Variants in the circadian clock genes PER2 and PER3 associate with familial sleep phase disorders.

Delayed sleep phase disorder and advanced sleep phase disorder cause disruption of the circadian clock and present with extreme morning/evening chronotype with unclear role of the genetic etiology, especially for delayed sleep phase disorder. To assess if genotyping can aid in clinical diagnosis, we examined the presence of genetic variants in circadian clock genes previously linked to both sleep disorders in Slovenian patient cohort. Based on Morning-evening questionnaire, we found 15 patients with extreme chronotypes, 13 evening and 2 morning, and 28 controls. Sanger sequencing was used to determine the presence of carefully selected candidate SNPs in regions of the CSNK1D, PER2/3 and CRY1 genes. In a patient with an extreme morning chronotype and a family history of circadian sleep disorder we identified two heterozygous missense variants in PER3 gene, c.1243C>G (NM_001377275.1 (p.Pro415Ala)) and c.1250A>G (NM_001377275.1 (p.His417Arg)). The variants were significantly linked to Advanced sleep phase disorder and were also found in proband's father with extreme morningness. Additionally, a rare SNP was found in PER2 gene in a patient with clinical picture of Delayed sleep phase disorder. The novel variant in PER2 (NM_022817.3):c.1901-218 G>T was found in proband's parent with eveningness, indicating an autosomal dominant inheritance. We identified a family with autosomal dominant inheritance of two PER3 heterozygous variants that can be linked to Advanced sleep phase disorder. We revealed also a rare hereditary form of Delayed sleep phase disorder with a new PER2 variant with autosomal dominant inheritance, shedding the light into the genetic causality.

Validation of the Slovene Version of the Stop-Bang Questionnaire in a Primary Practice Setting.

Aim: The aim of our study was to validate the Slovene translation of the STOP-BANG (SBQ) questionnaire for use in the primary practice setting. Methods: We recruited 158 randomly selected visitors at four primary practice clinics who came to the practice for any reason. Participants completed the Slovene SBQ and underwent type 3 respiratory polygraphy, which was analysed by an experienced somnologist. The SBQ was previously translated in to Slovene and validated for the sleep clinic. Results: Of 158 participants, 153 had valid recordings. The mean age of the participants was 49.5 years (±13.0 years), and 47.7% were male. OSA was identified in 49.0% of the participants. The questionnaire, with a cutoff of ≥3, demonstrated an area under the curve of 0.823 for any OSA (REI≥5), 0.819 for moderate and severe OSA (REI≥15) and 0.847 for severe OSA (REI≥30). Sensitivity was 65.3%, 81.8%, and 90.0%, and specificity was 87.2%, 73.3% and 65.0% for any, moderate to severe and severe OSA, respectively. Conclusions: The Slovene translation of the SBQ is a reliable instrument for OSA risk stratification in the primary practice setting.

The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023.

Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).

Is obstructive sleep apnea a circadian rhythm disorder?

Obstructive sleep apnea is the most common sleep-related breathing disorder worldwide and remains underdiagnosed. Its multiple associated comorbidities contribute to a decreased quality of life and work performance as well as an increased risk of death. Standard treatment seems to have limited effects on cardiovascular and metabolic aspects of the disease, emphasising the need for early diagnosis and additional therapeutic approaches. Recent evidence suggests that the dysregulation of circadian rhythms, processes with endogenous rhythmicity that are adjusted to the environment through various cues, is involved in the pathogenesis of comorbidities. In patients with obstructive sleep apnea, altered circadian gene expression patterns have been demonstrated. Obstructive respiratory events may promote circadian dysregulation through the effects of sleep disturbance and intermittent hypoxia, with subsequent inflammation and disruption of neural and hormonal homeostasis. In this review, current knowledge on obstructive sleep apnea, circadian rhythm regulation, and circadian rhythm sleep disorders is summarised. Studies that connect obstructive sleep apnea to circadian rhythm abnormalities are critically evaluated. Furthermore, pathogenetic mechanisms that may underlie this association, most notably hypoxia signalling, are presented. A bidirectional relationship between obstructive sleep apnea and circadian rhythm dysregulation is proposed. Approaching obstructive sleep apnea as a circadian rhythm disorder may prove beneficial for the development of new, personalised diagnostic, therapeutic and prognostic tools. However, further studies are needed before the clinical approach to obstructive sleep apnea includes targeting the circadian system.

Shaky hands are a part of motor neuron disease phenotype: clinical and electrophysiological study of 77 patients.

BACKGROUND: In the sharp contrast with the existing literature, we frequently observe minipolymyoclonus, tremor and pseudodystonic thumb posturing in patients with motor neuron disease. We conducted a clinical and electrophysiological study to describe phenomenology, prevalence and pathophysiology of involuntary movements in motor neuron disease. METHODS: We included 77 consecutive patients. Involuntary movements were assessed at rest and on action. Patients were videotaped. Arm muscle tone, power and deep tendon reflexes were evaluated. Accelerometry with electromyography was recorded in a subset of patients. RESULTS: Involuntary movements were observed in 68.9% of patients and could be separated into rest minipolymyoclonus, thumb tremor, pseudodystonic thumb posture, action minipolymyoclonus, and action tremor. One-third of patients reported negative impact of involuntary movements on hand use. Logistic regression showed that rest minipolymyoclonus and thumb tremor were more likely to occur in patients with more prominent distal muscle weakness and less spasticity. Similarly, action involuntary movements were more likely to appear in weaker patients. Patients with brisk tendon reflexes were more likely to display action tremor than action minipolymyoclonus. Action tremor was characterized by accelerometer and corresponding electromyography peak frequency, which decreased with mass loading, suggesting a mechanical-reflex tremor. CONCLUSIONS: Involuntary movements are common, but poorly recognized feature of motor neuron disease that may add to functional impairment. Results of our study suggest that involuntary movements are likely of peripheral origin, with a non-fused contraction of enlarged motor units being a common driving mechanism. Minipolymyoclonus appears if no synchronization of motor units occurs. When synchronization occurs via stretch reflex, mechanical-reflex tremor is generated.

European guideline and expert statements on the management of narcolepsy in adults and children.

BACKGROUND AND PURPOSE: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. METHODS: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. RESULTS: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. CONCLUSION: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

European guideline and expert statements on the management of narcolepsy in adults and children.

BACKGROUND AND AIM: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. METHODS: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. RESULTS: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong), methylphenidate, amphetamine derivates (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) excessive daytime sleepiness in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivates (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. CONCLUSION: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

Translation and validation of the STOP-Bang questionnaire into Slovene.

PURPOSE: To translate, culturally adapt and evaluate the Slovene version of the STOP-Bang questionnaire (SBQ) for use in the sleep clinic. METHODS: Standard forward-backward translation and harmonisation of the Slovene translation of the SBQ were performed. Test-retest reliability was performed on a sample of healthy subjects. A cross-sectional study was performed with patients referred for a sleep study. Patients filled out the Slovene translation of the SBQ before undergoing sleep study. RESULTS: The validation group consisted of 256 patients, of which 237 (92.6%) were included. Mean age was 52.5 ± 14.6, 63.3% of patients were male. Obstructive sleep apnoea (OSA) (apnoea-hypopnea index (AHI) ≥ 5) was present in 69.6% of patients, of whom 22.4% had mild (AHI ≥ 5 and < 15), 21.9% moderate (AHI ≥ 15 and < 30), and 25.3% severe (AHI ≥ 30) OSA. A SBQ score of 3 had a sensitivity of 92.1 (86.9-95.7), specificity of 44.4 (32.7-56.6), PPV of 79.2 (75.5-82.4) and AUC of 0.757 (95% CI 0.692-0.823; p < 0.001) for all OSA (AHI ≥ 5). Each increase in the SBQ score was associated with an increase in the probability of OSA. CONCLUSION: This study shows that the Slovene version of the SBQ is a valid tool for evaluating the risk of OSA in a sleep clinic.

Breathing patterns in relation to sleep stages in acute unilateral lateral medullary infarction: An exploratory study.

Our aim was to perform an exploratory study of various irregular breathing patterns (IBPs) across different sleep stages in patients with acute unilateral lateral medullary infarction (ULMI) and compare them to apparently healthy individuals. Polysomnography (PSG) was analyzed for IBPs, such as periodic breathing, ataxic breathing and tachypnea. IBPs were found in 52 % of healthy and 90 % of ULMI subjects (p = 0.001) and occurred in long (≥ 10 min) episodes in 8% of healthy and 68 % of ULMI (p < 0.001). In healthy subjects, short (< 10 min) episodes of mild to moderate ataxic breathing were observed in wakefulness and light sleep and short episodes of periodic breathing upon sleep onset. In ULMI, the most common IBPs were ataxic and periodic breathing (80 % of patients), followed by shallow tachypnea (28 %). Ataxic breathing predominated in wakefulness, ataxic or periodic breathing in light sleep, while breathing tended to normalize in deep and REM sleep. Considering the IBPs occurring in the healthy group as physiological, probably pathological breathing patterns (tachypnea, long episodes of moderate/severe ataxic or long episodes of periodic breathing) occurred in 67 % of ULMI patients. Our findings suggest that ULMI might exacerbate physiological sleep-stage-dependent breathing pattern irregularities, such as ataxic and periodic breathing, in terms of intensity and duration or might even induce non-physiological IBP, such as shallow tachypnea with sustained hypoxia.

Diagnosis of central disorders of hypersomnolence: A reappraisal by European experts.

The aim of this European initiative is to facilitate a structured discussion to improve the next edition of the International Classification of Sleep Disorders (ICSD), particularly the chapter on central disorders of hypersomnolence. The ultimate goal for a sleep disorders classification is to be based on the underlying neurobiological causes of the disorders with clear implication for treatment or, ideally, prevention and or healing. The current ICSD classification, published in 2014, inevitably has important shortcomings, largely reflecting the lack of knowledge about the precise neurobiological mechanisms underlying the majority of sleep disorders we currently delineate. Despite a clear rationale for the present structure, there remain important limitations that make it difficult to apply in routine clinical practice. Moreover, there are indications that the current structure may even prevent us from gaining relevant new knowledge to better understand certain sleep disorders and their neurobiological causes. We suggest the creation of a new consistent, complaint driven, hierarchical classification for central disorders of hypersomnolence; containing levels of certainty, and giving diagnostic tests, particularly the MSLT, a weighting based on its specificity and sensitivity in the diagnostic context. We propose and define three diagnostic categories (with levels of certainty): 1/"Narcolepsy" 2/"Idiopathic hypersomnia", 3/"Idiopathic excessive sleepiness" (with subtypes).

Improvements in the multidisciplinary care are beneficial for survival in amyotrophic lateral sclerosis (ALS): experience from a tertiary ALS center.

Objective: The Ljubljana ALS Centre, established in 2002, is the only tertiary center for amyotrophic lateral sclerosis (ALS) in Slovenia. The aim of our study was to evaluate the impact of therapeutic interventions and improvements in the multidisciplinary care on the survival of our patients.Methods: All patients diagnosed with ALS at our center during years 2003-2005 (early group) and 2011-2012 (late group) were included in this retrospective cohort study (n = 124). Kaplan-Meier survival analysis and multiple regression analysis with Cox proportional hazards model were performed to compare survival and to evaluate the differences between the two cohorts.Results: Median survival from the time of diagnosis was 13.0 (95% CI 10.2-15.8) months in the early group and 21.8 (95% CI 17.2-26.4) months in the late group (p = 0.005). In the Cox proportional hazards analysis, the late group of patients was associated with better survival independently of all other prognostic factors (hazard ratio (HR)=0.51, 95% CI = 0.32-0.81, p = 0.004). Survival was also associated with patients' age, use of noninvasive ventilation (NIV) and gastrostomy. The model fit significantly improved when the interaction between the NIV use and the observed time period was added to the model (HR = 0.34, 95% CI = 0.12-0.96, p = 0.041).Conclusions: Our findings suggest that improvements in the multidisciplinary care were beneficial for survival of our patients with ALS. The survival benefit in the late group of our patients could be partially explained by the improvements in the NIV use at our center.

Prospective study of sleep-disordered breathing in 28 patients with acute unilateral lateral medullary infarction.

OBJECTIVE: Acute unilateral lateral medullary infarction (ULMI) is complicated by respiratory failure in 2-6% of patients. However, studies investigating milder respiratory disorders not leading to overt respiratory failure, i.e., sleep-disordered breathing (SDB) and its outcome, are lacking. The aim of our study was to identify and prospectively follow SDB in acute ULMI. METHODS: We prospectively followed 28 patients with MRI-confirmed acute ULMI. Polysomnography (PSG) was performed 1-3 times in the acute phase (at 1-4, 5-10, and 14-21 days after onset of symptoms) and after 3-6 months. PSG recordings in the acute phase were analyzed and compared to the follow-up. RESULTS: Apnea-hypopnea index (AHI) ≥ 5/h, AHI ≥ 15/h, and AHI ≥ 30/h in the acute phase were observed in 22 (79%), 19 (68%), and 10 (36%) patients, respectively. CSA, OSA, mixed CSA/OSA, or multiple interchanging SDB types were observed in the acute phase in 12 (43%), 2 (7%), 2 (7%), and 6 (21%) patients, respectively. Peak AHI varied in individual patients (median at 7 (3-14) days after onset). At follow-up, AHI and central AHI tended to decrease (p = 0.007, p = 0.003, respectively), obstructive AHI did not change (p = 0.396). Sleep architecture partially improved with significantly higher percentage of N2 and lower percentage of wakefulness after sleep onset (p = 0.007, p = 0.012, respectively). CONCLUSIONS: Our data show that SDB, particularly CSA, is common in the acute phase of ULMI and that the frequency of central events decreases in the subacute phase. Further studies are needed to clarify the clinical significance and possible treatment options of SDB in these patients.

Sleep and Safety Improve Physicians' Psychological Functioning at Work During Covid-19 Epidemic.

PURPOSE: The COVID-19 pandemic caused a massive healthcare crisis. To investigate what makes healthcare system resilient and physicians better at coping during a crisis situation, our study investigated the role risk exposure, such as working at COVID-19 entry points, sleep, and perceived work safety played in reducing negative psychological functioning at work, as well as their effects on adverse and potentially fatal incidences of compromised safety and medical errors. METHODS: Our study included a representative sample of 1,189 physicians, from all 12 Slovenian regions and all medical occupations, as registered by the Medical Chamber of Slovenia. For the purposes of this study, a Questionnaire of Sleep and Psychological Functioning at Work was developed in the form of an online retrospective self-report. Additionally, our study included items assessing physicians perceived work safety and frequency of negative outcomes (compromised safety and medical errors) during the first month of the Covid-19 epidemic. RESULTS: Physicians working at COVID-19 entry points were more likely to experience night awakening, slept less than 5 h per night, experience nightmares, and had lower levels of psychological functioning in comparison to other physicians. Both hypothesized models showed adequate fit. A higher score on the sleep scale (sleep quantity, sleep quality, and shorter sleep latency) has been shown to predict lower levels of negative psychological functioning at work and, indirectly, reduced incidences of compromised safety and medical errors. Contrary to our expectations, no significant direct effect of sleep on compromised safety and medical errors was found. When perceived work safety was added into the model, the model showed improved fit, with perceived work safety predicting better sleep, less negative psychological functioning at work, and less compromised safety. CONCLUSION: Sleep and safety both play an important role in reducing negative psychological functioning at work and, by doing so, decreasing the negative and potentially fatal incidents during the pandemic, such as compromised safety and medical errors. Further, research is needed to see how medical guidelines can be updated to ensure physicians sleep and that their safety is protected.

Validity and reliability of the Slovene version of the Morningness-Eveningness Questionnaire.

Morningness-eveningness (ME) can be defined as individual differences in sleep-wake patterns, and the time of day people feel and perform best. Various self-report instruments that measure ME have been developed. The Horne and Östberg Morningness-Eveningness Questionnaire (MEQ) has most frequently been used for classifying ME types. The aim of this study was to investigate the validity and reliability of the Slovene version of the MEQ (Slovene MEQ). Two hundred and sixty-five participants (65.3% women, 34,7% men, mean age 38,1 years, range 19-67) took the Slovene MEQ twice, 2 weeks apart (MEQ test and retest). Internal consistency of the Slovene MEQ items was high, with Cronbach's Alpha coefficients of 0.86. The test-retest reliability was also high, with intraclass correlation coefficient (ICC) of 0.96. The classification of chronotypes on middle-aged population offered a more balanced representation of the five chronotypes than those proposed by the authors Horne and Östberg . Age changes in chronotype could be confirmed in this study in the supposed direction with older adults being more morning-oriented. The criterion validity of the Slovene MEQ through the relationship of morningness and basic personality traits showed that conscientiousness and agreeableness demonstrated positive and significant correlations with morningness. A low negative correlation was observed between openness and morningness, with higher eveningness among more open participants.

Neuropathic changes in the tongue protruder muscles in patients with snoring or obstructive sleep apnea.

OBJECTIVE: Both myopathic and neuropathic tongue protruder muscle changes have been demonstrated to occur in obstructive sleep apnea (OSA) patients using different methods. We tried to elucidate this dilemma using quantitative electromyographic (EMG) methods. METHODS: In a group of consecutive patients with suspected OSA a full overnight polysomnography (PSG) and quantitative needle EMG of the tongue protruder, biceps brachii and vastus lateralis muscles were performed. EMG findings were compared to control subjects. RESULTS: Of 23 patients, 8 were classified as simple snorers and the remaining 15 as OSA patients by PSG. Motor unit potential (MUP) parameters obtained in tongue protruder muscles, but not biceps brachii or vastus lateralis muscles, were significantly larger in patients compared to controls. However, no correlation was found between tongue protruder muscle MUP parameters and patient characteristics. DISCUSSION: Our study confirmed previous findings of neuropathic changes in the tongue protruder muscles of OSA patients, and extended these to simple snorers. Changes were limited to the upper airway muscle, and could not been explained by the severity or duration of the sleep breathing disorder. The possible role of denervation injury caused by the upper airway vibrations should be tested in the future by appropriately designed studies.

Differential expression of microRNAs and other small RNAs in muscle tissue of patients with ALS and healthy age-matched controls.

Amyotrophic lateral sclerosis is a late-onset disorder primarily affecting motor neurons and leading to progressive and lethal skeletal muscle atrophy. Small RNAs, including microRNAs (miRNAs), can serve as important regulators of gene expression and can act both globally and in a tissue-/cell-type-specific manner. In muscle, miRNAs called myomiRs govern important processes and are deregulated in various disorders. Several myomiRs have shown promise for therapeutic use in cellular and animal models of ALS; however, the exact miRNA species differentially expressed in muscle tissue of ALS patients remain unknown. Following small RNA-Seq, we compared the expression of small RNAs in muscle tissue of ALS patients and healthy age-matched controls. The identified snoRNAs, mtRNAs and other small RNAs provide possible molecular links between insulin signaling and ALS. Furthermore, the identified miRNAs are predicted to target proteins that are involved in both normal processes and various muscle disorders and indicate muscle tissue is undergoing active reinnervation/compensatory attempts thus providing targets for further research and therapy development in ALS.

Differential Expression of Several miRNAs and the Host Genes AATK and DNM2 in Leukocytes of Sporadic ALS Patients.

Genetic studies have managed to explain many cases of familial amyotrophic lateral sclerosis (ALS) through mutations in several genes. However, the cause of a majority of sporadic cases remains unknown. Recently, epigenetics, especially miRNA studies, show some promising aspects. We aimed to evaluate the differential expression of 10 miRNAs, including miR-9, miR-338, miR-638, miR-663a, miR-124a, miR-143, miR-451a, miR-132, miR-206, and let-7b, for which some connection to ALS was shown previously in ALS culture cells, animal models or patients, and in three miRNA host genes, including C1orf61 (miR-9), AATK (miR-338), and DNM2 (miR-638), in leukocyte samples of 84 patients with sporadic ALS. We observed significant aberrant dysregulation across our patient cohort for miR-124a, miR-206, miR-9, let-7b, and miR-638. Since we did not use neurological controls we cannot rule out that the revealed differences in expression of investigated miRNAs are specific for ALS. Nevertheless, the group of these five miRNAs is worth of additional research in leukocytes of larger cohorts from different populations in order to verify their potential association to ALS disease. We also detected a significant up-regulation of the AAKT gene and down-regulation of the DNM2 gene, and thus, for the first time, we connected these with sporadic ALS cases. These findings open up new research toward miRNAs as diagnostic biomarkers and epigenetic processes involved in ALS. The detected significant deregulation of AAKT and DNM2 in sporadic ALS also represents an interesting finding. The DNM2 gene was previously found to be mutated in Charcot-Marie-Tooth neuropathy-type CMT2M and centronuclear myopathy (CNM). In addition, as recent studies connected AATK and frontotemporal dementia (FTD) and DNM2 and hereditary spastic paraplegia (HSP), these two genes together with our results genetically connect, at least in part, five diseases, including FTD, HSP, Charcot-Marie-Tooth (type CMT2M), CNM, and ALS, thus opening future research toward a better understanding of the cell biology involved in these partly overlapping pathologies.

European guideline for the diagnosis and treatment of insomnia.

This European guideline for the diagnosis and treatment of insomnia was developed by a task force of the European Sleep Research Society, with the aim of providing clinical recommendations for the management of adult patients with insomnia. The guideline is based on a systematic review of relevant meta-analyses published till June 2016. The target audience for this guideline includes all clinicians involved in the management of insomnia, and the target patient population includes adults with chronic insomnia disorder. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to grade the evidence and guide recommendations. The diagnostic procedure for insomnia, and its co-morbidities, should include a clinical interview consisting of a sleep history (sleep habits, sleep environment, work schedules, circadian factors), the use of sleep questionnaires and sleep diaries, questions about somatic and mental health, a physical examination and additional measures if indicated (i.e. blood tests, electrocardiogram, electroencephalogram; strong recommendation, moderate- to high-quality evidence). Polysomnography can be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders), in treatment-resistant insomnia, for professional at-risk populations and when substantial sleep state misperception is suspected (strong recommendation, high-quality evidence). Cognitive behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (strong recommendation, high-quality evidence). A pharmacological intervention can be offered if cognitive behavioural therapy for insomnia is not sufficiently effective or not available. Benzodiazepines, benzodiazepine receptor agonists and some antidepressants are effective in the short-term treatment of insomnia (≤4 weeks; weak recommendation, moderate-quality evidence). Antihistamines, antipsychotics, melatonin and phytotherapeutics are not recommended for insomnia treatment (strong to weak recommendations, low- to very-low-quality evidence). Light therapy and exercise need to be further evaluated to judge their usefulness in the treatment of insomnia (weak recommendation, low-quality evidence). Complementary and alternative treatments (e.g. homeopathy, acupuncture) are not recommended for insomnia treatment (weak recommendation, very-low-quality evidence).

Bed Rest and Hypoxic Exposure Affect Sleep Architecture and Breathing Stability.

Objective: Despite over 50 years of research on the physiological effects of sustained bed rest, data characterizing its effects on sleep macrostructure and breathing stability in humans are scarce. This study was conducted to determine the effects of continuous exposure to hypoxia and sustained best rest, both individually and combined, on nocturnal sleep and breathing stability. Methods: Eleven participants completed three randomized, counter-balanced, 21-days trials of: (1) normoxic bed rest (NBR, PIO2 = 133.1 ± 0.3), (2) hypoxic ambulatory confinement (HAMB, PIO2 = 90.0 ± 0.4) and (3) hypoxic bed rest (HBR, PIO2 = 90.0 ± 0.4; ~4,000 m equivalent altitude). Full objective polysomnography was performed at baseline, on Night 1 and Night 21 in each condition. Results: In NBR Night 1, more time was spent in light sleep (10 ± 2%) compared to baseline (8 ± 2%; p = 0.028); Slow-wave sleep (SWS) was reduced from baseline in the hypoxic-only trial by 18% (HAMB Night 21, p = 0.028) and further reduced by 33% (HBR Night 1, p = 0.010), and 36% (HBR Night 21, p = 0.008) when combined with bed rest. The apnea-hypopnea index doubled from Night 1 to Night 21 in HBR (32-62 events·h-1) and HAMB (31-59 events·h-1; p = 0.002). Those who experienced greatest breathing instability from Night 1 to Night 21 (NBR) were correlated to unchanged or higher (+1%) night SpO2 concentrations (R2 = 0.471, p = 0.020). Conclusion: Bed rest negatively affects sleep macrostructure, increases the apnea-hypopnea index, and worsens breathing stability, each independently exacerbated by continuous exposure to hypoxia.