is a self-assessment of spasticity using the mean Numeric Rating Scale score over 7 days. The main outcome will be the difference in this score at 4 weeks compared to baseline. Secondary outcomes include assessments of spasticity as measured by a clinician, pain, fatigue, sleep, bowel, bladder, and sexual dysfunction, restless legs syndrome, mental health, quality of life, mobility, cognitive functioning, and adverse events. Treatment responders are eligible for a 12-week extension phase, using the same treatment allocation and assessments. Previous clinical studies examined the efficacy of cannabis-based medicines in PwMS, mostly using products with 1:1 THC/CBD ratio. The major barrier to effectively use cannabis in real-world clinical settings is the lack of evidence on benefits of specific cannabinoids and information on possible related risks. The CANSEP study will contribute to overcome these limitations and identify the risks and benefits of cannabis-based treatments in PwMS. ClinicalTrials.Gov, NCT05092191.

An Examination of John Henryism in Adults Living with Sickle Cell Disease.

John Henryism (JH) is a behavioral predisposition for high-effort coping with adversity. JH has been associated with hypertension in Black Americans with low socioeconomic status (SES) and is also found to be associated with psychological well-being. Sickle cell disease (SCD), a rare genetic disease largely affecting Black Americans in the United States, presents as a chronic condition that may benefit from a deeper understanding of the impact of JH on overall health. This study examined the association between high and low JH and diastolic blood pressure, systolic blood pressure, hypertension prevalence, and sleep function. We relied on the biopsychosocial transaction model to adjust for relevant clinical and sociodemographic variables. This was a cross-sectional secondary analysis of 274 adults with SCD living in the United States and recruited between 2014 and 2020. Study visits consisted of physical examinations, medical history, demographic, and psychosocial questionnaires. Adjusted linear regressions estimated associations between high and low JH and diastolic and systolic blood pressure as well as self-reported sleep function. Multivariable logistic regression was used to examine associations with hypertension prevalence. High JH was significantly associated with lower diastolic blood pressure (β = - 2.98; 95% confidence interval = - 5.92, - 0.04) but higher sleep dysfunction (β = 2.76; 95% confidence interval = 1.45, 4.07). Overall, we found positive psychological coping resources associated with high JH, with the exception of sleep. gov Identifier: NCT02156102.