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Spinal anesthesia and peripheral nerve block anesthesia are used in total knee replacement. The aim of the study was to examine whether peripheral nerve block anesthesia would provide a more stable hemodynamic profile and analgesic effect in elderly patients undergoing total knee replacement, as compared to spinal anesthesia. This is a single-center case-control trial, with patients from our prospectively followed registry. The patients were divided into two groups, those with peripheral nerve block anesthesia and spinal anesthesia. Propensity score analysis was performed in 1:1 ratio. The primary outcome was analgesia with total analgesic effect and the secondary outcome was intraoperative hemodynamic status. The patients in peripheral nerve block anesthesia group had a longer length of analgesia (606.19±219.35 vs 359.48±106.82, P

Endogenous biological clocks, orchestrated by the suprachiasmatic nucleus, time the circadian rhythms that synchronize physiological and behavioural functions in humans. The circadian system influences most physiological processes, including sleep, alertness and cognitive performance. Disruption of circadian homeostasis has deleterious effects on human health. Neurodegenerative disorders involve a wide range of symptoms, many of which exhibit diurnal variations in frequency and intensity. These disorders also disrupt circadian homeostasis, which in turn has negative effects on symptoms and quality of life. Emerging evidence points to a bidirectional relationship between circadian homeostasis and neurodegeneration, suggesting that circadian function might have an important role in the progression of neurodegenerative disorders. Therefore, the circadian system has become an attractive target for research and clinical care innovations. Studying circadian disruption in neurodegenerative disorders could expand our understanding of the pathophysiology of neurodegeneration and facilitate the development of novel, circadian-based interventions for these disabling disorders. In this Review, we discuss the alterations to the circadian system that occur in movement (Parkinson disease and Huntington disease) and cognitive (Alzheimer disease and frontotemporal dementia) neurodegenerative disorders and provide directions for future investigations in this field. In this Review, Nassan and Videnovic discuss the alterations to the circadian system that occur in neurodegenerative disorders and highlight future directions for research in the field, including opportunities for the development of circadian-based therapeutic interventions.

Background This review highlights the recent scientific advances that have enabled rational design of novel clinical trials for pantothenate kinase-associated neurodegeneration (PKAN), a rare autosomal recessive neurogenetic disorder associated with progressive neurodegenerative changes and functional impairment. PKAN is caused by genetic variants in the PANK2 gene that result in dysfunction in pantothenate kinase 2 (PANK2) enzyme activity, with consequent disruption of coenzyme A (CoA) synthesis, and subsequent accumulation of brain iron. The clinical phenotype is varied and may include dystonia, rigidity, bradykinesia, postural instability, spasticity, loss of ambulation and ability to communicate, feeding difficulties, psychiatric issues, and cognitive and visual impairment. There are several symptom-targeted treatments, but these do not provide sustained benefit as the disorder progresses. Objectives A detailed understanding of the molecular and biochemical pathogenesis of PKAN has opened the door for the design of novel rationally designed therapeutics that target the underlying mechanisms. Methods Two large double-blind phase 3 clinical trials have been completed for deferiprone (an iron chelation treatment) and fosmetpantotenate (precursor replacement therapy). A pilot open-label trial of pantethine as a potential precursor replacement strategy has also been completed, and a trial of 4-phosphopantetheine has begun enrollment. Several other compounds have been evaluated in pre-clinical studies, and additional clinical trials may be anticipated. Conclusions Experience with these trials has encouraged a critical evaluation of optimal trial designs, as well as the development of PKAN-specific measures to monitor outcomes. PKAN provides a valuable example for understanding targeted drug development and clinical trial design for rare disorders. © 2021 International Parkinson and Movement Disorder Society.

Background: Subtle gait deficits can be seen in people with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD), a prodromal stage of Parkinson’s disease (PD) and related alpha-synucleinopathies. It is unknown if the presence and level of REM sleep without atonia (RSWA, the electromyographic hallmark of RBD) is related to the severity of gait disturbances in people with PD. Objective: We hypothesized that gait disturbances in people with mild-to-moderate PD would be greater in participants with RSWA compared to those without RSWA and matched controls, and that gait impairment would correlate with measures of RSWA. Methods: Spatiotemporal characteristics of gait were obtained from 41 people with PD and 21 age-matched controls. Overnight sleep studies were used to quantify muscle activity during REM sleep and group participants with PD into those with RSWA (PD-RSWA+, n = 22) and normal REM sleep muscle tone (PD-RSWA-, n = 19). Gait characteristics were compared between groups and correlated to RSWA. Results: The PD-RSWA+ group demonstrated significantly reduced gait speed and step lengths and increased stance and double support times compared to controls, and decreased speed and cadence and increased stride velocity variability compared to PD-RSWA- group. Larger RSWA scores were correlated with worse gait impairment in the PD group. Conclusion: The presence and level of muscle tone during REM sleep is associated with the severity of gait disturbances in PD. Pathophysiological processes contributing to disordered gait may occur earlier and/or progress more rapidly in people with PD and RBD.

We find ourselves at our present crossroads with a well-traveled toolkit, perhaps too well worn but with aspirational hopes and dreams for the field of sleep neurotherapeutics. This volume is organized thematically into six topical domains that parallel the major subspecialty areas of contemporary clinical sleep neurology practice, as well as novel directions and opportunities. The issue begins with an overview of the central disorders of hypersomnolence, including narcolepsy, idiopathic hypersomnia and other hypersomnia disorders, and the related use of the entire broad range of stimulant and wake-promoting pharmacotherapies. Next, the range of behavioral therapies, application of light and light restriction and melatonin therapies, and hypnotic pharmacotherapies useful in insomnia and circadian sleep–wake rhythm disorders are reviewed, followed by an overview of treatment options for sleep-related breathing disorders including positive airway pressure and the novel approach of hypoglossal neurostimulation for obstructive sleep apnea. The parasomnias and sleep-related movement disorders, including NREM disorders of arousal, REM parasomnias (nightmares and isolated sleep paralysis and idiopathic/isolated REM sleep behavior disorder, and restless legs syndrome are then discussed, and the applications of sleep neurotherapeutics in sleep and neurological disease are reviewed, including neurodevelopmental, epileptic, autoimmune encephalopathies, and neurodegenerative diseases. Last, the novel directions and opportunities in sleep neurology offered by cannabinoid therapies and machine learning/artificial intelligence methodology conclude this comprehensive survey of contemporary sleep neurology. We hope that you find this volume to be a useful and inspirational support tool for the work that matters most, your care of all our sleep neurology patients in the clinics. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01032-7.

International audience; BackgroundExcessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide.ObjectiveThe aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS.MethodsThe method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score.ResultsBoth doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: −1.4 [−2.49; −0.31], P = 0.012) but did not change significantly with the 200/18 dosage.ConclusionsTHN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society

Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency. Genetic predisposition with a family history is common. The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. Evaluation begins with a thorough history and examination, and iron measures, including ferritin and transferrin saturation, should be checked at presentation and with worsened symptoms, especially when augmentation develops. Augmentation is characterized by more intense symptom severity, earlier symptom occurrence, and often, symptom spread from the legs to the arms or other body regions. Some people with RLS have adequate symptom control with non-pharmacological measures such as massage or temperate baths. First-line management options include iron-replacement therapy in those with evidence for reduced body-iron stores or, alternatively, with prescribed gabapentin or pregabalin, and dopamine agonists such as pramipexole, ropinirole, and rotigotine. Second-line therapies include intravenous iron infusion in those who are intolerant of oral iron and/or those having augmentation with intense, severe RLS symptoms, and opioids including tramadol, oxycodone, and methadone. RLS significantly impacts patients’ quality of life and remains a therapeutic area sorely in need of innovation and a further pipeline of new, biologically informed therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01019-4.

Introduction/Objective. Spinal anesthesia is often used for hip endoprosthesis surgery. Significant surgical stress response consisting of hormonal, metabolic and inflammatory changes can be initiated by the hip replacement surgery. Intrathecal opioids, as adjuvants to local anesthetics, make spinal block sufficient even with lower doses of the local anesthetics, and the incidence of the side effects reduce to minimum. Methods. This study included 162 patients of either sex, American Society of Anesthesiology classification (ASA) 1?2, scheduled for total hip arthroplasty. The patients had spinal anesthesia with 10 mg of 0.5% bupivacaine with 20 ?g (Group I), or 25 ?g (Group II) or 30 ?g fentanyl intrathecally (Group III). Results. Mean time to achieve maximum motor and sensory blockade was with no significant difference among the groups. Time of motor block duration was shorter in the Group III. Four hours after the operation, patients in the Group I had significantly higher cortisol serum levels. Blood glucose levels were with no significant difference among the groups. Levels of CRP increased remarkably postoperatively in the Group I. Incidence of hypotension, bradycardia, nausea and vomiting was significantly higher in the Group III. Pruritus and shevering were not recorded among the groups. The first time an analgetic was needed postoperatively was the longest in the Group III. Conclusion. The dose of 10 mg of bupivacaine combined with 25 ?g fentanyl was the optimal option to achieve hemodynamic stability, sufficient sensory and motor blockade, and reduce the stress response and incidence of the opioids side effects such as vomiting, nausea, pruritus etc.

Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light–dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep–wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep–wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders – Third Edition, including jet lag and shift work disorders, delayed and advanced sleep–wake phase rhythm disorders, non-24-h sleep–wake rhythm disorder, and irregular sleep–wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01031-8

Introduction Individuals with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for a clinical diagnosis of an α‐synucleinopathy (aSN). They could serve as a key population for disease‐modifying trials. Abnormal dopamine transporter (DAT) imaging is a strong candidate biomarker for risk of aSN diagnosis in iRBD. Our primary objective was to identify a quantitative measure of DAT imaging that predicts diagnosis of clinically‐defined aSN in iRBD. Methods The sample included individuals with iRBD, early Parkinson’s Disease (PD), and healthy controls (HC) enrolled in the Parkinson Progression Marker Initiative, a longitudinal, observational, international, multicenter study. The iRBD cohort was enriched with individuals with abnormal DAT binding at baseline. Motor and nonmotor measures were compared across groups. DAT specific binding ratios (SBR) were used to calculate the percent of expected DAT binding for age and sex using normative data from HCs. Receiver operative characteristic analyses identified a baseline DAT binding cutoff that distinguishes iRBD participants diagnosed with an aSN in follow‐up versus those not diagnosed. Results The sample included 38 with iRBD, 205 with PD, and 92 HC who underwent DAT‐SPECT at baseline. Over 4.7 years of mean follow‐up, 14 (36.84%) with iRBD were clinically diagnosed with aSN. Risk of aSN diagnosis was significantly elevated among those with baseline putamen SBR ≤ 48% of that expected for age and sex, relative to those above this cutoff (hazard ratio = 17.8 [95%CI: 3.79–83.3], P = 0.0003). Conclusion We demonstrate the utility of DAT SBR to identify individuals with iRBD with increased short‐term risk of an aSN diagnosis.

ObjectiveTo test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and β-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies.MethodsA total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1–2 years).Resultsβ-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual β-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean β-glucocerebrosidase activity by 0.85 μmol/L/h (95% confidence interval, −1.17, −0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in β-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02).ConclusionsResidual activity of the β-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. β-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.

An impulse radio ultra-wideband (IR-UWB) transmitter (TX) consuming ultra-low power is presented. The low-complexity topology features control of the power spectral density (PSD) and central frequency for a broad range of applications. The PSD and frequency adjustment are accomplished by employing a tunable pulse generator and an adjustable driver. The IR-UWB TX suitable for on–off keying coding is fabricated in a low-cost 180 nm UMC CMOS technology and occupies the total die area of 0.63 mm2. The measurement results show the transmitter output swing of 320 mVpp (peak-to-peak amplitude) with the pulse duration of 0.6 ns, and the spectrum covering the frequency range from 3 to 7.5 GHz. The total DC power consumption is 1 mW resulting in energy consumption of 5 pJ/pulse at 200 MHz data rate.

Bright white light therapy (LT) can improve fatigue in several disease states but has not been studied in multiple sclerosis (MS). To determine whether controlled home-based LT is feasible, tolerable, and well-adhered to in MS-associated fatigue. A randomized, controlled trial of twice-daily 1-h bright white LT (BWLT) (10,000 lx, active arm) versus dim red LT (DRLT) (

Fosmetpantotenate; Randomized controlled trial Fosmetpantotenato; Ensayo controlado aleatorizado Fosmetpantotenat; Assaig controlat aleatoritzat Background Pantothenate kinase–associated neurodegeneration (PKAN) currently has no approved treatments. Objectives The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression. Methods This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL. Results Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was −0.09 (−1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups. Conclusions Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. The FORT trial was supported by Retrophin, Inc.

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.

Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by an urge to move that appears during rest or is exacerbated by rest, that occurs in the evening or night and that disappears during movement or is improved by movement. Symptoms vary considerably in age at onset, frequency and severity, with severe forms affecting sleep, quality of life and mood. Patients with RLS often display periodic leg movements during sleep or resting wakefulness. RLS is considered to be a complex condition in which predisposing genetic factors, environmental factors and comorbidities contribute to the expression of the disorder. RLS occurs alone or with comorbidities, for example, iron deficiency and kidney disease, but also with cardiovascular diseases, diabetes mellitus and neurological, rheumatological and respiratory disorders. The pathophysiology is still unclear, with the involvement of brain iron deficiency, dysfunction in the dopaminergic and nociceptive systems and altered adenosine and glutamatergic pathways as hypotheses being investigated. RLS is poorly recognized by physicians and it is accordingly often incorrectly diagnosed and managed. Treatment guidelines recommend initiation of therapy with low doses of dopamine agonists or α2δ ligands in severe forms. Although dopaminergic treatment is initially highly effective, its long-term use can result in a serious worsening of symptoms known as augmentation. Other treatments include opioids and iron preparations. Restless legs syndrome is a common disorder that is characterized by an urge to move the legs. This Primer reviews the epidemiology, mechanisms, diagnosis and treatment of restless legs syndrome, and also summarizes the quality-of-life issues faced by patients and future research avenues.

The mechanisms contributing to increased expression of motor and cognitive impairment in people with Parkinson9s disease who lack muscle atonia during rapid eye movement (REM) sleep compared to those with muscle atonia are poorly understood. This study used tract-based spatial statistics to compare diffusion measures of white matter microstructure between people with Parkinson9s disease with and without REM sleep without atonia as well as the relationships of these measures to motor and cognitive function. Thirty-eight individuals with mild-to-moderate Parkinson9s disease and twenty-one matched control subjects underwent ultra-high-field MRI (7Tesla), quantitative motor assessments of gait and bradykinesia, and neuropsychological testing. The Parkinson9s disease cohort was separated post-hoc into those with and without elevated chin or leg muscle activity during REM sleep based on polysomnography findings. Fractional anisotropy was significantly higher, and radial and mean diffusivity significantly lower, in diffuse regions of the corpus callosum, projection, and association white matter pathways in the Parkinson9s group with normal REM sleep compared to controls. In contrast, there was no significant difference in fractional anisotropy between the Parkinson9s group with elevated muscle tone and controls. Fractional anisotropy was also significantly higher in a subset of pathways in the Parkinson9s disease group with normal REM sleep muscle tone compared to those with elevated REM sleep muscle tone. The group with elevated REM sleep muscle tone had significant impairments in gait and upper arm speed compared to controls and significantly worse scores in specific cognitive domains (executive function, visuospatial memory) compared to the Parkinson9s disease group with normal REM sleep muscle tone. Regression analyses showed that gait speed and step length in the Parkinson9s disease cohort were predicted by measures of mean fractional anisotropy of the anterior corona radiata, whereas elbow flexion velocity was predicted by fractional anisotropy of the superior corona radiata. Visuospatial memory task performance was predicted by the radial diffusivity of the posterior corona radiata. These findings demonstrate that people with mild-to-moderate severity of Parkinson9s disease who have normal muscle tone during REM sleep show alterations in white matter microstructure that are associated with preserved motor and cognitive function, but these adaptations are reduced or absent in those with increased REM sleep motor tone.

Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes, and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible.

IMPORTANCE: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (

Sleep disorders are common among PD patients and affect quality of life. They are often under-recognized and under-treated. Mechanisms of sleep disorders in PD remain relatively poorly understood. Improved awareness of common sleep problems in PD. Tailored treatment and evidence for efficacy are lacking. The purpose of this review is to provide an overview and update on the most common sleep disorders in PD. We review specific features of the most common sleep disorders in PD, including insomnia, excessive daytime sleepiness, sleep-disordered breathing, restless legs syndrome, circadian rhythm disorders and REM sleep behavior disorders.

Introduction/Objective. Stanford type A aortic dissection is a surgical emergency associated with high mortality. The aim of this study was to determine which group of patients and which characteristics were associated with postoperative, in-hospital mortality. Methods. The retrospective study included 116 patients with type A aortic dissection surgically treated over a five-year period. The association between postoperative, in-hospital mortality and patient characteristics was examined. Results. Total postoperative, in-hospital mortality was 22.4% (26 out of 116 patients). The variables that, after a multivariate analysis, showed a direct correlation with mortality were as follows: admission creatinine value [OR 1.026 (1.006?1.046), p = 0.009], C-reactive protein (CRP) > 10 mg/L [OR 4.764 (1.066?21.283), p = 0.041], and stroke [OR 6.097 (1.399?26.570), p = 0.016]. The receiver operating characteristic (ROC) curve showed that creatinine could be a good predictor of mortality (area under the ROC curve = 0.767; p < 0.0005). The cut-off point was 124.5 ?mol/L. The sensitivity was 65% and the specificity was 80%. The cut-off point for CRP was 14.5 mg/L ? sensitivity 71.4%, specificity 75% (area under the ROC curve = 0.702, p = 0.021). Conclusion. Surgery for type A aortic dissection is still associated with relatively high mortality. A lower chance of survival may be indicated by elevated admission creatinine and CRP values, as well as stroke.

An ultralow-power and low-complexity impulse radio ultrawideband (IR-UWB) transmitter (TX) is fabricated in the low-cost 180-nm United Microelectronics Corporation (UMC) CMOS technology. The TX offers control of the power spectral density (PSD) by using a tunable pulse generator and a controllable switched oscillator. It supports on-off keying (OOK) coding and occupies a total die area of 0.35 mm2. The measured results show the transmitter output amplitude of 130 mVp-p with the pulse width of 1.0 ns, and the PSD with 10-dB bandwidth from 3 to 8.8 GHz. The total dc power consumption is 0.6 mW, corresponding to the energy consumption of 3 pJ/pulse at 200-MHz pulse repetition frequency.

This article focuses on irregular sleep-wake rhythm disorder (ISWRD) and its associations with several other comorbidities. Irregular sleep-wake rhythm disorder is a circadian disorder characterized by a lack of a clear sleep-wake pattern. The disorder has yet to be fully understood from pathophysiologic perspective. Treatments are available, but there is a need for development of novel interventions. The goal of this article is to focus on multiple aspects of ISWRD.

Background Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegenerative disorder with brain iron accumulation (NBIA). Objectives To assess PKAN diagnostic pathway, history, and burden across the spectrum of PKAN severity from patient and/or caregiver perspectives. Methods Caregivers of patients (n = 37) and patients themselves (n = 2) were interviewed in a validation study of the PKAN-Activities of Daily Living (ADL) scale. The current study used quartiles of the PKAN-ADL total score to divide patients by severity of impairment (Lowest, Second Lowest, Third Lowest, Highest). Diagnostic and treatment history, healthcare utilization, disease burden, and caregiver experience were compared between groups. Results The analyses included data from 39 patients. Mean age at PKAN symptom onset (P = 0.0007), initial MRI (P = 0.0150), and genetic testing (P = 0.0016) generally decreased across the PKAN severity spectrum. The mean duration of illness did not differ among PKAN severity groups (range, 9.7–15.2 years; P = 0.3029). First MRI led to diagnosis in 56.4% of patients (range, 30.0–90.0%). A mean (SD) of 13.0 (13.1) medical and 55.2 (78.5) therapy visits (eg, physical, speech) occurred in the past year. More patients in the higher PKAN severity groups experienced multiple current functional losses and/or earlier onset of problems (P-values

Parkinson’s disease (PD) is the second-most common progressive neurodegenerative disorder. Although the clinical diagnosis of PD is still based on its cardinal motor dysfunctions, several non-motor symptoms (NMS) have been established as integral part of the disease. Unlike motor disorders, development of therapies against NMS are still challenging and remain a critical unmet clinical need. During the last decade, several studies have characterised the molecular, physiological and behavioural alterations of the circadian system in PD patients. As a consequence, and given the ubiquitous nature of circadian rhythms in the entire organism, the biological clock has emerged as a potential therapeutic target to ease suffering from both motor and NMS in PD patients. Here we discuss the emerging field of using bright light, physical exercise and melatonin as chronotherapeutic tools to alleviate motor disorders, sleep/wake alterations, anxiety and depression in PD patients. We also highlight the potential of these readily available therapies to improve the general quality of life and wellbeing of PD patients. Finally, we provide specific data- and mechanisms-driven recommendations that might help improve the therapeutic benefit of light and physical exercise in PD patients.

Background Solriamfetol is approved (US and EU) for excessive daytime sleepiness (EDS) in narcolepsy and obstructive sleep apnea. Objectives Evaluate solriamfetol safety/efficacy for EDS in Parkinson's disease (PD). Methods Phase 2, double-blind, 4-week, crossover trial: adults with PD and EDS were randomized to sequence A (placebo, solriamfetol 75, 150, 300 mg/d), B (solriamfetol 75, 150, 300 mg/d, placebo), or C (placebo). Outcomes (safety/tolerability [primary]; Epworth Sleepiness Scale [ESS]; Maintenance of Wakefulness Test [MWT]) were assessed weekly. P values are nominal. Results Common adverse events (n = 66): nausea (10.7%), dizziness (7.1%), dry mouth (7.1%), headache (7.1%), anxiety (5.4%), constipation (5.4%), dyspepsia (5.4%). ESS decreased both placebo (-4.78) and solriamfetol (-4.82 to -5.72; P > 0.05). MWT improved dose-dependently with solriamfetol, increasing by 5.05 minutes with 300 mg relative to placebo (P = 0.0098). Conclusions Safety/tolerability was consistent with solriamfetol's known profile. There were no significant improvements on ESS; MWT results suggest possible benefit with solriamfetol in PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.

Disruptions of sleep and circadian rhythms are among the most debilitating symptoms in patients with neurodegenerative diseases. Their underlying pathophysiology is multilayered and multifactorial. Recent evidence suggests that sleep and circadian disturbances may influence the neurodegenerative processes as well as be their consequence. In this perspective, we provide an update of the current understanding of sleep and circadian dysregulation in Alzheimer’s, Parkinson’s, and Huntington’s diseases.

Objectives/background Most middle-aged and older adult patients with isolated (idiopathic) REM sleep behavior disorder (RBD) eventually develop parkinsonism, dementia with Lewy bodies, or multiple system atrophy. We aimed to describe the current sleep medicine specialist approach toward RBD prognostic counseling, and to determine physician beliefs and characteristics that impact provision of counseling. Patients/methods We surveyed 70 sleep medicine physicians with RBD expertise for demographic information, counseling practices, and their beliefs and understandings concerning the association between RBD and synucleinopathies, among other questions. Responses were summarized by descriptive statistics. Results Among the 44 respondents (63% response rate), 41 (93.2%) regularly provided prognostic counseling for most RBD patients, but only 31.8% routinely asked about patient preferences on receiving counseling. 41.8% believed that the risk for developing overt synucleinopathy following RBD diagnosis was >80%, but only 15.9% routinely provided this detailed phenoconversion risk estimate to their patients. Most respondents were concerned that RBD prognostic counseling could adversely impact on the patient's and family's mental health. Conclusions Most expert RBD sleep clinicians routinely counsel their patients regarding the high risk for phenoconversion to parkinsonism or dementia, yet relatively few routinely ask patients about their preferences for receiving this information, and fewer provide details concerning the known high risk estimates for developing a synucleinopathy. Future research should analyze patients’ values and preferences in RBD populations to inform approaches toward shared decision making for RBD prognostic counseling.

The advancements in analog electronic design automation (EDA) tools for layout design are still lagging behind than its counterpart digital EDA tools. Due to which, the analog layout design is still done manually therefore time-consuming and difficult to clear the physical verification checks. Over the recent years, many tools are introduced for the automatic layout generation of analog circuits. This paper presents a study of one such popular layout generator for analog layout design referred as Berkeley Analog Generator (BAG). A step by step workflow of the layout generation in BAG is presented and the performance comparison of the automatic layout generated using BAG and full-custom layout for analog circuits is demonstrated. As a test-case, a typical dynamic comparator is used for comparison. The layout of dynamic comparator is done for the same aspect ratios of transistors and specifications in both environments. The performance validation of layouts is done after parasitic extraction in Cadence Spectre environment using TSMC 28 nm standard CMOS process. A clock signal of 50 MHz for the comparator is considered at a supply voltage of 1.0 V.

We report the case of a 62-year-old male patient, admitted for aortic valve replacement. Bilateral common carotid artery occlusion and bilateral internal carotid artery occlusion have been reported, as well as right vertebral artery occlusion. Aortic valve replacement was performed in the standard fashion using the cardiopulmonary bypass. No neurological deficit was apparent on emergence from anesthesia. Keywords: bilateral carotid occlusion, the vertebral artery occlusion, cardiac surgery

AIM The aim of the study was to examine the effectiveness of intraoral thermoformed splint with a magnet device over a period of 3 months, that is, to assess acceptability of this method of treatment using both objective and self-reported measures. MATERIALS AND METHODS This study was designed as a prospective clinical pilot trial. 22 patients with xerostomia and hyposalivation were included. Xerostomia was assessed using a 4-question xerostomia questionnaire score and a test for unstimulated salivary flow rates. Evaluations were performed before the treatment and 3 months after the treatment using a thermoformed splint with a magnet device. RESULTS There was a significant reduction in subjective symptoms after using a thermoformed splint with a magnet device for 3 months. For all 4 scored items, there was a statistically significant difference (P

Objective Pantothenate kinase‐associated neurodegeneration (PKAN) is an autosomal‐recessive, neurodegenerative disorder with a mixed‐motor phenotype caused by a defective PanK2 enzyme, for which there are few adequate treatment options. Clinimetrically sound measures of patient‐reported outcomes are necessary to facilitate therapeutic development for this debilitating disease. This study's objective was to develop such a scale and assess its clinimetric properties. Methods A conceptually driven, iterative, content development process incorporating input from experts, caregivers, and patients was used. Scale items were initially adapted from the Unified Parkinson's Disease Rating Scale (UPDRS) Part II resulting in the 12‐item Pantothenate Kinase‐Associated Neurodegeneration Activities of Daily Living (PKAN‐ADL). The PKAN‐ADL scale was administered to caregivers (n = 37) and patients (n = 2) twice over 2 weeks, along with selected Quality of Life in Neurological Disorders (Neuro‐QoL) measures, selected attributes of the Health Utilities Index (HUI)‐2/3, and the Stroke Aphasia Depression Questionnaire (SADQ‐10) to assess construct validity. Results Internal consistency was 0.93, with excellent test‐retest reliability (intraclass correlation coefficient = 0.99). Of the 12 items, 25% (n = 3) showed a ceiling effect >30% (range, 31–54) and 42% (n = 5) showed a floor effect >30% (range, 31–46), reflecting disease heterogeneity. Convergent validity was shown with Neuro‐QoL measures (rs > 0.90) and HUI‐2/3 attributes (rs ≥ 0.48); divergent validity was demonstrated with the SADQ‐10 (r = 0.11). Participants reported a high level of comprehension (98%), and average item relevance ratings (0–10 scale) ranged from 7.0 to 9.9. Conclusion The PKAN‐ADL scale demonstrated acceptable content validity, with evidence of construct validity and excellent reliability. Overall results support the use of the PKAN‐ADL scale in clinical trials.

Chronic obstructive pulmonary disease (COPD) significantly reduces quality of life and is one of the main causes of chronic morbidity and mortality worldwide. Acute exacerbation of COPD (AECOPD) is a life-threatening condition that causes rapid deterioration of respiratory symptoms (worsening of dyspnea, cough and/or abundant sputum production) requiring urgent treatment. This review article examines the evidence underlying supplemental oxygen therapy and ventilator support during exacerbations of COPD. In the introduction, we discuss the epidemiology and pathophysiology of hypercapnic respiratory failure, and then we explain that the key to achieving appropriate levels of oxygenation is using controlled low-flow oxygen therapy. In patients with risk of hypercapnia a target oxygen saturation (SaO2) range of 88%-92% is now generally accepted unless hypercapnia is disproved by gas analysis of arterial blood. However, if the partial pressure of carbon dioxide in arterial blood (PaCO2) is normal, oxygen therapy may target the usual saturation range of 94%-98%. Many COPD patients may have a lower stable SaO2, such that chasing this target (94%-98%) is not usually necessary unless the patient is unwell. Further, we review current recommendations for ventilatory support in patients with AEHOBP. Noninvasive ventilation has assumed an important role in managing patients with acute respiratory failure. The use of invasive ventilation is the last remaining option, associated with a poor outcome.

Introduction/Objective. In this study, the effects of applied anesthetic techniques were investigated in a retrospective analysis of obese patients and those with normal body mass index undergoing in vitro fertilization, using bispectral index as an indicator of anesthetic depth. Methods. In total 116 patients with normal body mass index were allocated to group N. Another 116 patients with body mass index > 30 kg/m2 were allocated to group O. Anesthetic protocol comprised midazolam for premedication, diclofenac for pre-emptive analgesia, propofol for induction and maintenance, alfentanil for analgesia, suxamethonium for muscle relaxation. We recorded and compared the monitored parameters using t-test and ?2 test. Results. Procedure duration and recovery time were significantly longer in O group (p < 0.01). There is a statistically significant difference (p = 0.000181) in the number of patients requiring mechanical ventilation after induction of anesthesia. Propofol consumption was significantly higher (p < 0.0001) in O group (2.7 ? 1.6 mg/kg) as compared to group N (2.1 ? 0.4 mg/kg). The incidence of postoperative nausea and vomiting was observed in six patients in N group (5.17%) and nine patients in O group (7.76%). Pain intensity was found higher in group O compared to group N (p < 0.0001). Assessment of patients? sedation using verbal scale reported no statistically significant difference between N and O groups (p = 0.2548). Conclusion. Induction and maintenance of anesthesia in obese patients results in increased consumption of propofol and the need for muscle relaxation. The statements of the patients who underwent the procedure under intravenous propofol and alfentanil serve as the best recommendation for clinical practice.

Mullerian anomalies include a range of abnormalities of the lower female genital tract that can involve the uterus, cervix, the upper vagina and fallopian tubes. Women with these anomalies have a higher incidence of infertility, miscarriages, premature births, and other reproductive problems. They have a wide range of manifestations. Here, we present a patient with cervical and vaginal duplication with a normal uterus.

We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts. A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (κw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the C-index. A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (κw=0.65, IQR 0.53–0.72, p20 years of experience (C-index=0.72, IQR 0.0–0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70–0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72–0.75). Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts., Academic status, access to MDT meetings and clinician experience predict accuracy of a clinical diagnosis of IPF http://ow.ly/k43W30cTMg1

Compare nocturnal REM sleep without atonia (nRWA) and REM sleep behavior disorder (RBD) between pediatric patients with and without narcolepsy and determine if the nRWA index is a valid diagnostic biomarker for narcolepsy.Retrospective cohort study of children ages 6 to 18 years who completed a nocturnal polysomnogram (PSG) and Multiple Sleep Latency Test (MSLT). Our study sample included 11 patients with narcolepsy type 1 (NT1), 6 with narcolepsy type 2 (NT2), 12 with idiopathic hypersomnia (IH), and 11 with subjective hypersomnia (sHS). We compared group nRWA indices (epochs of RWA/total stage R sleep epochs) from the nocturnal PSGs and analyzed nRWA index receiver operating curve (ROC) statistics for narcolepsy diagnosis.The median nRWA index of patients with NT1 was 15 to 30 times higher compared to sHS and IH (The nRWA index is a very good diagnostic biomarker of pediatric narcolepsy. Depending on the clinical cutoffs utilized, this biomarker can identify more children/adolescents with narcolepsy using just the PSG or reduce false-positive diagnostic results.

Even today, when over 3.5 billion passengers travel on commercial flights each year, there is confusion about the duties and role of doctors and other licensed medical professionals volunteering to provide assistance to a passenger whose life is in jeopardy, especially when it comes to measures of cardiopulmonary resuscitation in the distinctive conditions of an airborne commercial aircraft. There are still no international, standardized guidelines, rulebooks, or instructions applying to all airlines when it comes to training and organizing the cabin crew, equipping emergency medical kits and covering the role of medical professionals volunteering their services in medical emergency situations. The aim of this work was to attempt to solve a common quandary among medical professionals when it comes to airplane travel. Based on the available literature, national and regional guidelines and rulebooks of airlines, in accordance with the ethical and legal principles binding medical professionals, we have attempted to answer the major questions related to cardiopulmonary resuscitation on commercial flights. All aspects are covered ? from a doctor volunteering to provide emergency medical care, through the marshalling of the cabin attendants, the availability of equipment, interaction with the flight captain and the captain?s decision whether to perform an emergency landing, to the possibility of obtaining additional information from medical call centers on the ground and calling medical crews to the nearest airport.

While the use of simulation in medical education has a long history, it has seen its greatest strides in the past 15-odd years. It may be defined as imitation, artificial while at the same time faithful, of various clinical situations through well-crafted medical ?scenarios? where, instead of actual people, we use standardized patients: plant, animal, or synthetic models, computerized interactive manikins ? simulators, with audiovisuals, as well as medical equipment used in everyday clinical practice. The fundamental goal of using simulation in medical education is an optimal balance between professional education on the one hand and complete safety and protection of patients on the other. Depending on the available finances and the level of advancement of the healthcare and education systems, medical simulation can take various forms ? from simple improvisation to the creation of a high-fidelity simulation in centers for medical simulation. Our example shows that, even with modest financial means, enthusiasm, creativity, and good ideas make it possible to establish a center for medical simulation. A separate section of the paper is devoted to the staging of a simulation scenario based on the authors? experiences.

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms and signs. Many reports suggest that diminished heart rate variability occurs early, even prior to the cardinal signs of PD. In a longitudinal study of PD, we evaluated whether heart rate variability (HRV) obtained using a 10 second ECG tracing, and the electrocardiographic QT-interval would be associated with PD severity and progression. Subjects were derived from a longitudinal study of 1741 individuals with early, stable PD. The severity of PD was measured using the global statistical test (GST). In a subset, the heart rate corrected QT-interval (QTcB) was calculated for each electrocardiogram (ECG). The HRV was measured for each ECG and then transformed to fit a normal distribution. The baseline analysis included 653 subjects, with 256 completing the 5-year follow up study. There was an association (P

An 8-year-old child is admitted to a surgical unit for abdominal pain, with clinical diagnosis of acute abdomen. At exploration, organoaxial gastric volvulus and splenic volvulus were found. Necrosis and gangrene of the whole stomach are treated with total gastrectomy. Gastric volvulus is a rare acute surgical condition in children. It requires urgent surgical treatment to avoid irreversible ischemic changes in the stomach and possibly spleen.

Introduction. Femoral hernia in children is very rare and it appears in 0.2% of all hernias during childhood. It is three times more frequent in girls. The aim of this paper is to present a female infant with incarcerated femoral hernia. Case outline. A female infant aged three months was hospitalized with classical clinical signs of incarcerated left femoral hernia. After preoperative preparation, a transversal inguinal incision was performed on the left side and an incarcerated femoral hernia was confirmed with a torn and gangrenous left ovary and fallopian tube. Following adnexectomy, the hernia sac was ligated and resected and hernioplasty was made by the reconstruction of the Cooper?s ligament. Conclusion. A delayed surgical intervention for incarcerated femoral hernia in a female can result in a loss of the ovary and the fallopian tube, which may lead to serious consequences later in life.