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Underlying neural mechanisms and cognitive implications of non-Rapid Eye Movement (NREM) sleep in isolated Rapid Eye Movement (REM) sleep behavior disorder (iRBD) are not yet fully elucidated. This study aims to evaluate brain metabolic connectivity of the anterior default mode network (ADMN) underlying a waveform that is an hallmark of NREM sleep, namely K-complex (KC) and their implication for neuropsychological functioning in iRBD patients. Combining polysomnographic and multivariate molecular imaging (FDG-PET) approaches may provide crucial insights regarding KCs role in the prodromal stages of synucleinopathies. We applied a seed-based interregional correlation analysis on FDG-PET data. iRBD patients with cognitive decline displayed a reduced KC density (KCd) in comparison to patients without cognitive impairments. KCd showed a significant positive correlation with global cognitive functioning, specifically with visuo-spatial and executive performances, two cognitive domains known to be relevant in predicting conversion into neurodegenerative disorders. Increased KCd was associated with a more preserved ADMN connectivity. Our study underlines the importance of NREM sleep in prodromal stages of synucleinopathies, and future investigations might clarify its role in iRBD.

Background: Insomnia Disorder is characterized by high degree of phenotypic heterogeneity, that might influence treatment response. Methods: 123 of 294 insomnia patients initially recruited (66.7% females, age=40.59±11.89) were assessed before and after group Cognitive-Behavioral Therapy for Insomnia (CBT-I), as well as at follow-up (7.8±1.6 years after the end-of-treatment). By use of latent class analysis (LCA) we identified insomnia subtypes according with baseline scores of insomnia severity and features, anxiety, depression, stress and sleepiness symptoms, circadian rhythm, and treatment effectiveness (Delta score of Insomnia Severity Index-ISI between baseline and end-of-treatment). Results: By LCA we revealed three classes: “PURE INSOMNIA”, "INSOMNIA+ANXIETY+DEPRESSION+STRESS", and “INSOMNIA+ANXIETY”. The improvements in insomnia severity was maintained up to 10 years after the end-of-treatment, but with differences between classes (p14). Limitations: The lack of a control group and the absence of a complete clinical assessment at the follow-up limit the interpretability of our results. Conclusions: Our data driven analysis suggest insomnia heterogeneity can be categorized into sub-classes by depression, anxiety, and stress symptoms. In addition, insomnia patients with stress and depression symptoms maintained highest percentage of clinical depression at the end-of-treatment and insomnia at follow-up, in comparison with others classes. Stress and depression symptoms should be considered risk factors that play an important role in the long-term outcome of CBT-I.

BACKGROUND: Two distinct insomnia disorder (ID) phenotypes have been proposed, distinguished on the basis of an objective total sleep time less or more than 6 hr. In particular, it has been recently reported that patients with objective short sleep duration have a blunted response to cognitive behavioral therapy for insomnia (CBT-I). The aim of this study was to investigate the differences of CBT-I response in two groups of ID patients subdivided according to total sleep time.METHODS: Two hundred forty-six ID patients were subdivided into two groups, depending on their reported total sleep time (TST) assessed by sleep diaries. Patients with a TST greater than 6 hr were classified as "normal sleepers" (NS), while those with a total sleep time less than 6 hr were classified as "short sleepers" (SS).RESULTS: The delta between Insomnia Severity Index scores and sleep efficiency at the beginning as compared to the end of the treatment was significantly higher for SS in comparison to NS, even if they still exhibit more insomnia symptoms. No difference was found between groups in terms of remitters; however, more responders were observed in the SS group in comparison to the NS group.CONCLUSIONS: Our results demonstrate that ID patients with reported short total sleep time had a beneficial response to CBT-I of greater magnitude in comparison to NS. However, these patients may still experience the presence of residual insomnia symptoms after treatment.

Dramatic changes have occurred recently in the field of epilepsy, including a fundamental shift in the etiology of epileptogenic substrates found at surgery. Hippocampal sclerosis is no longer the most common etiology found at epilepsy surgery and this decrease has been associated with an increase in the incidence of focal cortical dysplasia and encephaloceles. Significant advances have been made in molecular biology and genetics underlying the basis of malformations of cortical development, and our ability to detect epileptogenic abnormalities with MR imaging has markedly improved. This article begins with a discussion of these trends and reviews imaging techniques essential for detecting of subtle epilepsy findings. Representative examples of subtle imaging findings are presented, which are often overlooked but should not be missed. These include temporal lobe encephaloceles, malformations of cortical development (and especially focal cortical dysplasia), hippocampal sclerosis, hippocampal malformation (also known as HIMAL), ulegyria, autoimmune encephalitis, and Rasmussen's encephalitis. Recent findings on the pathophysiology and genetic underpinnings of several causes of localization-related epilepsy are incorporated. For instance, it has been recently found that focal cortical dysplasia IIb, tuberous sclerosis, hemimegalencephaly, and gangliogliomas are all the result of mutations of the mTOR pathway for cell growth.

Pneumonia is a leading cause of mortality and a common indication for antibiotic in elderly patients. However, its diagnosis is often inaccurate. We aim to compare the diagnostic accuracy, the clinical and cost outcomes and the use of antibiotics associated with three imaging strategies in patients65 years old with suspected pneumonia in the emergency room (ER): chest X-ray (CXR, standard of care), low-dose CT scan (LDCT) or lung ultrasonography (LUS).This is a multicentre randomised superiority clinical trial with three parallel arms. Patients will be allocated in the ER to a diagnostic strategy based on either CXR, LDCT or LUS. All three imaging modalities will be performed but the results of two of them will be masked during 5 days to the patients, the physicians in charge of the patients and the investigators according to random allocation. The primary objective is to compare the accuracy of LDCT versus CXR-based strategies. As secondary objectives, antibiotics prescription, clinical and cost outcomes will be compared, and the same analyses repeated to compare the LUS and CXR strategies. The reference diagnosis will be established a posteriori by a panel of experts. Based on a previous study, we expect an improvement of 16% of the accuracy of pneumonia diagnosis using LDCT instead of CXR. Under this assumption, and accounting for 10% of drop-out, the enrolment of 495 patients is needed to prove the superiority of LDCT over CRX (alpha error=0.05, beta error=0.10).Ethical approval: CER Geneva 2019-01288.NCT04978116.

Objective Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) frequently represents the prodromal stage of alpha-synucleinopathies, and similar to these pathologies, iRBD patients show neuropsychological deficits, particularly in the domain of visuospatial abilities and executive functions. We hypothesized that the qualitative scoring of the Mini-Mental State Examination pentagon test (QSPT) may detect subtle visuospatial deficits in these subjects, and we evaluated its relationship with indexes of sleep quality, as measured by polysomnography. Methods A total of 80 polysomnography-confirmed iRBD patients and 40 healthy controls (HCs) were retrospectively recruited. Global and specific qualitative performances were evaluated according to QSPT procedure. Comparisons between iRBD and HC regarding all QSPT parameters, neuropsychological tests, and polysomnographic recordings were performed. Results Patients displayed significantly lower scores in both “closing-in” and total score parameters in comparison to HC. The QSPT total score exhibited significant positive correlations with verbal comprehension, fluency, visuospatial abilities, and executive functions. Notably, iRBD patients with impaired performance at QSPT showed decreased neuropsychological performances and higher percentages of slow wave sleep (SWS). In addition, SWS percentages negatively correlated with verbal comprehension, fluency, visuospatial abilities, executive functions, and QSPT total score. Conclusion QSPT may represent a brief and easy to administer tool for the detection of subtle visuospatial changes in iRBD patients. Furthermore, polysomnographic findings suggest a possible slowdown of electroencephalographic pattern during non-REM sleep in iRBD patients in line with the presence of cognitive decline.

Introduction The International Restless Legs Study Group (IRLSSG) has developed the IRLS (International Restless Legs Syndrome Severity Scale) and validated it as a clinician/researcher administered scale to be used when both patient and examiner are present. The IRLSSG recognized the need for a self-completing scale that can be used economically in clinical practice and in large population-based studies. In this study the validity and the reliability of the IRLS as a self-administered scale (sIRLS) is assessed. Methods Established RLS patients were recruited by eight centers in four countries and consented to participate in this study. The validity of the sIRLS was assessed by patients completing the sIRLS before a clinician administered the IRLS. The reliability of the sIRLS was assessed by patients completing the sIRLS again, two weeks after the first one, provided no change had occurred. Results Overall, 173 patients were recruited and 164 of them were included in the analyses. The sIRLS showed satisfactory scaling assumptions and no relevant floor or ceiling effect. One factor explained 61.3% of the variance. Cronbach's alpha was 0.93 and the item homogeneity index was 0.59. Intraclass correlation coefficient between the sIRLS and the IRLS was 0.94. The sIRLS standard error of measurement was 3.61 (½ SD at baseline = 4.11). The results mostly overlapped those of the IRLS analyzed in parallel. Discussion The sIRLS is a reliable, valid and precise instrument that showed tight association with the IRLS. These findings support the use of the sIRLS for self-evaluation of RLS severity. The responses obtained on the sIRLS and the IRLS scale varied slightly. Therefore, we recommend that either the sIRLS or the IRLS scale be used as the only scale for serial measures over time.

Several studies report an association between REM Sleep Behavior Disorder (RBD) and neurodegenerative diseases, in particular synucleinopathies. Interestingly, the onset of RBD precedes the development of neurodegeneration by several years. This review and meta-analysis aims to establish the rate of conversion of RBD into neurodegenerative diseases. Longitudinal studies were searched from the PubMed, Web of Science, and SCOPUS databases. Using random-effect modeling, we performed a meta-analysis on the rate of RBD conversions into neurodegeneration. Furthermore, we fitted a Kaplan-Meier analysis and compared the differences between survival curves of different diseases with log-rank tests. The risk for developing neurodegenerative diseases was 33.5% at five years follow-up, 82.4% at 10.5 years and 96.6% at 14 years. The average conversion rate was 31.95% after a mean duration of follow-up of 4.75±2.43 years. The majority of RBD patients converted to Parkinson's Disease (43%), followed by Dementia with Lewy Bodies (25%). The estimated risk for RBD patients to develop a neurodegenerative disease over a long-term follow-up is more than 90%. Future studies should include control group for the evaluation of REM sleep without atonia as marker for neurodegeneration also in non-clinical population and target RBD as precursor of neurodegeneration to develop protective trials.

NUT midline carcinoma (NMC) is a rare, aggressive subtype of squamous carcinoma that is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and NUT recruits the p300 histone acetyltransferse (HAT) to activate transcription of oncogenic target genes. BET-selective bromodomain inhibitors have demonstrated on-target activity in patients with NMC, but with limited efficacy. P300, like BRD4, contains a bromodomain. We show that combining selective p300/CBP and BET bromodomain inhibitors, GNE-781 and OTX015, respectively, induces cooperative depletion of MYC and synergistic inhibition of NMC growth. Treatment of NMC cells with the novel dual p300/CBP and BET bromodomain–selective inhibitor, NEO2734, potently inhibits growth and induces differentiation of NMC cells in vitro; findings that correspond with potentiated transcriptional effects from combined BET and p300 bromodomain inhibition. In three disseminated NMC xenograft models, NEO2734 provided greater growth inhibition, with tumor regression and significant survival benefit seen in two of three models, compared with a lead clinical BET inhibitor or “standard” chemotherapy. Our findings provide a strong rationale for clinical study of NEO2734 in patients with NMC. Moreover, the synergistic inhibition of NMC growth by CBP/p300 and BET bromodomain inhibition lays the groundwork for greater mechanistic understanding of the interplay between p300 and BRD4-NUT that drives this cancer.

Propriospinal myoclonus (PSM) consists of paroxysmal and sudden jerks involving axial flexion trunk and hip muscles, conditioning sudden myoclonias of the trunk and arms/limbs, both spontaneous and triggered by sensory stimulations, emerging in relaxed wakefulness typically during the transition between wake and sleep. Generally, PSM originates from a thoracic myelomere and spreads caudally and rostrally, provoking flexion and/or extension movements, leading to jumps or trunk jerks. They appear triggered by the lying-down position and disappear when the subject stands up. The main consequences are the difficulties in sleep start and the reappearance during the period of wakefulness after sleep onset.

Study objectives We tested the hypothesis that patients with extreme sleep state misperception display higher levels of psychopathology and reduced quantitative estimation abilities compared to other patients with insomnia. Secondary aims included the evaluation of group differences in subjective self-reported quality of life and sleep quality and objective sleep parameters. Methods In this cross-sectional, observational study, 249 patients with insomnia underwent a video-polysomnography with a subsequent morning interview to assess self-reported sleep estimates and filled in a large battery of questionnaires. Patients were classified into High Misperception (HM) and Moderate Misperception (MM) groups, according to the complement of the ratio between self-reported total sleep time and objective total sleep time (Misperception Index). Results No significant differences emerged in any of the psychopathological measures considered between the HM and the MM group. Similarly, no effect was observed in quantitative estimation abilities. HM patients displayed a significantly increased number of awakenings per hour of sleep and a reduced dream recall rate. Their overall sleep quality and quality of life was significantly impaired. Conclusions Future research on sleep misperception should focus on factors other than the level of psychopathology and estimation abilities, in particular sleep microstructure and quantitative EEG studies in both REM and NREM sleep.

International audience; Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

Rapid Eye Movement (REM) sleep is involved in nightly emotional processing; therefore, its disruption might be associated with an impaired ability of emotional regulation during daytime. Accordingly, the aim of the present study was to evaluate the presence of emotional dysregulation in insomnia patients and to test its correlation with REM sleep features. Forty-six subjects (23 insomnia patients and 23 healthy controls) were enrolled. All subjects underwent an assessment for the evaluation of emotion dysregulation (Difficulties in Emotion Regulation Scale, DERS), sleep quality, insomnia severity, excessive daytime sleepiness, worry, rumination, depressive and anxious symptomatology. Insomnia patients underwent a nocturnal polysomnographic recording to characterize sleep macrostructure and REM sleep microstructure variables. Insomnia patients reported increased values of emotional dysregulation. REM sleep percentage and REM sleep latency significantly correlated with DERS total score, and with the subscales “Lack of Confidence in Emotional Regulation Skills”, “Difficulties in Behavioral Control” and “Difficulty in recognizing emotions”. Furthermore, positive correlations between REM arousal index and emotion dysregulation were found, whereas REM density negatively correlated with DERS. Our results suggest the presence of a relationship between REM sleep and emotional regulation in insomnia patients.

Objective Restless legs syndrome (RLS) is a sleep disorder characterized by an urge to move legs or arms, with a typical circadian rhythm. RLS can be treated with pharmacological and non-pharmacological therapies. Nevertheless, in some patients RLS can be refractory to all medical and non-medical treatments. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been reported to improve RLS symptoms in Parkinson's disease (PD) patients with RLS. We describe the case of a patient suffering from refractory idiopathic RLS implanted with bilateral GPi DBS. Method The patient underwent DBS targeting the bilateral GPi. Follow up for three years involved clinical evaluation and polysomnography (PSG). Results The patient reported subjective improvement, with reduction in the IRLS score. Furthermore, the polysomnography (PSG) showed an objective improvement of polysomnographic parameters, which remained stable during the follow-up. Conclusion DBS for RLS can be a new therapeutic approach for severe RLS, but further studies are needed.

Acute neurologic emergencies in pregnancy often require neuroimaging to guide diagnosis and treatment. Implementation of a patient-centered care model in radiology can alleviate a patient's stress, reinforce appropriate imaging workup, improve patient satisfaction, and lead to improved outcomes. The authors present the evaluation, differential diagnosis, and recommended imaging protocols for the three most common acute neurologic symptoms in pregnancy and the postpartum period: headache, seizure, and focal neurologic deficits. With the patient's symptoms as a reference point, the referring physician in consultation with the radiologist can effectively implement the optimal imaging procedures.

The 'catalogue of knowledge and skills' for sleep medicine presents the blueprint for a curriculum, a textbook, and an examination on sleep medicine. The first catalogue of knowledge and skills was presented by the European Sleep Research Society in 2014. It was developed following a formal Delphi procedure. A revised version was needed in order to incorporate changes that have occurred in the meantime in the International Classification of Sleep Disorders, updates in the manual for scoring sleep and associated events, and, most important, new knowledge in sleep physiology and pathophysiology. In addition, another major change can be observed in sleep medicine: a paradigm shift in sleep medicine has taken place. Sleep medicine is no longer a small interdisciplinary field in medicine. Sleep medicine has increased in terms of recognition and importance in medical care. Consequently, major medical fields (e.g. pneumology, cardiology, neurology, psychiatry, otorhinolaryngology, paediatrics) recognise that sleep disorders become a necessity for education and for diagnostic assessment in their discipline. This paradigm change is considered in the catalogue of knowledge and skills revision by the addition of new chapters., info:eu-repo/semantics/published

Histone modifications, largely regulated by histone acetyltransferases (HAT) and histone deacetylases, have been recognized as major regulatory mechanisms governing human diseases, including cancer. Despite significant effort and recent advances, the mechanism by which the HAT and transcriptional coactivator p300 mediates tumorigenesis remains unclear. Here, we use a genetic and chemical approach to identify the microphthalmia-associated transcription factor (MITF) as a critical downstream target of p300 driving human melanoma growth. Direct transcriptional control of MITF by p300-dependent histone acetylation within proximal gene regulatory regions was coupled to cellular proliferation, suggesting a significant growth regulatory axis. Further analysis revealed forkhead box M1 (FOXM1) as a key effector of the p300–MITF axis driving cell growth that is selectively activated in human melanomas. Targeted chemical inhibition of p300 acetyltransferase activity using a potent and selective catalytic p300/CBP inhibitor demonstrated significant growth inhibitory effects in melanoma cells expressing high levels of MITF. Collectively, these data confirm the critical role of the p300–MITF–FOXM1 axis in melanoma and support p300 as a promising novel epigenetic therapeutic target in human melanoma. Significance: These results show that MITF is a major downstream target of p300 in human melanoma whose expression is predictive of melanoma response to small-molecule inhibition of p300 HAT activity.

p300 and CBP are highly related histone acetyltransferase (HAT) enzymes that regulate gene expression, and their dysregulation has been linked to cancer and other diseases. p300/CBP is composed of a number of domains including a HAT domain which is inhibited by the small molecule A-485 and an acetyl-lysine binding bromodomain which was recently found to be selectively antagonized by the small molecule I-CBP112. Here we show that the combination of I-CBP112 and A-485 can synergize to inhibit prostate cancer cell proliferation. We find that the combination confers a dramatic reduction in p300 chromatin occupancy compared to the individual effects of blocking either domain alone. Accompanying this loss of p300 on chromatin, combination treatment leads to the reduction of specific mRNAs including androgen-dependent and pro-oncogenic prostate genes such as KLK3 (PSA) and c-Myc. Consistent with p300 chromatin binding directly affecting gene expression, mRNAs that are significantly reduced by combination treatment also exhibit a strong reduction in p300 chromatin occupancy at their gene promoters. The relatively few mRNAs that are up-regulated upon combination treatment show no correlation with p300 occupancy. These studies provide support for the pharmacologic advantage of concurrent targeting of two domains within one key epigenetic modification enzyme.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense RNA virus causing coronavirus disease 2019 (COVID-19), an ongoing pandemic claiming millions of lives [1–3]. Rapidly evolving SARS-Cov-2 outbreak continues with recent spikes in cases in some countries, while few have significantly curbed the numbers of new cases thanks to the recent deployment of vaccines [3]. Connecticut is a relatively small-sized northeastern state (approximate population 3.5 million) that is ranked #3 in healthcare access among the US states, according to US News data. The geographical proximity of the state of Connecticut to New York, an epicenter of the initial outbreak in the USA, resulted in the immediate spread of the virus in the Connecticut area as well. Governors of New York, New Jersey and Connecticut followed a similar course of action, and the timeline of the pandemic followed a similar path in this region. The first case in our hospital system was seen on 8 March 2020. Decreased numbers of screening studies and elective surgeries, as well as on in-person appointments took in place in parallel with state-wide administrative policy implementations. COVID-19 has less favorable clinical outcomes in patients with preexisting health conditions including cancer [4]. Unprecedented strain in healthcare systems and rapid development of the outbreak led to readjustment of cancer treatment, deferral of procedures and alteration of surveillance algorithms [5]. The dual danger of COVID-19 and cancer have forced practitioners to make decisions based on experience and risk/benefit analysis, particularly at the early stage of the pandemic, due mainly to the scarcity of clinical and epidemiologic data on COVID-19. Identification of factors that are potentially associated with the decline in molecular cancer imaging, will help better understand the dynamics of cancer imaging at the time of respiratory outbreaks. Providing real-world data during a pandemic may play a role in understanding potential vulnerabilities in similar future outbreaks or the future waves of COVID-19 outbreak that may ensue. This may also assist oncology practitioners to manage imaging studies of their patient population in an evidence-based approach. A decline in the volume of radiology studies as well as in nationwide new cancer diagnoses in 2020 as compared to prior years has been shown [6,7]. Two Italian studies recently demonstrated a potential increase in interstitial lung findings in cancer patients during the COVID-19 pandemic [8,9]. The impact of the COVID-19 pandemic on cancer imaging based on factors such as cancer types, patient demographics and imaging findings is not well-demonstrated in the literature, particularly with respect to epidemiologic dynamics. In this study, we aimed to analyze the impact of the ongoing pandemic on molecular imaging of cancer patients in a comprehensive cancer hospital by in-depth analysis of all PET/CT studies from 1 January 2020 through 15 June 2020. The aims of this study were: (1) to determine temporal changes in PET/CT utilization during the COVID-19 pandemic; (2) to correlate PET/CT utilization and state-wide number of COVID-19 cases within the same period in the light of restrictive policy implementations; (3) to examine the impact of demographic and oncological factors on PET/CT utilization and (4) to examine the number of cases discussed in multidisciplinary tumor boards during the same period.

Sophisticated methods are currently used to investigate the properties of brain DNA and clarify its role under physiological conditions and in neurological and psychiatric disorders. Attention is now called on a DNA fraction present in the adult rat brain that is characterized by an elevated turnover and is not involved in cell division or DNA repair. The fraction, known as brain metabolic DNA (BMD), is modulated by strain, stress, circadian oscillations, exposure to enriched or impoverished environment, and notably by several training protocols and post-trial sleep. BMD is frequently localized in glial cells but is also present in neurons, often in the perinucleolar region. Its distribution in repetitive and non-repetitive DNA fractions shows that BMD differs from native DNA and that in learning rats its profile differs from that of control rats. More detailed knowledge of the molecular, cellular, and time-dependent BMD features will be necessary to define its role in memory acquisition and processing and in the pathogenesis of neurologic disorders.

Study objectives To define statistically the upper limit of the intermovement interval (IMI, the time interval between the onset of consecutive movements) of periodic leg movements during sleep (PLMS). Methods We computed the IMI distribution of a large sample (n = 141) of patients with restless legs syndrome (RLS) and analyzed it with two independent approaches, based on fitting either empirical functions or normal and exponential functions to the data. Results The two fitting approaches consistently pointed to an upper limit of the PLMS IMI in the range between 50 and 60 s. Decreasing the upper limit of PLMS IMI from 90 to 60 s evidently decreased the PLMS index in patients with RLS and control participants; nevertheless, the PLMS index remained significantly higher in RLS vs. control participants. Shifting the upper limit of PLMS IMI to 60 s did not significantly modify the effectiveness of discrimination of PLMS between controls and patients with RLS. Conclusion These results seem to indicate that a conservative, yet data-driven upper limit for IMI contributing to the PLMS in patients with RLS might be 60 s instead of 90 s, as recommended by the present guidelines.

Contains fulltext : 215333.pdf (Publisher’s version ) (Closed access) BACKGROUND: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. METHODS: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). FINDINGS: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3.3 years (IQR 2.8-3.8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7.3%] of 5558 vs 480 [8.6%] of 5596; HR 0.85 [95% CI 0.74-0.97], p=0.013). The same effect was not observed in patients without PCI (p=0.76, pinteraction=0.16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3.1%] with ticagrelor vs 183 (3.3%) with placebo; HR 0.96 [95% CI 0.78-1.18], p=0.68), as well as all-cause death (282 [5.1%] vs 323 [5.8%]; 0.88 [0.75-1.03], p=0.11). TIMI major bleeding occurred in 111 (2.0%) of 5536 patients receiving ticagrelor and 62 (1.1%) of 5564 patients receiving placebo (HR 2.03 [95% CI 1.48-2.76], p

Introduction Although lifestyle intervention and behavior modification are effective in the prevention and treatment of chronic disease, few medical schools provide specific training in stress management, nutrition, or physical activity. While the prevalence of chronic disease rises, medical students and physicians lack sufficient knowledge and skills to promote their patients’ as well as their own wellness across these domains. Methods We developed three hour-long workshops delivered to third-year medical students. We employed interactive lectures, small-group discussions, and reflective activities to teach the pillars of lifestyle medicine. These sessions focused on knowledge and skills to advance lifestyle counseling and behavior modification interventions with patients and to promote student wellness. We assessed student satisfaction with each session as well as self-perceived knowledge, skills, and attitudes toward lifestyle medicine and behavior change before and after the curriculum. Results Over 2 years, 183 students participated in the workshop series. The sessions received high ratings, with a mean of 4.2 on a 5-point Likert scale. Participating in the curriculum significantly enhanced students’ understanding of the connection between lifestyle factors and the health of patients and improved their confidence about counseling for behavioral change. Discussion Lifestyle medicine provides an evidence-based framework for teaching students about the impact of lifestyle modification on chronic disease. While receiving knowledge and skills to advance patient care in the domains of stress management, nutrition, and physical activity, students who completed this curriculum also had the opportunity to reflect on their own health promotion, which could mitigate professional burnout.

OBJECTIVE. A common goal in patients with newly discovered brain lesions is to determine if the lesions are primary malignant brain neoplasms, metastases, or benign entities. Such patients often undergo CT of the chest, abdomen, and pelvis (CT CAP) to identify a primary neoplasm that may have metastasized to the brain. The aim of this study is to determine the frequency of finding a primary cancer on CT CAP. MATERIALS AND METHODS. A large academic hospital imaging database was searched for cases of new intracranial lesions with subsequent CT CAP performed for metastatic workup. The frequency of primary neoplasms diagnosed in the chest versus abdominal and pelvic portions of CT scans was determined in patients with newly identified intraaxial and extraaxial brain lesions. Lesion characteristics were recorded including size, number, and the presence of enhancement and hemorrhage. Ancillary signs of an abdominopelvic neoplasm were also recorded. RESULTS. A total of 227 of 287 (79%) cases of newly discovered intracranial lesions were malignant (primary or metastatic) and 60 (21%) were benign. Of the 227 malignant cases, 136 (60%) were primary brain neoplasms and 91 (40%) were brain metastases, and 68 of the 91 (75%) lung primary. Chest CT (CTC) identified a primary neoplasm in 65 of 287 (23%) cases; 63 of those 65 (96%) neoplasms arose in the lungs. CT of the abdomen and pelvis (CTAP) identified a primary neoplasm in only 3 of 287 (1%) cases. In 26 cases in which the intracranial lesions did not enhance, only one was metastatic. CONCLUSION. In patients with newly discovered brain lesions, CTC is warranted, but CTAP is unlikely to be useful in patients without ancillary signs of abdominopelvic neoplasm.

Introduction Transgender patients frequently experience discrimination within health care settings due to provider lack of knowledge and bias resulting in poor service delivery. Team-based interprofessional collaboration is becoming a best practice for health professionals to improve patient-centered care and address these health disparities. Methods A team-based interprofessional education simulation activity was developed as a teaching activity at a university for graduate health care learners in medicine, nursing, occupational therapy, physical therapy, physician assistant, social work, and health care administration programs over 2 years (N = 494). The simulation focused on a transgender patient brought to the emergency department (ED) after a workplace assault. Students were placed in interprofessional teams and asked to critique the initial ED interaction with the patient and then complete a team huddle and discharge planning meeting with a standardized patient. Student preparedness to engage in the Interprofessional Education Collaborative (IPEC) competencies was assessed through a posttest measure. Results Student learners reacted overwhelmingly positively to the activities of the workshop. The averaging of 2 years of data yielded students responses of strongly agree and agree at 90% or higher for all IPEC core competencies, as well as for educational objectives of the workshop. Discussion Reducing the structural, interpersonal, and individual stigma experienced by transgender patients requires institutions to offer experiential learning opportunities for future health care providers. This interprofessional education simulation experience focusing on transgender patients calls attention to the negative impact of stigma while also promoting competency in interprofessional practice.

OBJECTIVES The aim of this study was to evaluate the effectiveness and safety of adalimumab (ADA) in children with ulcerative colitis (UC) previously treated with infliximab (IFX). METHODS Retrospective study including children with UC from a national registry who received ADA therapy. The primary endpoint was the rate of corticosteroid-free remission at week 52. Secondary outcomes were the rate of sustained clinical remission, primary nonresponse, and loss of response at weeks 12, 30, and 52 and rate of mucosal healing and side effects at week 52. RESULTS Thirty-two children received ADA (median age 10 ± 4 years). Median disease duration before ADA therapy was 27 months. All patients received previous IFX (43% intolerant, 50% nonresponders [37.5% primary, 42.5% secondary nonresponders], 6.7% positive anti-IFX antibodies). Fifty-two weeks after ADA initiation, 13 patients (41%) were in corticosteroid-free remission. Mucosal healing occurred in 9 patients (28%) at 52 weeks. The cumulative probability of a clinical relapse-free course was 69%, 59%, and 53% at 12, 30, and 52 weeks, respectively. Ten patients (31%) had a primary failure and 5 (15%) a loss of response to ADA. No significant differences in efficacy were reported between not-responders and intolerant to IFX (P = 1.0). Overall, 19 patient (59%) maintained ADA during 52-week follow-up. Seven patients (22%) experienced an adverse event, no serious side effects were observed and none resulted in ADA discontinuation. CONCLUSIONS Based on our data, ADA seems to be effective in children with UC, allowing to recover a significant percentage of patients intolerant or not-responding to IFX. The safety profile was good.

In Southern France, approximately 4% of E. coli isolates from community-acquired urinary tract infections are extended spectrum beta-lactamase producers, while carriage rates for enterobacteriaceae (ESBL-E) range from 3 to 6%. General practitioners (GP) are unfamiliar with the management of patients harboring ESBL-E. Providing them with a specific tool kit should assist in their therapeutic approach and optimize antimicrobial prescription an ESBL-E tool kit was developed by a multidisciplinary team: infectious diseases (ID) specialists, microbiologists, pharmacologists, and nursing home staff. This tool kit includes treatment protocols, GP and patient information leaflets, a list of infection control measures, and contact details of ID physicians for specialized advice. A community-based (including nursing homes) prospective study was conducted in 2012 in Southeastern France to test the tool kit in the context of ESBL-E-related urinary tract infections (UTI). ESBL-E-related UTI were identified in 88 patients, 66 GPs were contacted by the microbiology laboratory, 56 stated they were offered the tool kit, 48 said they had received it, and 41 stated they had read its contents. Use of the tool kit was significantly correlated with appropriate antibiotic prescription, which concerned 36/39 tool kit users versus 13/20 non-users (p = 0.0125) and 40 GPs expressed an average satisfaction rate of 4.2 on a scale of 0 to 5. Availability of a specific tool for managing patients harboring ESBL-E, now completed with a website, can assist community-based GPs and improve antimicrobial prescription.

Idiopathic Hypersomnia (IH) is a rare sleep disorder characterised by excessive daytime sleepiness (EDS) that leads to invalidating daytime consequences. Till now the treatment of IH has mirrored that of sleepiness in narcolepsy, and it is mainly focused on symptoms' management. In this study, we employed an anodal transcranic Direct Current Stimulation (tDCS) treatment in order to induce a shift toward arousal in IH patients' cortex during the day. Every patient underwent a 4 weeks treatment (3 stimulations per week, for a total of 12 stimulations over a period of 28 days), with an assessment at the baseline and after treatment aimed to the evaluation of subjective daytime sleepiness, neurocognitive functions, and attentional domain tested by means of the Attentional Network Task (ANT). The dependent variables of the ANT are accuracy and reaction times, which represent the objective outcome of our study. A significant effect of tDCS' treatment in reducing EDS was found. Besides the amelioration in subjective EDS, an objective improvement in reaction times in all conditions of the ANT, in particular in the more difficult component, was observed. Our results indicate that tDCS may foster the management of EDS in la improving also the attentional domain.

Periodic leg movements during sleep (PLMS) are sequences of ≥4 motor events with intermovement intervals (IMI) of 10–90 s. PLMS are a supportive diagnostic criterion for restless legs syndrome (RLS) and entail cardiac activation, particularly when associated with arousal. RLS patients also over-express short-interval leg movements during sleep (SILMS), which have IMI

Summary Paradoxical insomnia is one of the most intriguing yet challenging subtypes of insomnia. Despite being recognized for a long time by the international community, it is still unclear whether this entity really exists, which are its features and boundaries. Much of the debate is fuelled by the lack of a consensus on its precise definition. To help filling some of the existing gaps, a systematic review of the literature was conducted, through which 19 different quantitative definitions were obtained. These definitions were then applied to two distinct datasets. The first consisted of 200 chronic primary insomnia patients, diagnosed according to the DSM-IV-TR criteria. The second consisted of 200 age- and sex-matched healthy persons without insomnia. For each dataset, available data from the objective sleep parameters and their subjective estimation were imported and analysed in MATLAB. Depending on the definition used, the prevalence of paradoxical insomnia ranged from 8 to 66%, while agreement between different definitions ranged from −0.19 to 0.9 (using Cohen's kappa coefficient). Based on the results garnered, necessary features for a quantitative definition of paradoxical insomnia were identified. Several open questions remain, such as whether there is a minimum number of hours a patient should sleep to fulfill the criteria for a diagnosis of paradoxical insomnia, and whether sleep latency can be used in the definition along with total sleep time. We conclude by advocating continued study of paradoxical insomnia and sleep state misperception and by providing specific directions for future research. Statement of significance The current understanding of paradoxical insomnia and, more broadly, of sleep state misperception, is greatly hampered by the lack of agreement on a quantitative and evidence-base measure of the discrepancy between subjective and objective sleep evaluation. The current study provides a critical analysis about the strength and the limitations of the available definitions, using both a data-driven and a theory-driven approach. The overarching goal is to motivate a rigorous discussion involving the main experts of the field, to build a consensus, and develop an evidence-based measure of sleep state misperception and/or of paradoxical insomnia.

Introduction: Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a sleep disorder characterized by an urge to move the legs, frequently associated or triggered by unpleasant sensations in the lower limbs that affects approximately 2.5% of adults. Therapy and management of RLS/WED require long-term interventions, since the typical manifestation of this disorder is chronic. Areas covered: In this review, we provide an update regarding the treatment of RLS/WED with particular attention to future challenges for its management. We reviewed a large variety of treatments studied in clinical trials and supported by the most updated guidelines. Alongside with first-line interventions other pharmacological options including opioids, benzodiazepines, iron therapy, and newly studied drugs are discussed. Furthermore, due to the occurrence of augmentation and worsening of symptoms we also reviewed the development of non-pharmacologic alternatives. Expert commentary: The management of RLS/WED is a challenge because of different long-term issues. Several complications, such as loss of the therapeutic effect of dopaminergic or non-dopaminergic agents and augmentation, are still unsolved concerns. However, the development of new drugs acting on adenosinergic and glutamatergic neurotransmission seems promising. Randomized controlled trials are needed in order to recognize effectiveness of new drugs or non-pharmacological treatment strategies.

Background Repetitive thought is a hallmark of several psychopathological conditions and in particular a perpetuating and maintaining factor in Insomnia Disorder. Accordingly, one of the primary complaints reported by Insomnia patients is the inability to shut-off or control thoughts. Worry and rumination are the two best-known styles of repetitive thought leading to sleep disturbances. The aim of this study was to investigate the relationship of these two cognitive processes on nocturnal sleep indices objectively recorded by polysomnography. Methods 27 Insomnia patients and 20 healthy controls matched for sex and age were recruited and completed a comprehensive assessment aimed to evaluate sleep quality, excessive daytime sleepiness, insomnia severity, worry, rumination, depressive and anxious symptomatology, and the ability to produce reasonable cognitive estimates. Sleep diaries indices and polysomnographic recordings were evaluated. Results Insomnia patients showed increased levels of worry and rumination in comparison to controls. Our polysomnographic study revealed that these two different types of repetitive thoughts were significantly associated with objective sleep variables. In particular, heightened worry levels were related to an augmented wake after sleep onset and diminished total sleep time, sleep efficiency and percentage of REM sleep, whereas rumination was associated with an increase of sleep latency and a decrement of sleep efficiency. However, after controlling for anxiety and depressive symptoms only worry maintained a significant relationship with polysomnographic variables. Remarkably, repetitive thoughts did not correlate with microstructural REM sleep features and quantitative EEG analysis. Conclusion Our study indicates the existence of a significant relationship between daytime levels of repetitive thought and sleep, thus corroborating the hypothesis of an interplay between cognitive and nocturnal electrophysiological activity in insomniacs.

Objective Cognitive-behavioral therapy for insomnia (CBT-I) is recognized as the first-choice intervention for insomnia. One of the best-known advantages of CBT-I in comparison with pharmacotherapy is its long-term effect. However, only few studies have assessed its benefits with follow-up periods of longer than three years. In this clinical case series study we aimed to describe the long-term effects of group CBT-I after a mean 7.8 ± 1.6 years of follow-up (range 4–10 years). Methods A total of 292 insomnia disorder (ID) patients were consecutively enrolled at the Sleep Disorders Center of San Raffaele Hospital, Milan; 123 patients (82 (66.7%) females and 41 (33.3%) males, mean age 40.59 ± 11.89 years) completed the follow-up evaluation within a range of 4–10 years. Results In the 258 patients who completed the treatment, insomnia severity index (ISI) total score improved significantly as well as all variables of the sleep diaries. Using ISI as the primary outcome, we demonstrated that the effect of CBT-I is maintained up to 10 years after the end of treatment. Furthermore, we found that patients that used only CBT-I techniques to deal with relapses were the ones with better outcomes, in particular compared to the patients that re-used medications. Conclusion To the best of our knowledge this is the longest follow-up evaluation in the literature, both for group and individual CBT-I. These findings have an important clinical implication both suggesting and confirming that CBT-I can be considered the treatment of choice for insomnia.

Study objectives To evaluate leg movement activity during sleep (LMS) in normal school-age children and adolescents, to eventually establish age-specific periodic LMS (PLMS) index thresholds that support the diagnosis of restless legs syndrome (RLS), and to evaluate the utility of other LMS indices. Methods Polysomnographic recordings from 61 controls, 46 children with RLS, and 44 children with narcolepsy type 1 (NT1) were analyzed for total leg movements (LMS), PLMS, and isolated leg movements (ISOLMS) duration and indices, separately for school-age children and adolescents. Moreover, intermovement interval (IMI) graphs and time-of-night distribution of LMS were analyzed, and cut-off thresholds for PLMS index and total LMS index were assessed for the separation of RLS from controls. Results All indices tended to decrease from school-age children to adolescents in normal controls and in NT1, whereas in RLS, only PLMS index increased. All school-age children had a similar IMI distribution with a single peak at IMI 2-4 s followed by gradual decline. In adolescents with RLS, a second peak at IMI 10-50 s was seen. Time-of-night distribution of most indices decreased in RLS, whereas most tended to increase in NT1. A PLMS index cutoff of 2 per hour best differentiated RLS from controls in school-age children (accuracy 70.0%) and in adolescents (accuracy 70.8%); however, most participants with NT1 also showed PLMS indices higher than this threshold. Conclusions PLMS index alone does not reliably predict the diagnosis of RLS in children and adolescents. However, analyses of IMI distribution and time-of-night distribution provide additional elements to support a diagnosis of RLS.

Dokkedal-Silva V, Kim LJ, Morelhão PK, Galduróz JCF, Tufik S, Andersen ML. Use of clonazepam in REM sleep behavior disorder: association with fall-related injuries and alternative treatments. J Clin Sleep Med. 2020;16(4):655–656.

BACKGROUND Nonsyndromic craniosynostosis may manifest with complex behavioral, attentional, and emotional sequelae. The authors characterized higher level brain connectivity in adolescent nonsyndromic craniosynostosis patients in response to emotional frustration. METHODS Surgically corrected patients older than 9 years with nonsyndromic craniosynostosis were age/sex/handedness matched to controls. Patients participated in a "go/no-go" task, structured as win/lose/recovery paradigms. BioImage Suite was used to analyze whole-brain intrinsic connectivity between tasks with cluster-corrected group-level t maps. A value of p < 0.05 was significant. RESULTS Seven unilateral coronal (average age, 12.2 years), six metopic (average age, 11.5 years), and controls were included. Unilateral coronal had worse emotional regulation scores on the Behavior Rating Inventory of Executive Function survey (p = 0.065) and performed poorly on the go/no-go task (p < 0.001). Metopic had four regions of interest, with the majority having decreased activity compared with controls, and few differences between tasks. Unilateral coronal patients had 11 regions of interest; the majority decreased during the win and lose conditions, but all increased during the recovery condition. Metopic patients had decreased blood oxygenation level- dependent signal in the posterior cingulate (p = 0.017) and middle temporal gyrus (p = 0.042). Unilateral coronal had decreased signal in the posterior cingulate (p = 0.023), middle temporal gyrus (p = 0.027), and thalamus (p = 0.033), but increased signal in the cuneus (p = 0.009) and cerebellum (p = 0.009). Right unilateral coronal, but not metopic/controls, had increased right brain activity in the caudate (p = 0.030), thalamus (p = 0.011), temporal lobe (p = 0.012), and cerebellum (p = 0.029). CONCLUSIONS Unilateral coronal patients may have emotional dysregulation in response to frustration, whereas metopic patients may have attenuated emotional reactions. Evidence of right unilateral coronal brain laterality suggests that the area of suture fusion may contribute to the mechanism of dysfunction. CLINICAL QUESTION/LEVEL OF EVIDENCE Risk, II.

Background To manage and analyse dosimetric data provided by computed tomography (CT) scanners from four Italian hospitals. Methods A radiation dose index monitoring (RDIM) software was used to collect anonymised exams stored in a cloud server. Since hospitals use different names for the same procedure, digital imaging and communications in medicine (DICOM) tags more appropriate to describe exams were selected and associated to study common names (SCNs) from a radiology playbook according to scan region and use of contrast media. Retrospective analysis was carried out to describe population and to evaluate dosimetric indexes and inaccuracies associated with SCNs. Results More than 400 procedures were clustered into 95 SCNs, but 78% of exams on adults were described with only 10 SCNs. Median values of dose-length product (DLP) and volumetric CT dose index (CTDIvol) for three analysed SCNs were in agreement with those previously published. The percentage of inaccuracies does not heavily affect the dosimetric analysis on the whole cloud, since variations in median values reached at most 8%. Conclusions Implementation of a cloud-based RDIM software and related issues were described, showing the strength of the chosen playbook-based clustering and its usefulness for homogeneous data analysis. This approach may allow for optimisation actions, accurate assessment of the risk associated with radiation exposure, comparison of different facilities, and, last but not least, collection of information for the implementation of the 2013/59 Euratom Directive.

INTRODUCTION: RLS is a common movement disorders with a strong genetic component in its pathophysiology, but, up to now, no causative mutation has been reported. METHODS: We re-evaluated the previously described RLS2 family by exome sequencing. RESULTS: We identified fifteen variations in the 14q critical region. The c.485G > A transition of the TRAPPC6B gene segregates with the RLS2 haplotype, is absent in 200 local controls and is extremely rare in 12988 exomes from the Exome Variant Server (EVS). This variant alters a splicing site and hampers the normal transcript processing by promoting exon 3-skipping as demonstrated by minigene transfection and by patient transcripts. CONCLUSIONS: We identified a TRAPPC6B gene mutation associated to the RLS locus on chromosome 14.

Background and objective Approximately one third of patients with restless legs syndrome (RLS) also show periodic leg movements (PLM) during relaxed wake fulness (PLMW). In contrast with the large amount of data published on periodic leg movements during sleep (PLMS), PLMW have received less attention from the scientific community. The objective of this study was to evaluate the correlations/differences of time–structure and response to a dopamine-agonist between PLMW and PLMS in patients with RLS. Methods Ninety idiopathic RLS patients and 28 controls were recruited. Subjects underwent clinical and neurophysiological evaluation, hematological screening, and one or two consecutive full-night polysomnographic studies. A subset of patients received 0.25 mg of pramipexole or placebo before the second recording. Polysomnographic recordings were scored and LM activity was analyzed during sleep and during the epochs of wakefulness occurring during the first recording hour. Results RLS patients had higher LM activity during wakefulness than controls, but with a similar periodicity. Even if correlated, the ability of the PLMW index to predict the PLMS index decreased with increasing LM activity. Intermovement intervals during wakefulness showed one peak only at approximately 4 s, gradually decreasing with increasing interval in both patients and controls. The effect of pramipexole was very limited and involved the small periodic portion of LM activity during wakefulness. Conclusions PLMW index and PLMS index were correlated; however, the magnitude of this correlation was not sufficient to suggest that PLMW can be good predictors of PLMS. Short-interval LM activity during wakefulness and sleep might be linked to the severity of sleep disruption in RLS patients and the differences between their features obtained during wakefulness or sleep might be relevant for the diagnosis of sleep disturbances in RLS.

Objective To evaluate the diagnostic accuracy of the standard periodic leg movement during sleep (PLMS) index, a recently introduced alternative one, and the periodicity index (PI) for restless legs syndrome (RLS). Subjects and methods A total of 107 patients with RLS were retrospectively identified and included (47 males and 60 females, mean age 56.9 years), along with 48 normal controls (24 males and 24 females, mean age 52.0 years). The standard PLMS index, the alternative PLMS index, and the PI were calculated from polysomnographic recordings. In order to establish the best performing threshold for the diagnosis of RLS, sensitivity and specificity were calculated with a series of threshold values ranging from 5 to 20/hour for the two PLMS indices, and from 0.2 to 0.9 for the PI. Results The optimal threshold was found to be between 15 and 16/hour for the standard PLMS index, close to 13/hour for the alternative index, and around 0.5 for the periodicity index. With these thresholds, all methods showed high values of sensitivity and specificity, with corresponding high positive and negative predictive values and accuracy; the receiver operating characteristic (ROC) curve areas were similar, and the Kappa coefficient of agreement indicated a ‘very good’ agreement between the PLMS indices. Conclusions This study assessed the cut-off values of the standard (15–16/hour) and alternative (13/hour) PLMS indices, and of the PI (0.5). The diagnostic accuracy of all indices for RLS vs controls was found to be acceptably high, with the new alternative PLMS index performing slightly higher than the other two indices.

Obstructive Sleep Apnoea (OSA) is a common sleep disorder characterized by episodes of complete or partial obstruction of respiratory airways during sleep that leads to hypoxaemia and sleep fragmentation. One relevant daytime consequence of OSA is a negative impact on neurocognitive domain, ranging from psychomotor performance to executive function. In spite of a huge amount of evidence regarding cognitive impairment, little is known about perceptual processing in these patients. The aim of this research is to investigate the effects of OSA on visual mechanisms by employing a visual search paradigm. 19 OSA patients and 19 age-matched healthy controls (HC) participated in a case-control study. After a nocturnal cardiorespiratory monitoring, patients performed a visual search task in which they had to detect the presence/absence of a target (letter T) embedded in the 50% of trials into a set of distractors (letters Os, Xs, or Ls). Target's salience and distractors' numerosity were manipulated as independent variables, whereas accuracy and reaction times (RT) were recorded as dependent variables. HC, after the exclusion of any sleep disorder or sleepiness, performed the same experiments. Results generally confirmed the typical effects of visual search. OSA patients reported significantly slower RT in comparison with HC, indicating an overall perceptual deficit consisting in a harder extraction of relevant information from noise. Neither patients' age nor the objective clinical indices were associated with RT. This study indicates the presence of an impairment in OSA patients involving basic mechanisms of visual processing and likely ascribable to the disorder per se.

Study Objectives We aimed to analyze quantitatively rapid eye movement (REM) sleep electroencephalogram (EEG) in controls, drug-naive idiopathic REM sleep behavior disorder patients (iRBD), and iRBD patients treated with clonazepam. Methods Twenty-nine drug-naive iRBD patients (mean age 68.2 years), 14 iRBD patients under chronic clonazepam therapy (mean age 66.3 years), and 21 controls (mean age 66.8 years) were recruited. Power spectra were obtained from sleep EEG (central derivation), using a 2-second sliding window, with 1-second steps. The power values of each REM sleep EEG spectral band (one every second) were normalized with respect to the average power value obtained during sleep stage 2 in the same individual. Results In drug-naive patients, the normalized power values showed a less pronounced REM-related decrease of power in all bands with frequency

It has been reported that insomnia characterized by difficulty returning to sleep following a nocturnal awakening, otherwise defined as the middle-of-the-night (MOTN) insomnia, is a common form of insomnia in adults with growing prevalence by increasing age. The aim of this study is to evaluate the efficacy and safety of different dosages of triazolam in insomnia patients when taken after a MOTN awakening with difficulty returning to sleep. In this double-blind, randomized, parallel group study, 24 patients (mean age 41.00±Â10.40, 10 female and 14 male) affected by MOTN insomnia were enrolled and randomized into three groups according to different dosages of triazolam: group A (0.0625Âmg), group B (0.125Âmg), and group C (0.250Âmg). A significant increment of total sleep time, sleep efficiency and a reduction of wake after sleep onset, number of awakening and non-REM sleep stage 1 was observed in T1 (triazolam) in comparison to T0 (placebo) by means of polysomnographic recording, irrespective of dosage. After 2Âweeks of the treatment, insomnia severity significantly improved in all three groups in comparison to baseline without diurnal residual effects. This study demonstrates that low dose of triazolam objectively and subjectively improves the sleep of patients having MOTN insomnia.

Study Objectives rapid-eye-movement (REM) sleep without atonia (RSWA) is a marker of REM sleep behavior disorder (RBD) and is common in narcolepsy. Available techniques for electromyogram (EMG) analysis are species-specific, limiting translational research on RSWA. We developed an automated technique based on distributions of normalized EMG values (DNE) to overcome this limitation. With DNE, we tested whether the control of neck and tibialis anterior (TA) muscles during sleep in wild-type rats and mice validly models the control of submentalis (chin) and TA muscles in healthy humans. We then applied DNE to REM sleep recordings of patients with idiopathic RBD and of mouse models of narcolepsy, testing for a common DNE signature of RSWA. Methods retrospective analysis of sleep recordings from 20 idiopathic RBD patients, 34 control subjects, 8 wild-type rats, 21 orexin-neuron deficient mice, 8 orexin knock-out mice, and 22 wild-type mice. Results neck EMG of rats and mice and human chin EMG progressively decreased from wakefulness to non-REM sleep and REM sleep, whereas the effects of sleep on TA EMG differed between rats, mice, and humans. DNE discriminated idiopathic RBD patients from controls based on higher median values of normalized chin EMG during REM sleep. The same parameter, computed on neck muscle EMG, discriminated narcoleptic mice from wild-type mice. Conclusions these results support the application of DNE in translational research on RSWA. Increased median values of normalized EMG of chin (humans) and neck (rats and mice) muscles may be a signature of RSWA in different species and pathological conditions.

Objective The aim of this study was to analyze statistically the number of single leg movements (LMs) forming bilateral LMs during sleep, along with their combined duration, to eventually provide evidence-based data for the adjustment of the current scoring rules defining bilateral LMs. Methods Polysomnographic recordings of 111 untreated patients with RLS with a median age of 56.0 years, along with 42 normal controls with a mean age of 60.0 years, were included. In each recording, we identified all LMs that were considered as bilateral when two or more LMs were overlapping or the onset of the following movement was 4 individual movements, and only 0.16% and 1.90% of bilateral LMs were >15 seconds in RLS patients and healthy controls, respectively. Conclusion Our results strongly suggest that bilateral LMs during sleep should be constituted by no more than four individual LMs and should have a maximum duration of 15 seconds.

Objectives The aim of this study was to develop and validate a questionnaire designed to measure the impact of sleep impairment on emotional distress in patients with various sleep disorders. Methods Five experts created an item data-bank pertaining to sleep-related psychological symptoms and somatic perceptions. Fifty patients in two focus groups examined each item for: a) word clarity (indicating any ambiguity of interpretation) and b) appropriateness for the target population. This process permitted to identify 36 appropriate items. Classical Test Theory and Rasch Analysis were used to further refine the questionnaire, yielding the final 17-item set. Concurrent validation of the new scale was tested with the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and the Anxiety and Depression questionnaires. Results Starting from the initial item data-bank, a 17-item questionnaire, the Maugeri Sleep Quality and Distress Inventory (MaSQuDI–17), was produced. Parallel Analysis on the MaSQuDI–17 confirmed the presence of a single dimension; exploratory factor analysis showed salient loading for each item, explaining 58.7% of total variance. Item-remainder correlation ranged from 0.72 to 0.39 and Cronbach alpha was 0.896. Rasch analysis revealed satisfactory psychometric properties of the new scale: the rating structure performed according to expectations, model fit was good and no item dependencies emerged. The scale presented good convergent validity and scores significantly distinguished healthy subjects from OSAS or Insomnia or BSD (p < 0.001). Conclusions MaSQuDI –17 shows good psychometric qualities, and can be used to assess the impact of sleep disorders such as Insomnia, OSAS, Central Hypersomnia and BSD on emotional stress.

Cleavage and polyadenylation specificity factor 30 (CPSF30) is a key protein involved in pre-mRNA processing. CPSF30 contains five Cys3His domains (annotated as "zinc-finger" domains). Using inductively coupled plasma mass spectrometry, X-ray absorption spectroscopy, and UV-visible spectroscopy, we report that CPSF30 is isolated with iron, in addition to zinc. Iron is present in CPSF30 as a 2Fe-2S cluster and uses one of the Cys3His domains; 2Fe-2S clusters with a Cys3His ligand set are rare and notably have also been identified in MitoNEET, a protein that was also annotated as a zinc finger. These findings support a role for iron in some zinc-finger proteins. Using electrophoretic mobility shift assays and fluorescence anisotropy, we report that CPSF30 selectively recognizes the AU-rich hexamer (AAUAAA) sequence present in pre-mRNA, providing the first molecular-based evidence to our knowledge for CPSF30/RNA binding. Removal of zinc, or both zinc and iron, abrogates binding, whereas removal of just iron significantly lessens binding. From these data we propose a model for RNA recognition that involves a metal-dependent cooperative binding mechanism.