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Radiation therapy is moving from CT based to MRI guided planning, particularly for soft tissue anatomy. An important requirement of this new workflow is the generation of synthetic-CT (sCT) from MRI to enable treatment dose calculations. Automatic methods to determine the acceptable range of CT Hounsfield Unit (HU) uncertainties to avoid dose distribution errors is thus a key step toward safe MRI-only radiotherapy. This work has analysed the effects of controlled errors introduced in CT scans on the delivered radiation dose for prostate cancer patients. Spearman correlation coefficient has been computed, and a global sensitivity analysis performed following the Morris screening method. This allows the classification of different error factors according to their impact on the dose at the isocentre. sCT HU estimation errors in the bladder appeared to be the least influential factor, and sCT quality assessment should not only focus on organs surrounding the radiation target, as errors in other soft tissue may significantly impact the dose in the target volume. This methodology links dose and intensity-based metrics, and is the first step to define a threshold of acceptability of HU uncertainties for accurate dose planning. [ABSTRACT FROM AUTHOR]

Following severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine1,2, European health authorities recommended that patients under the age of 55 years who received one dose of ChAdOx1-S-nCoV-19 receive a second dose of the Pfizer BNT162b2 vaccine as a booster. However, the effectiveness and the immunogenicity of this vaccination regimen have not been formally tested. Here we show that the heterologous ChAdOx1-S-nCoV-19 and BNT162b2 combination confers better protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than the homologous BNT162b2 and BNT162b2 combination in a real-world observational study of healthcare workers (n = 13,121). To understand the underlying mechanism, we conducted a longitudinal survey of the anti-spike immunity conferred by each vaccine combination. Both combinations induced strong anti-spike antibody responses, but sera from heterologous vaccinated individuals displayed a stronger neutralizing activity regardless of the SARS-CoV-2 variant. This enhanced neutralizing potential correlated with increased frequencies of switched and activated memory B cells that recognize the SARS-CoV-2 receptor binding domain. The ChAdOx1-S-nCoV-19 vaccine induced a weaker IgG response but a stronger T cell response than the BNT162b2 vaccine after the priming dose, which could explain the complementarity of both vaccines when used in combination. The heterologous vaccination regimen could therefore be particularly suitable for immunocompromised individuals.An observational study of more than 13,000 healthcare workers shows that a prime–boost vaccine regimen of AstraZeneca ChAdOx1-S-nCoV-19 with Pfizer BNT162b2 provides enhanced protection against SARS-CoV-2 infection compared with two doses of BNT162b2. [ABSTRACT FROM AUTHOR]

The association between restless legs syndrome (RLS) and iron homeostasis remains unclear. We compared serum hepcidin and ferritin levels in patients with RLS and controls, and assessed their relationships with RLS phenotype, drug intake, and history of augmentation syndrome. 102 drug-free RLS patients (age 58.9 [24.5–77.2], 63 females) and 73 controls (age 56.8 [23.46–76.6], 45 females) underwent a polysomnography recording. Hepcidin levels were quantified by ELISA. 34 RLS patients had a second assessment after starting dopaminergic drugs. Ferritin level was low (< 50 µg/l) in 14.7% of patients and 25% of controls, with no between-group differences in the mean values. Hepcidin levels were higher in patients even after adjustment for confounding factors, and excluding participants with low ferritin levels. Ferritin and hepcidin levels were comparable before and after treatment, and between patients with (n = 17) and without history of augmentation. Ferritin and hepcidin levels correlated with age, body mass index, and periodic leg movements. Higher hepcidin levels were associated with older age, older age at RLS onset, less daytime sleepiness and familial RLS. In conclusion, serum hepcidin levels but not ferritin were higher in RLS patients regardless of treatment and history of augmentation. Serum hepcidin may be a more relevant biomarker of RLS than ferritin. [ABSTRACT FROM AUTHOR]

Background and Purpose: During head-and-neck (H&N) radiotherapy, the parotid glands (PGs) may be overdosed; thus, a tool is required to monitor the delivered dose. This study aimed to assess the dose accuracy of a patient-specific density assignment method (DAM) for dose calculation to monitor the dose to PGs during treatment.Patients and Methods: Forty patients with H&N cancer received an intensity modulated radiation therapy (IMRT), among whom 15 had weekly CTs. Dose distributions were calculated either on the CTs (CTref), on one-class CTs (1C-CT, water), or on three-class CTs (3C-CT, water-air-bone). The inter- and intra-patient DAM uncertainties were evaluated by the difference between doses calculated on CTref and 1C-CTs or 3C-CTs. PG mean dose (Dmean) and spinal cord maximum dose (D2%) were considered. The cumulated dose to the PGs was estimated by the mean Dmean of the weekly CTs.Results: The mean (maximum) inter-patient DAM dose uncertainties for the PGs (in cGy) were 23 (75) using 1C-CTs and 12 (50) using 3C-CTs (p ≤ 0.001). For the spinal cord, these uncertainties were 118 (245) and 15 (67; p ≤ 0.001). The mean (maximum) DAM dose uncertainty between cumulated doses calculated on CTs and 3C-CTs was 7 cGy (45 cGy) for the PGs. Considering the difference between the planned and cumulated doses, 53% of the ipsilateral and 80% of the contralateral PGs were overdosed by +3.6 Gy (up to 8.2 Gy) and +1.9 Gy (up to 5.2 Gy), respectively.Conclusion: The uncertainty of the three-class DAM appears to be clinically non-significant (<0.5 Gy) compared with the PG overdose (up to 8.2 Gy). This DAM could therefore be used to monitor PG doses and trigger replanning. [ABSTRACT FROM AUTHOR]

Narcolepsy type 1 (NT1) is a rare sleep disorder caused by the very specific loss of hypothalamic hypocretin (Hcrt)/orexin neurons. The exact underlying process leading to this destruction is yet unknown, but indirect evidence strongly supports an autoimmune origin. The association with immune-related genetic factors, in particular the strongest association ever reported in a disease with an allele of a human leukocyte antigen (HLA) gene, and with environmental factors (i.e., the H1N1 influenza infection and vaccination during the pandemic in 2009) are in favor of such a hypothesis. The loss of Hcrt neurons is irreversible, and NT1 is currently an incurable and disabling condition. Patients are managed with symptomatic medication, targeting the main symptoms (excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep), and they require a lifelong treatment. Improved diagnostic tools, together with an increased understanding of the pathogenesis of NT1, may lead to new therapeutic and even preventive interventions. One future treatment could include Hcrt replacement, but this neuropeptide does not cross the blood-brain barrier. However, Hcrt receptor agonists may be promising candidates to treat NT1. Another option is immune-based therapies, administered at disease onset, with already some initiatives to slow down or stop the dysimmune process. Whether immune-based therapy could be beneficial in NT1 remains, however, to be proven. [ABSTRACT FROM AUTHOR]

Relationships between symptoms of hypersomnolence, psychiatric disorders, and hypersomnia disorders (i.e., narcolepsy and idiopathic hypersomnia) are complex and multidirectional. Hypersomnolence is a common complaint across mood disorders; however, patients suffering from mood disorders and hypersomnolence rarely have objective daytime sleepiness, as assessed by the current gold standard test, the Multiple Sleep Latency Test. An iatrogenic origin of symptoms of hypersomnolence, and sleep apnea syndrome must be considered in a population of psychiatric patients, often overweight and treated with sedative drugs. On the other hand, psychiatric comorbidities, especially depression symptoms, are often reported in patients with hypersomnia disorders, and an endogenous origin cannot be ruled out. A great challenge for sleep specialists and psychiatrists is to differentiate psychiatric hypersomnolence and a central hypersomnia disorder with comorbid psychiatric symptoms. The current diagnostic tools seem to be limited in that condition, and further research in that field is warranted. [ABSTRACT FROM AUTHOR]

Narcolepsy type 1 (NT1) and type 2 (NT2) are two rare neurological diseases, classified as central disorders of hypersomnolence. The pathophysiology of NT1 is well known; it is caused by the selective destruction of hypocretin (Hcrt) neurons, by a highly suspected autoimmune process. On the contrary, little is known about NT2 etiology, sharing with NT1 somnolence and signs of dysregulation of rapid eye movement (REM) sleep, but not cataplexy. Management strategies are rather codified, at least in adults, with a lifelong treatment required in NT1, whereas no pharmacological study focused only on NT2 patients, with sometimes spontaneous improvement or disappearance of their symptoms. We recommend that medications and guidelines in NT2 should be the same as for NT1 (except for cataplexy), but the benefit risk ratio should be reassessed regularly. The main symptom in both diseases is a disabling excessive daytime sleepiness (EDS). First-line medications should be stimulants such as modafinil, armodafinil, or sodium oxybate, second-line methylphenidate and pitolisant, where available, and amphetamines as third-line therapy. Sodium oxybate has the advantage to be also effective to manage the fragmented nocturnal sleep, another common symptom in NT1. We advise to wait a few weeks with a stimulant drug before starting an anticataplectic treatment in NT1, except for severe cataplexy. Furthermore, cataplexy treatment should not be systematic. First-line strategy is the use of sodium oxybate, the only drug approved for cataplexy and EDS in adults. However, antidepressant agents such as venlafaxine are also commonly used, with few adverse effects and a good efficacy, although based on expert consensus only. A clinically relevant tool is required to quantify the severity of narcolepsy, subjective symptoms, and their consequences, to monitor the treatment efficacy, and to finally optimize narcolepsy management. In the future, Hcrt replacement or Hcrt agonists will certainly be options to treat NT1, but for now the different peptides do not cross easily the blood brain barrier. Immune-based therapies are other possibilities in NT1, at disease onset, with already some successful attempts to slow down or stop the autoimmune process. [ABSTRACT FROM AUTHOR]

Narcolepsy type 1 and narcolepsy type 2 are central disorders of hypersomnolence. Narcolepsy type 1 is characterized by excessive daytime sleepiness and cataplexy and is associated with hypocretin-1 deficiency. On the other hand, in narcolepsy type 2, cerebrospinal fluid hypocretin-1 levels are normal and cataplexy absent. Despite major advances in our understanding of narcolepsy mechanisms, its current management is only symptomatic. Treatment options may vary from a single drug that targets several symptoms, or multiple medications that each treats a specific symptom. In recent years, narcolepsy treatment has changed with the widespread use of modafinil/armodafinil for daytime sleepiness, antidepressants (selective serotonin and dual serotonin and noradrenalin reuptake inhibitors) for cataplexy, and sodium oxybate for both symptoms. Other psychostimulants can also be used, such as methylphenidate, pitolisant and rarely amphetamines, as third-line therapy. Importantly, clinically relevant subjective and objective measures of daytime sleepiness are required to monitor the treatment efficacy and to provide guidance on whether the treatment goals are met. Associated symptoms and comorbid conditions, such as hypnagogic/hypnopompic hallucinations, sleep paralysis, disturbed nighttime sleep, unpleasant dreams, REM- and non REM-related parasomnias, depressive symptoms, overweight/obesity, and obstructive sleep apnea, should also be taken into account and managed, if required. In the near future, the efficacy of new wake-promoting drugs, anticataplectic agents, hypocretin replacement therapy and immunotherapy at the early stages of the disease should also be evaluated. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is frequently comorbid with hypertension and cardiovascular diseases; however this relationship and underlying mechanisms remain controversial. After clinical evaluation, 84 drug-free patients with primary RLS (53 women; mean age 55.1 ± 12.3 years) and 76 controls (47 women; mean age 52.2 ± 15.3 years) underwent 24-hour ambulatory blood pressure (BP) and polysomnographic monitoring, and peripheral arterial tonometry to assess endothelial function for 61 patients and 69 controls. Hypertension was diagnosed in 11.9% of patients with RLS based on office measurement, and in 46.4% on the 24 h recording, with nighttime hypertension, two times more frequent than daytime hypertension. Periodic limb movement during sleep (PLMS), markers of sleep fragmentation, and systolic and mean BP non-dipping profile were more frequent among patients. BP non-dipping status was associated with older age, later RLS onset and diagnosis, RLS severity and higher sleep fragmentation. The mean 24-hour, daytime and nighttime BP values, the frequency of hypertension and the endothelial function were comparable between groups. However, both systolic and diastolic BP trajectories over a 24-hour period differed between groups. In conclusion, patients with RLS exhibit a 24-hour BP deregulation with increased frequency of systolic non-dipping profiles that could worsen the risk for CVD morbidity and mortality. [ABSTRACT FROM AUTHOR]

Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph—a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies. The diagnosis of sleep disorders such as narcolepsy and insomnia currently requires experts to interpret sleep recordings (polysomnography). Here, the authors introduce a neural network analysis method for polysomnography that could reduce time spent in sleep clinics and automate narcolepsy diagnosis. [ABSTRACT FROM AUTHOR]