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Study objectives: Fluid overload shifting from the legs to the upper airway during sleep promotes obstructive sleep apnea (OSA) and interventions targeting fluid attenuate OSA. Fluid shift has been previously measured by bioelectrical impedance, a complex and time-consuming technique not applicable in the daily clinical settings. The aim of this study is to evaluate the presence of clinically detectable fluid overload and shift and its association with OSA. Methods: Patients undergoing sleep study for suspected OSA were asked to report the presence of 11 signs/symptoms associated to excessive accumulation of fluid in different parts of the body at different times of the day. Results: Among 392 patients (male: 53%, median [interquartile range] age: 56years [1], body mass index, BMI: 29kg/m2 [2]) included in the study, 135 (34%) had moderate-to-severe OSA (apnea hypopnea index, AHI ≥ 15). Daytime fluid accumulation and nocturnal fluid shift, clinically detectable by patient-reported “evening sock marks,” “heavy legs during the day,” and “morning stuffed nose,” were prevalent in the entire population (46%, 43%, and 33%, respectively). In multivariate analysis, evening sock marks was an independent correlate of having an AHI ≥ 15, together with male sex, older age, and self-reported snoring and apneas. Conclusions: Clinically detectable fluid overload and shift are prevalent in patients addressed for suspected OSA, and evening sock marks, a marker for leg swelling, is an independent correlate of moderate-to-severe OSA. This sign might contribute to OSA diagnosis and identification of patients likely to be treated by interventions targeting fluid overload and shift.

Rationale: In patients with chronic obstructive pulmonary disease (COPD), increased activity of neck inspiratory muscles has been reported as a compensatory response to hyperinflation-related diaphragmatic dysfunction. The persistence of this activity during sleep could attenuate sleep-related hypoventilation and also negatively impact sleep and clinical outcomes.Objectives: To assess the persistence of neck-muscle activity during sleep in patients with COPD recovering from severe exacerbations (i.e., requiring hospitalization) and its impact on sleep quality and recurrence of exacerbations.Methods: Video polysomnography with neck-muscle EMG was performed in patients with COPD who were recovering from a severe exacerbation. The follow-up period lasted 6 months to record the next severe exacerbation.Measurements and Main Results: Twenty-nine patients were included in the study (median [25th-75th percentile] age, 71 [64-72] yr; 55% male; body mass index, 24 [21-29]; FEV1% predicted, 37 [29-45]; and BODE [body mass index, airflow obstruction, dyspnea, and exercise] index, 6 [5-7]). Twenty-six of these patients exhibited sleep-related neck-muscle activity, which was intermittent (limited to stage 3 sleep) in 17 and permanent throughout sleep in 9. α-Delta EEG activity during stage 3 sleep was observed in 87% of the patients. Compared with patients with no or intermittent neck-muscle activity, those with permanent neck-muscle activity showed more disrupted sleep, had experienced more exacerbations in the previous year, and suffered their next severe exacerbation earlier.Conclusions: Sleep-related neck-muscle activity occurs frequently in patients with COPD who are recovering from a severe exacerbation and seems to negatively affect sleep quality and prognosis; therefore, identification of this activity might improve COPD management after a severe exacerbation.

Objective: Automated voxel-based analysis methods are used to detect cortical hypometabolism typical of Alzheimer’s Disease (AD) on FDG-PET brain scans. We compared the accuracy of two clinically validated tools for their ability to identify those MCI subjects progressing to AD at followup, to evaluate the impact of the analysis method on FDG-PET diagnostic performance. Methods: SPMGrid and BRASS (Hermes Medical Solutions, Stockholm, Sweden) were tested on 131 MCI and elderly healthy controls from the EADC PET dataset. The concordance between the tools was tested by correlating the quantitative parameters (z- and t-values), calculated by the two software tools, and by measuring the topographical overlap of the abnormal regions (Dice score). Three independent expert readers blindly assigned a diagnosis based on the two map sets. We used conversion to AD dementia as the gold standard. Results: The t-map and z-map calculated with SPMGrid and BRASS, respectively, showed a good correlation (R > .50) for the majority of individual cases (128/131) and for the majority of selected regions of interest (ROIs) (98/116). The overlap of the hypometabolic patterns from the two tools was, however, poor (Dice score .36). The diagnostic performance was comparable, with BRASS showing significantly higher sensitivity (.82 versus .59) and SPMGrid showing higher specificity (.87 versus .52). Conclusion: Despite similar diagnostic performance in predicting conversion to AD in MCI subjects, the two tools showed significant differences, and the maps provided by the tools showed limited overlap. These results underline the urgency for standardization across FDG-PET analysis methods for their use in clinical practice.

New finding What is the central question of this study? Transition to supine posture induces an inspiratory load associated with cortical activation in awake healthy subjects. Some obstructive sleep apnoea patients exhibit this cortical activity in the sitting position contributing to the arousal-dependent compensation of their upper airway abnormalities. Does a transition to the supine posture in awake obstructive sleep apnoea patients increase this cortical activity? What is the main finding and its importance? The transition to supine posture induces a reduction in the cortical activity despite evidence of an increase in genioglossus activity, suggesting that genioglossus activation is not driven by cortical activity. Abstract The anatomy and mechanical properties of the upper airway (UA) depend on posture. Lying in a supine position causes cephalad fluid shift to the neck, thus narrowing the UA and predisposing the individual to obstructive sleep apnoea (OSA). Increased UA dilator muscle activity during wakefulness prevents the UA collapse but the underlying mechanism has not yet been elucidated. In the sitting position during wakefulness, some OSA patients exhibit preinspiratory cortical activity (preinspiratory potential, PIP) probably related to UA abnormalities. The aim of this study was to investigate changes in the preinspiratory cortical activity and UA dilator muscle in OSA patients during postural challenge. An electroencephalogram was used to detect PIP, and the genioglossus electromyographic activity and ventilation were analysed in 17 awake, male OSA patients while they were sitting, just after lying down, and then in response to leg positive pressure to enhance cephalad fluid shift. The prevalence of PIP decreased from 53% (sitting) to 12% (supine) (P = 0.002) in association with increased genioglossus activity (tonic from median (25th, 75th centiles) 2.3 (1.8, 2.8)% to 3.6 (1.7, 5.0)% of voluntary deglutition, P = 0.019; phasic from 2.3 (1.9, 2.8)% to 3.7 (2.0, 6.1)%, P = 0.024), and with increased transcutaneous carbon dioxide pressure (from 43.0 (42.4, 44.2) to 44.6 (43.5, 45.2) mmHg). No change was observed during leg-positive-pressure application. Moving from the sitting position to the supine position reduces respiratory-related premotor cortical activity in awake OSA patients. The concomitant increase in genioglossus activity, therefore, is not driven by cortical respiratory activity.

Sleep disorders are prevalent in patients with multiple sclerosis. In contrast, a frank increase of rapid eye movement (REM) sleep time is a rare phenomenon, mostly described in the context of REM sleep rebound (after sleep deprivation, abrupt withdrawal of antidepressants or neuroleptics, and during the first night of ventilation for severe sleep apnea), but not in link with specific brain lesions. We incidentally found an isolated, marked increase in REM sleep time (200 min, 40% of total sleep time, normative values: 18.2–20.3%) and in rapid eye movements density during REM sleep in a patient with a secondary progressive multiple sclerosis, associated with an anterior pontine demyelinating lesion on magnetic resonance imaging. This result suggests that a network blocking REM sleep in the pons has been damaged. CITATION: Zeidan S, Redolfi S, Papeix C, et al. Unexpected REM sleep excess associated with a pontine lesion in multiple sclerosis. J Clin Sleep Med. 2021;17(5):1117–1119.

International audience; Sleep apnea test (SAT) is a cost-effective approach to evaluate subjects without associated comorbidities suspected for obstructive sleep apnea (OSA), a disorder particularly common in obese subjects. The association of obesity with awake hypercapnia (carbon dioxide arterial pressure, PaCO2 ≥45 mmHg) defines the obesity-hypoventilation syndrome (OHS), which in turn results in increased morbidity and mortality compared to simple OSA. Isolated hypoventilation during sleep in obese patients (obesity-related sleep hypoventilation, ORSH) is now considered as an early stage of OHS. The aim of this study was to assess the performance of SAT in diagnosing OSA and predicting the presence of ORHS among patients with grade III obesity without awake hypercapnia. Methods: Over a 14-months period, patients with grade III obesity (body mass index≥40 kg/m 2) presenting moderate-to-severe OSA (apnea-hypopnea index [AHI]≥15) upon SAT and normal awake PaCO2 at arterial blood gas analysis, systematically underwent in-lab nocturnal polysomnography combined with transcutaneous carbon dioxide pressure (PtcCO2) monitoring. Results: Among 48 patients included in the study, 16 (33%) presented an AHI

Aims: To compare the incidence of intra-operative haemorrhage from ovarian vessels during ovariectomy (OV) and ovariohysterectomy (OVH) in dogs and cats performed by inexperienced surgeons using surgeon's and constrictor knots to ligate the ovarian pedicles.Methods: All client-owned female dogs (n = 51) and cats (n = 102) that presented for OV or OVH at two referral clinics in Belgium and France from January to June 2019 were included. Surgeries were performed by inexperienced surgeons under the supervision of diplomates or residents of the European College of Veterinary Surgeons. During routine and emergency OV or OVH one pedicle of each animal was ligated using a constrictor knot and the other with a surgeon's knot, the side assigned randomly. Time taken to perform each knot and the number of ligatures that resulted in intraoperative haemorrhage from the ovarian vessels were recorded. Body condition score (BCS) was recorded for 33 dogs and 22 cats.Results: The median time taken to perform constrictor knots in dogs (81 seconds), was longer than for surgeon's knots (69 seconds; p = 0.005). In cats, the median time taken to perform constrictor knots (109 seconds) was also longer than for surgeon's knots (90.5 seconds; p = 0.02).The number of dogs that had intra-operative haemorrhages from pedicles ligated with constrictor knots (2/102; 3.9%) was less than those ligated with surgeon's knots (10/102; 19.6%; p = 0.027). The median BCS of dogs that experienced haemorrhage (n = 8; median 5/9, min 3/9, max 7/9) was higher (p = 0.019) than that of dogs that did not experience haemorrhage (n = 25; median 4/9, min 3/9, max 8/9).There was no evidence (p = 1.0) of a difference in the proportion of cats that experienced intra-operative haemorrhage from pedicles ligated with constrictor knots (3/44; 6.8%) and those ligated with surgeon's knots (2/44; 4.5%). Two-thirds of the haemorrhages with constrictor knots were caused by pedicle rupture during tightening.Conclusions: The rate of intraoperative haemorrhage from the ovarian pedicle was lower when a constrictor knot was used compared to a surgeon's knot in dogs but not in cats. While the constrictor knot was more time consuming to tie this is not likely to have a clinical impact. Use of this knot by inexperienced surgeons in dogs may help to reduce the risk of intraoperative haemorrhage during OVH/OV.

Background Obstructive sleep apnea (OSA) is highly prevalent in conditions characterized by fluid overload. Chronic venous insufficiency (CVI) is associated to fluid overload that might interfere with OSA occurrence and severity. Methods A total of 180 patients with symptomatic CVI completed the Berlin questionnaire and were assessed for the presence of symptoms and signs of OSA and fluid shift. Results According to the Berlin questionnaire, 59 patients (33%) had high risk of OSA. The predictors of having a positive Berlin questionnaire were male sex, body mass index and symptoms possibly related to fluid shift. Conclusions Patients with CVI, a disease characterized by fluid overload, present high risk of OSA, which might be related to fluid shift.

IntroductionHippocampal volume is one of the main biomarkers of Alzheimer’s Dementia (AD). Over the years, advanced tools that performed automatic segmentation of Magnetic Resonance Imaging (MRI) T13D scans have been developed, such as FreeSurfer (FS) and ACM-Adaboost (AA). Hippocampal volume is considered abnormal when it is below the 5th percentile of the normative population. The aim of this study was to set norms, established from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) population, for hippocampal volume measured with FS v.6.0 and AA tools in the neuGRID platform (www.neugrid2.eu) and demonstrate their applicability for the Italian population.MethodsNorms were set from a large group of 545 healthy controls belonging to ADNI. For each pipeline, subjects with segmentation errors were discarded, resulting in 532 valid segmentations for FS and 421 for AA (age range 56–90 years). The comparability of ADNI and the Italian Brain Normative Archive (IBNA), representative of the Italian general population, was assessed testing clinical variables, neuropsychological scores and normalized hippocampal volumes. Finally, percentiles were validated using the Italian Alzheimer’s disease Repository Without Borders (ARWiBo) as external independent data set to evaluate FS and AA generalizability.ResultsHippocampal percentiles were checked with the chi-square goodness of fit test. P-values were not significant, showing that FS and AA algorithm distributions fitted the data well. Clinical, neuropsychological and volumetric features were similar in ADNI and IBNA (p > 0.01). Hippocampal volumes measured with both FS and AA were associated with age (p < 0.001). The 5th percentile thresholds, indicating left/right hippocampal atrophy were respectively: (i) below 3,223/3,456 mm3 at 56 years and 2,506/2,415 mm3 at 90 years for FS; (ii) below 4,583/4,873 mm3 at 56 years and 3,831/3,870 mm3 at 90 years for AA. The average volumes computed on 100 cognitively intact healthy controls (CN) selected from ARWiBo were close to the 50th percentiles, while those for 100 AD patients were close to the abnormal percentiles.DiscussionNorms generated from ADNI through the automatic FS and AA segmentation tools may be used as normative references for Italian patients with suspected AD.

Alzheimer's disease (AD) is the most frequent cause of dementia in the elderly. Few cases are familial (FAD), due to autosomal dominant mutations in presenilin-1 (PS1), presenilin-2 (PS2) or amyloid precursor protein (APP). The three proteins are involved in the generation of amyloid-beta (Aβ) peptides, providing genetic support to the hypothesis of Aβ pathogenicity. However, clinical trials focused on the Aβ pathway failed in their attempt to modify disease progression, suggesting the existence of additional pathogenic mechanisms. Ca2+ dysregulation is a feature of cerebral aging, with an increased frequency and anticipated age of onset in several forms of neurodegeneration, including AD. Interestingly, FAD-linked PS1 and PS2 mutants alter multiple key cellular pathways, including Ca2+ signaling. By generating novel tools for measuring Ca2+ in living cells, and combining different approaches, we showed that FAD-linked PS2 mutants significantly alter cell Ca2+ signaling and brain network activity, as summarized below.

International audience; Sleep-related breathing disorders, including sleep apnea and hypoxemia during sleep, are common in pulmonary arterial hypertension, but the underlying mechanisms remain unknown. Overnight fluid shift from the legs to the upper airway and to the lungs promotes obstructive and central sleep apnea, respectively, in fluid-retaining states. The main objective was to evaluate if overnight rostral fluid shift from the legs to the upper part of the body is associated with sleep-related breathing disorders in pulmonary arterial hypertension. In a prospective study, a group of stable patients with idiopathic, heritable, related to drugs, toxins, or treated congenital heart disease pulmonary arterial hypertension underwent a polysomnography and overnight fluid shift measurement by bioelectrical impedance in the month preceding or following a one-day hospitalization according to regular pulmonary arterial hypertension follow-up schedule with a right heart catheterization. Results show that among 15 patients with pulmonary arterial hypertension (women: 87%; median (25-75th percentiles); age: 40 (32-61) years; mean pulmonary arterial pressure 56 (46-68) mmHg; pulmonary vascular resistance 8.8 (6.4-10.1) Wood units), two patients had sleep apnea and eight (53%) had hypoxemia during sleep without apnea. The overnight rostral fluid shift was 168 (118-263) mL per leg. Patients with hypoxemia during sleep had a greater fluid shift (221 (141- 361) mL) than those without hypoxemia (118 (44-178) mL, p = 0.045). In conclusion, this pilot study suggests that hypoxemia during sleep is associated with overnight rostral fluid shift in pulmonary arterial hypertension.

Normative modelling is an emerging method for quantifying how individuals deviate from the healthy populational pattern. Several machine learning models have been implemented to develop normative models to investigate brain disorders, including regression, support vector machines and Gaussian process models. With the advance of deep learning technology, the use of deep neural networks has also been proposed. In this study, we assessed normative models based on deep autoencoders using structural neuroimaging data from patients with Alzheimer’s disease (n = 206) and mild cognitive impairment (n = 354). We first trained the autoencoder on an independent dataset (UK Biobank dataset) with 11,034 healthy controls. Then, we estimated how each patient deviated from this norm and established which brain regions were associated to this deviation. Finally, we compared the performance of our normative model against traditional classifiers. As expected, we found that patients exhibited deviations according to the severity of their clinical condition. The model identified medial temporal regions, including the hippocampus, and the ventricular system as critical regions for the calculation of the deviation score. Overall, the normative model had comparable cross-cohort generalizability to traditional classifiers. To promote open science, we are making all scripts and the trained models available to the wider research community.

Alzheimer’s disease (AD) is a neurodegenerative disorder which spans several years from preclinical manifestations to dementia. In recent years, interest in the application of machine learning (ML) algorithms to personalized medicine has grown considerably, and a major challenge that such models face is the transferability from the research settings to clinical practice. The objective of this work was to demonstrate the transferability of the Subtype and Stage Inference (SuStaIn) model from well-characterized research data set, employed as training set, to independent less-structured and heterogeneous test sets representative of the clinical setting. The training set was composed of MRI data of 1043 subjects from the Alzheimer’s disease Neuroimaging Initiative (ADNI), and the test set was composed of data from 767 subjects from OASIS, Pharma-Cog, and ViTA clinical datasets. Both sets included subjects covering the entire spectrum of AD, and for both sets volumes of relevant brain regions were derived from T1-3D MRI scans processed with Freesurfer v5.3 cross-sectional stream. In order to assess the predictive value of the model, subpopulations of subjects with stable mild cognitive impairment (MCI) and MCIs that progressed to AD dementia (pMCI) were identified in both sets. SuStaIn identified three disease subtypes, of which the most prevalent corresponded to the typical atrophy pattern of AD. The other SuStaIn subtypes exhibited similarities with the previously defined hippocampal sparing and limbic predominant atrophy patterns of AD. Subject subtyping proved to be consistent in time for all cohorts and the staging provided by the model was correlated with cognitive performance. Classification of subjects on the basis of a combination of SuStaIn subtype and stage, mini mental state examination and amyloid-β1-42 cerebrospinal fluid concentration was proven to predict conversion from MCI to AD dementia on par with other novel statistical algorithms, with ROC curves that were not statistically different for the training and test sets and with area under curve respectively equal to 0.77 and 0.76. This study proves the transferability of a SuStaIn model for AD from research data to less-structured clinical cohorts, and indicates transferability to the clinical setting.

Heterogeneity of cohorts, in terms of inclusion criteria, design of follow-up visits and batteries of cognitive assessments, hinders any thorough comparisons between them. For that reason, we build a cross-cohort model of cognitive decline that can be personalized to any patient, allowing to impute partially or totally missing scores. This enables to compare at an individual level disease progression of subjects from different cohorts, with a temporal realignment and regarding a broader set of biomarkers.

Study Objectives: In heart failure (HF), we observed two patterns of hyperpnea during Cheyne-Stokes respiration with central sleep apnea (CSR-CSA): a positive pattern where end-expiratory lung volume remains at or above functional residual capacity, and a negative pattern where it falls below functional residual capacity. We hypothesized the negative pattern is associated with worse HF. Methods: Patients with HF underwent polysomnography. During CSR-CSA, hyperpnea, apnea-hyperpnea cycle, and lung to finger circulation times (LFCT) were measured. Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration and left ventricular ejection fraction (LVEF) were assessed. Results: Of 33 patients with CSR-CSA (31 men, mean age 68 years), 9 had a negative hyperpnea pattern. There was no difference in age, body mass index, and apnea-hypopnea index between groups. Patients with a negative pattern had longer hyperpnea time (39.5 ± 6.4 versus 25.8 ± 5.9 seconds, P < .01), longer cycle time (67.8 ± 15.9 versus 51.7 ± 9.9 seconds, P < .01), higher NT-proBNP concentrations (2740 [6769] versus 570 [864] pg/ml, P = .01), and worse New York Heart Association class (P = .02) than those with a positive pattern. LFCT and LVEF did not differ between groups. Conclusions: Patients with HF and a negative CSR-CSA pattern have evidence of worse cardiac function than those with a positive pattern. Greater positive expiratory pressure during hyperpnea is likely generated during the negative pattern and might support stroke volume in patients with worse cardiac function. Commentary: A commentary on this article appears in this issue on page 1227. Clinical Trial Registration: The trial is registered with Current Controlled Trials (www.controlled-trials.com; ISRCTN67500535) and Clinical Trials (www. clinicaltrials.gov; NCT01128816).

New Findings: What is the central question of this study? Moving to supine induces upper airway modifications and a fluid shift to the neck, which represent inspiratory load that predisposes to upper airway collapse.Is there cortical participation in the response to the load induced by transition to a supine posturein awake healthy subjects? What is the main finding and its importance? Moving to supine induces transient cortical activation in awake healthy subjects, with greater fluid shift, supporting possible cortical participation in the response to upper airway load induced by transition to a supine posture. Our findings open new perspectives in the understanding of the pathogenesis of obstructive sleep apnoea. Abstract: Moving from sitting upright to lying supine causes anatomical modifications and a fluid shift to the neck, which represent inspiratory loads that predispose to upper airway collapse. The pre-inspiratory potential (PIP) corresponds to the cortical activity observed during inspiratory load. In the sitting position during wakefulness, some obstructive sleep apnoea patients exhibit PIP, probably in relationship to upper airway abnormalities. The aim of this study was to investigate whether moving to the supine position induces respiratory-related cortical activation (PIP) in awake healthy subjects. The ECG was analysed to detect PIP, and EMG activity of the genioglossus muscle and ventilation were measured in the sitting position, immediately after moving to the supine position, and during application of leg positive pressure in the supine position to promote fluid shift, which was measured by bioelectrical impedance. Twenty-four subjects were included. From sitting to lying, PIP prevalence increased from 1/24 to 11/24 (P=0.002), and ventilation decreased with no change in genioglossus activity. The fluid shift from sitting to supine was higher in the subjects exhibiting PIP while supine compared with the subjects without PIP [median (25th; 75th centiles) 440(430; 520) versus 320(275; 385)ml, P=0.018], without any other differences. From before to during leg positive pressure, PIP disappeared (P=0.006). These results indicate that moving from sitting to lying induces transient respiratory-related cortical activity in awake healthy subjects with greater fluid shift, supporting possible cortical participation in the response to upper airway loading induced by moving from sitting upright to lying supine. This study offers new perspectives in the understanding of obstructive sleep apnoea pathogenesis.

Background: After a stroke, up to three-quarters of acute and subacute stroke survivors exhibit cognitive impairment, with a significant impact on functional recovery, quality of life, and social engagement. Robotic therapy has shown its effectiveness on motor recovery, but its effectiveness on cognitive recovery has not fully investigated. Objective: This study aims to assess the impact of a technological rehabilitation intervention on cognitive functions in patients with stroke, using a set of three robots and one sensor-based device for upper limb rehabilitation. Methods: This is a pilot study in which 51 patients were enrolled. An upper limb rehabilitation program was performed using three robots and one sensor-based device. The intervention comprised motor/cognitive exercises, especially selected among the available ones to train also cognitive functions. Patients underwent 30 rehabilitation sessions, each session lasting 45 minutes, 5 days a week. Patients were assessed before and after the treatment with several cognitive tests (Oxford Cognitive Scale, Symbol Digit Modalities Test, Digit Span, Rey–Osterrieth Complex Figure, Tower of London, and Stroop test). In addition, motor (Fugl–Meyer Assessment and Motricity Index) and disability (modified Barthel Index) scales were used. Results: According to the Oxford Cognitive Scale domains, a significant percentage of patients exhibited cognitive deficits. Excluding perception (with only one patient impaired), the domain with the lowest percentage of patients showing a pathological score was praxis (about 25%), while the highest percentage of impaired patients was found in calculation (about 70%). After the treatment, patients improved in all the investigated cognitive domains, as measured by the selected cognitive assessment scales. Moreover, motor and disability scales confirmed the efficacy of robotics on upper limb rehabilitation in patients with stroke. Conclusions: This explorative study suggests that robotic technology can be used to combine motor and cognitive exercises in a unique treatment session. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04164381.

The lack of efficient targeting strategies poses significant limitations on the effectiveness of chemotherapeutic treatments. This issue also affects drug-loaded nanocarriers, reducing nanoparticles cancer cell uptake. We report on the fabrication and in vitro characterization of doxorubicin-loaded magnetic liposomes for localized treatment of liver malignancies. Colloidal stability, superparamagnetic behavior and efficient drug loading of our formulation were demonstrated. The application of an external magnetic field guaranteed enhanced nanocarriers cell uptake under cell medium flow in correspondence of a specific area, as we reported through in vitro investigation. A numerical model was used to validate experimental data of magnetic targeting, proving the possibility of accurately describing the targeting strategy and predict liposomes accumulation under different environmental conditions. Finally, in vitro studies on HepG2 cancer cells confirmed the cytotoxicity of drug-loaded magnetic liposomes, with cell viability reduction of about 50% and 80% after 24 h and 72 h of incubation, respectively. Conversely, plain nanocarriers showed no anti-proliferative effects, confirming the formulation safety. Overall, these results demonstrated significant targeting efficiency and anticancer activity of our nanocarriers and superparamagnetic nanoparticles entrapment could envision the theranostic potential of the formulation. The proposed magnetic targeting study could represent a valid tool for pre-clinical investigation regarding the effectiveness of magnetic drug targeting.

Backgrounds To explain the excess cardiovascular mortality observed in the SERVE-HF study, it was hypothesized that the high-pressure ASV default settings used lead to inappropriate ventilation, cascading negative consequences (i.e. not only pro-arrythmogenic effects through metabolic/electrolyte abnormalities, but also lower cardiac output). The aims of this study are: i) to describe ASV-settings for long-term ASV-populations in real-life conditions; ii) to describe the associated minute-ventilations (MV) and therapeutic pressures for servo-controlled-flow versus servo-controlled-volume devices (ASV-F Philips®-devices versus ASV-V ResMed®-devices). Methods The OTRLASV-study is a cross-sectional, 5-centre study including patients who underwent ASV-treatment for at least 1 year. The eight participating clinicians were free to adjust ASV settings, which were compared among i) initial diagnosed sleep-disordered-breathing (SBD) groups (Obstructive-Sleep-Apnea (OSA), Central-Sleep-Apnea (CSA), Treatment-Emergent-Central-Sleep-Apnea (TECSA)), and ii) unsupervised groups (k-means clusters). To generate these clusters, baseline and follow-up variables were used (age, sex, body mass index (BMI), initial diagnosed Obstructive-Apnea-Index, initial diagnosed Central-Apnea-Index, Continuous-Positive-Airway-Pressure used before ASV treatment, presence of cardiopathy, and presence of a reduced left-ventricular-ejection-fraction (LVEF)). ASV-data were collected using the manufacturer’s software for 6 months. Results One hundred seventy-seven patients (87.57% male) were analysed with a median (IQ25–75) initial Apnea-Hypopnea-Index of 50 (38–62)/h, an ASV-treatment duration of 2.88 (1.76–4.96) years, 61.58% treated with an ASV-V. SDB groups did not differ in ASV settings, MV or therapeutic pressures. In contrast, the five generated k-means clusters did (generally described as follows: (C1) male-TECSA-cardiopathy, (C2) male-mostly-CSA-cardiopathy, (C3) male-mostly-TECSA-no cardiopathy, (C4) female-mostly-elevated BMI-TECSA-cardiopathy, (C5) male-mostly-OSA-low-LVEF). Of note, the male-mostly-OSA-low-LVEF-cluster-5 had significantly lower fixed end-expiratory-airway-pressure (EPAP) settings versus C1 (p = 0.029) and C4 (p = 0.007). Auto-EPAP usage was higher in the male-mostly-TECSA-no cardiopathy-cluster-3 versus C1 (p = 0.006) and C2 (p p = 0.002) and ASV-V (p Conclusions Real-life ASV settings are associated with combinations of baseline and follow-up variables wherein cardiological variables remain clinically meaningful. At the patient level, a hyperventilation risk exists regardless of cluster or ASV-monitoring type, spotlighting a future role of MV-telemonitoring in the interest of patient-safety. Trial registration The OTRLASV study was registered on ClinicalTrials.gov (Identifier: NCT02429986). 1 April 2015.

A 40-y-old woman with severe acute respiratory syndrome coronavirus 2 infection developed neurologic manifestations (confusion, agitation, seizures, dyskinesias, and parkinsonism) a few weeks after the onset of severe acute respiratory syndrome. MRI and cerebrospinal fluid analyses were unremarkable, but 18F-FDG PET/CT showed limbic and extralimbic hypermetabolism. A full recovery, alongside 18F-FDG normalization in previously hypermetabolic areas, was observed after intravenous immunoglobulin administration.

A problem of current agriculture is the large amount of agrochemicals used to boost production due to their cost and the environmental pollution they cause. A partial solution to this problem consists in developing selective spraying techniques through the measurement of a green index that allows the selection of the precise amount of pesticide to be applied according to the specific conditions of each part of the field. Some of the problems of the existing systems are the inability to discriminate between types of vegetation and to pinpoint its location, since they only detect general patches of vegetation. In this work, we introduce a system prototype capable of measuring the presence of vegetation in an area using low-cost devices combined with current computer vision techniques. The system allows to generate a mask with the presence of vegetation in a certain area and it is also capable of distinguishing between different materials unlike current methods, which only allow to distinguish between green and non-green areas. The presented method opens the door to future research which can allow distinguishing between crops and weeds to make an even more selective application. The output of the system can be used also to design another type of weeding method that is not based on the application of agrochemicals.

Alzheimer’s disease (AD) is the most common form of dementia. Even though most AD cases are sporadic, a small percentage is familial due to autosomal dominant mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes. AD mutations contribute to the generation of toxic amyloid β (Aβ) peptides and the formation of cerebral plaques, leading to the formulation of the amyloid cascade hypothesis for AD pathogenesis. Many drugs have been developed to inhibit this pathway but all these approaches currently failed, raising the need to find additional pathogenic mechanisms. Alterations in cellular calcium (Ca2+) signaling have also been reported as causative of neurodegeneration. Interestingly, Aβ peptides, mutated presenilin-1 (PS1), and presenilin-2 (PS2) variously lead to modifications in Ca2+ homeostasis. In this contribution, we focus on PS2, summarizing how AD-linked PS2 mutants alter multiple Ca2+ pathways and the functional consequences of this Ca2+ dysregulation in AD pathogenesis.

Introduction: With the shift of research focus to personalized medicine in Alzheimer's Dementia (AD), there is an urgent need for tools that are capable of quantifying a patient's risk using diagnostic biomarkers. The Medical Informatics Platform (MIP) is a distributed e-infrastructure federating large amounts of data coupled with machine-learning (ML) algorithms and statistical models to define the biological signature of the disease. The present study assessed (i) the accuracy of two ML algorithms, i.e., supervised Gradient Boosting (GB) and semi-unsupervised 3C strategy (Categorize, Cluster, Classify-CCC) implemented in the MIP and (ii) their contribution over the standard diagnostic workup. Methods: We examined individuals coming from the MIP installed across 3 Italian memory clinics, including subjects with Normal Cognition (CN, n = 432), Mild Cognitive Impairment (MCI, n = 456), and AD (n = 451). The GB classifier was applied to best discriminate the three diagnostic classes in 1,339 subjects, and the CCC strategy was used to refine the classical disease categories. Four dementia experts provided their diagnostic confidence (DC) of MCI conversion on an independent cohort of 38 patients. DC was based on clinical, neuropsychological, CSF, and structural MRI information and again with addition of the outcome from the MIP tools. Results: The GB algorithm provided a classification accuracy of 85% in a nested 10-fold cross-validation for CN vs. MCI vs. AD discrimination. Accuracy increased to 95% in the holdout validation, with the omission of each Italian clinical cohort out in turn. CCC identified five homogeneous clusters of subjects and 36 biomarkers that represented the disease fingerprint. In the DC assessment, CCC defined six clusters in the MCI population used to train the algorithm and 29 biomarkers to improve patients staging. GB and CCC showed a significant impact, evaluated as +5.99% of increment on physicians' DC. The influence of MIP on DC was rated from "slight" to "significant" in 80% of the cases. Discussion: GB provided fair results in classification of CN, MCI, and AD. CCC identified homogeneous and promising classes of subjects via its semi-unsupervised approach. We measured the effect of the MIP on the physician's DC. Our results pave the way for the establishment of a new paradigm for ML discrimination of patients who will or will not convert to AD, a clinical priority for neurology.

Presenilin-2 (PS2) is one of the three proteins that are dominantly mutated in familial Alzheimer’s disease (FAD). It forms the catalytic core of the γ-secretase complex—a function shared with its homolog presenilin-1 (PS1)—the enzyme ultimately responsible of amyloid-β (Aβ) formation. Besides its enzymatic activity, PS2 is a multifunctional protein, being specifically involved, independently of γ-secretase activity, in the modulation of several cellular processes, such as Ca2+ signaling, mitochondrial function, inter-organelle communication, and autophagy. As for the former, evidence has accumulated that supports the involvement of PS2 at different levels, ranging from organelle Ca2+ handling to Ca2+ entry through plasma membrane channels. Thus FAD-linked PS2 mutations impact on multiple aspects of cell and tissue physiology, including bioenergetics and brain network excitability. In this contribution, we summarize the main findings on PS2, primarily as a modulator of Ca2+ homeostasis, with particular emphasis on the role of its mutations in the pathogenesis of FAD. Identification of cell pathways and molecules that are specifically targeted by PS2 mutants, as well as of common targets shared with PS1 mutants, will be fundamental to disentangle the complexity of memory loss and brain degeneration that occurs in Alzheimer’s disease (AD).

IntroductionPreventing in-flight hypoxia in pilots is typically achieved by wearing oxygen masks. These masks must be as comfortable as possible to allow prolonged and repeated use. The consequences of mask-induced facial contact pressure have been extensively studied, but little is known about mask-induced breathing discomfort. Because breathlessness is a strong distractor and engages cerebral resources, it could negatively impact flying performances.MethodsSeventeen volunteers (age 20–32) rated respiratory discomfort while breathing with no mask and with two models of quick-donning full-face crew oxygen masks with regulators (mask A, mask B). Electroencephalographic recordings were performed to detect a putative respiratory-related cortical activation in response to inspiratory constraint (experiment 1, n=10). Oxygen consumption was measured using indirect calorimetry (experiment 2, n=10).ResultsWith mask B, mild respiratory discomfort was reported significantly more frequently than with no mask or mask A (experiment 1: median respiratory discomfort on visual analogue scale 0.9 cm (0.5–1.4), experiment 1; experiment 2: 2 cm (1.7–2.9)). Respiratory-related cortical activation was present in 1/10 subjects with no mask, 1/10 with mask A and 6/10 with mask B (significantly more frequently with mask B). Breathing pattern, sigh frequency and oxygen consumption were not different.ConclusionsIn a laboratory setting, breathing through high-end aeronautical full-face crew oxygen masks can induce mild breathing discomfort and activate respiratory-related cortical networks. Whether or not this can occur in real-life conditions and have operational consequences remains to be investigated. Meanwhile, respiratory psychometric and neuroergonomic approaches could be worth integrating to masks development and evaluation processes.

Background With the shift of research focus towards the pre-dementia stage of Alzheimer’s disease (AD), there is an urgent need for reliable, non-invasive biomarkers to predict amyloid pathology. The aim of this study was to assess whether easily obtainable measures from structural MRI, combined with demographic data, cognitive data and apolipoprotein E (APOE) ε4 genotype, can be used to predict amyloid pathology using machine-learning classification. Methods We examined 810 subjects with structural MRI data and amyloid markers from the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery study, including subjects with normal cognition (CN, n = 337, age 66.5 ± 7.2, 50% female, 27% amyloid positive), mild cognitive impairment (MCI, n = 375, age 69.1 ± 7.5, 53% female, 63% amyloid positive) and AD dementia (n = 98, age 67.0 ± 7.7, 48% female, 97% amyloid positive). Structural MRI scans were visually assessed and Freesurfer was used to obtain subcortical volumes, cortical thickness and surface area measures. We first assessed univariate associations between MRI measures and amyloid pathology using mixed models. Next, we developed and tested an automated classifier using demographic, cognitive, MRI and APOE ε4 information to predict amyloid pathology. A support vector machine (SVM) with nested 10-fold cross-validation was applied to identify a set of markers best discriminating between amyloid positive and amyloid negative subjects. Results In univariate associations, amyloid pathology was associated with lower subcortical volumes and thinner cortex in AD-signature regions in CN and MCI. The multi-variable SVM classifier provided an area under the curve (AUC) of 0.81 ± 0.07 in MCI and an AUC of 0.74 ± 0.08 in CN. In CN, selected features for the classifier included APOE ε4, age, memory scores and several MRI measures such as hippocampus, amygdala and accumbens volumes and cortical thickness in temporal and parahippocampal regions. In MCI, the classifier including demographic and APOE ε4 information did not improve after additionally adding imaging measures. Conclusions Amyloid pathology is associated with changes in structural MRI measures in CN and MCI. An automated classifier based on clinical, imaging and APOE ε4 data can identify the presence of amyloid pathology with a moderate level of accuracy. These results could be used in clinical trials to pre-screen subjects for anti-amyloid therapies.

This work deals with the formation kinetic of tungsten (W) blisters under smooth plasma conditions, i.e. low hydrogen flux and energy in order to analyze the first stages of their formation. In addition, we focus on determining the W grain orientation where blisters grow preferentially. For this purpose, mirror-polished polycrystalline tungsten samples were exposed to hydrogen plasma under fixed hydrogen flux of 2.2 × 1020 m−2 s−1, with a fluence in the range of ~ 1024 m−2, ion energy of ~ 20, 120 and 220 eV, and sample surface temperature of ~ 500 K. The formation of blisters at the surface was investigated using SEM, AFM and EBSD to determine the size, the distribution and the orientation of grain where blisters are formed, respectively. The critical fluence for initiating blisters was established around 2.3 × 1024 m−2. The evolution of blister size distribution and density is discussed as function of fluence and ion energy. At lower ion energy, i.e. 20 eV, only nanoblisters (less than 150 nm) are observed whatever the fluence value (1.5 and 2.3 × 1024 m−2). At higher ion energy i.e. 120 and 220 eV, micrometric (~ few to tens of µm) blisters are observed and their density highly depends on fluence. We show that blisters can also be formed on (001) oriented grains contrarily to previous results from the literature where the (111) orientation seemed more favorable. Such information is of importance for tungsten based fusion tokamak operation and design.

International audience; Sleep apnea is a common condition associated with increased morbidity and mortality. Continuous positive airway pressure and oral appliances are efficient for treating sleep apnea; however, they are often poorly tolerated. Therefore, alternative therapies are needed. Overnight rostral fluid shift has been implicated in the pathogenesis of sleep apnea, particularly in conditions associated with fluid overload. Fluid shift predisposes to both obstructive and central sleep apnea, with the type of sleep apnea being related to whether the fluid shifts from the legs into the neck or chest, respectively. The amount of fluid that shifts from the legs to the upper part of the body at night is correlated with the severity of sleep apnea. As a result of this observation, it has been suggested that the prevention of overnight fluid shift may reduce sleep apnea severity. It has recently been shown that interventions targeting fluid overload and daytime fluid accumulation in the legs consistently attenuate nocturnal fluid shift and sleep apnea, as greater reductions in fluid shift are correlated with greater reductions in sleep apnea severity. This review will focus on interventions that counteract fluid shift, such as diuretics, ultrafiltration/dialysis, physical activity, compression stockings and salt/fluid restriction, which have been shown to have efficacy in reducing sleep apnea severity.

Calcium (Ca2+) signaling coordinates are crucial processes in brain physiology. Particularly, fundamental aspects of neuronal function such as synaptic transmission and neuronal plasticity are regulated by Ca2+, and neuronal survival itself relies on Ca2+-dependent cascades. Indeed, impaired Ca2+ homeostasis has been reported in aging as well as in the onset and progression of neurodegeneration. Understanding the physiology of brain function and the key processes leading to its derangement is a core challenge for neuroscience. In this context, Ca2+ imaging represents a powerful tool, effectively fostered by the continuous amelioration of Ca2+ sensors in parallel with the improvement of imaging instrumentation. In this review, we explore the potentiality of the most used animal models employed for Ca2+ imaging, highlighting their application in brain research to explore the pathogenesis of neurodegenerative diseases.

O uso inapropriado de um medicamento pode ocasionar danos e problemas de saúde, neste contexto a conciliação de medicamentos é um processo que visa identificar identificar e comparar os medicamentos de uso domiciliar para garantir melhor assistência ao paciente. Neste contexto, o presente estudo teve como objetivo comparar discrepâncias, tanto as intencionais, quanto as não-intencionais encontradas nos pacientes admitidos na clínica cirúrgica de um hospital público. Através de entrevista estruturada, realizada antes da admissão e comparada com as prescrições após a admissão. A classificação das discrepâncias foi em intencionais e não-intencionais. Em cem (100) pacientes analisados, cinquenta e nove (59) apresentaram alguma discrepância. Desses, a maioria era do sexo feminino (68%), com mediana de idade de 59 anos. Das cinquenta e sete (57) discrepâncias não-intencionais encontradas, 78,9% ocorreram por omissão, e 15,8% por dose. Já as intencionais foram sessenta e seis (66), sendo 84,9% por omissão, devido a protocolos estabelecidos pelo hospital. Sendo assim, o estudo demonstra uma alta taxa de discrepâncias encontradas nos pacientes, sugerindo a importância da implantação da conciliação realizada pelo farmacêutico visando reduzir o número de problemas relacionados à farmacoterapia, para garantir a segurança do paciente.

Introduction Both types of sleep-disordered breathing (SDB), obstructive and central sleep apnoea (OSA and CSA, respectively), are common in patients with heart failure and reduced ejection fraction (HFrEF). In such patients, SDB is associated with increased cardiovascular morbidity and mortality but it remains uncertain whether treating SDB by adaptive servo-ventilation (ASV) in such patients reduces morbidity and mortality. Aim ADVENT-HF is designed to assess the effects of treating SDB with ASV on morbidity and mortality in patients with HFrEF. Methods ADVENT-HF is a multicentre, multinational, randomized, parallel-group, open-label trial with blinded assessment of endpoints of standard medical therapy for HFrEF alone vs. with the addition of ASV in patients with HFrEF and SDB. Patients with a history of HFrEF undergo echocardiography and polysomnography. Those with a left ventricular ejection fraction ≤45% and SDB (apnoea–hypopnoea index ≥15) are eligible. SDB is stratified into OSA with ≥50% of events obstructive or CSA with >50% of events central. Those with OSA must not have excessive daytime sleepiness (Epworth score of ≤10). Patients are then randomized to receive or not receive ASV. The primary outcome is the composite of all-cause mortality, cardiovascular hospital admissions, new-onset atrial fibrillation requiring anti-coagulation but not hospitalization, and delivery of an appropriate discharge from an implantable cardioverter-defibrillator not resulting in hospitalization during a maximum follow-up time of 5 years. Conclusion The ADVENT-HF trial will help to determine whether treating SDB by ASV in patients with HFrEF improves morbidity and mortality.

International audience; To understand the mechanisms of N3 sleep interruptions in patients with sleepwalking episodes and/or sleep terrors (SW/ST), we evaluated whether autonomic reactions preceded or accompanied behavioural arousals from NREM sleep stage N3. In 20 adult patients with SW/ST and 20 matched controls without parasomnia, heart rate and pulse wave amplitude were measured beat-to-beat during the 10 beats preceding and during the 15 beats succeeding a motor arousal from N3 sleep. Respiratory rate and amplitude were measured during the same 25 successive beats. In patients with SW/ST, the N3 arousals were associated with a 33% increase in heart rate, a 57% decrease in pulse wave amplitude (indicating a major vasoconstriction), a 24% increase in respiratory rate and a doubling of respiratory amplitude. Notably, tachycardia and vasoconstriction started 4 s before motor arousals. A similar profile (tachycardia and vasoconstriction gradually increasing from the 4 s preceding arousal and post-arousal increase of respiratory amplitude, but no polypnea) was also observed, with a lower amplitude, during the less frequent 38 quiet N3 arousals in control subjects. Parasomniac arousals were associated with greater tachycardia, vasoconstriction and polypnea than quiet arousals, with the same pre-arousal gradual increases in heart rate and vasoconstriction. Autonomic arousal occurs 4 s before motor arousal from N3 sleep in patients with SW/ST (with a higher adrenergic reaction than in controls), suggesting that an alarming event during sleep (possibly a worrying sleep mentation or a local subcortical arousal) causes the motor arousal.

Backgrounds As a consequence of the increased mortality observed in the SERVE-HF study, many questions concerning the safety and rational use of ASV in other indications emerged. The aim of this study was to describe the clinical characteristics of ASV-treated patients in real-life conditions. Methods The OTRLASV-study is a prospective, 5-centre study including patients who underwent ASV-treatment for at least 1 year. Patients were consecutively included in the study during the annual visit imposed for ASV-reimbursement renewal. Results 177/214 patients were analysed (87.57% male) with a median (IQ25–75) age of 71 (65–77) years, an ASV-treatment duration of 2.88 (1.76–4.96) years, an ASV-usage of 6.52 (5.13–7.65) hours/day, and 54.8% were previously treated via continuous positive airway pressure (CPAP). The median Epworth Scale Score decreased from 10 (6–13.5) to 6 (3–9) (p p 45% in 92.7% of patients. Associated comorbidities/etiologies were cardiac in nature for 75.7% of patients (neurological for 12.4%, renal for 4.5%, opioid-treatment for 3.4%). 9.6% had idiopathic central-sleep-apnea. 6.2% of the patients were hospitalized the year preceding the study for cardiological reasons. In the 6 months preceding inclusion, night monitoring (i.e. polygraphy or oximetry during ASV usage) was performed in 34.4% of patients, 25.9% of whom required a subsequent setting change. According to multivariable, logistic regression, the variables that were independently associated with poor adherence (ASV-usage ≤4 h in duration) were TECSA group versus CSA group (p = 0.010), a higher Epworth score (p = 0.019) and lack of a night monitoring in the last 6 months (p Conclusions In real-life conditions, ASV-treatment is often associated with high cardiac comorbidities and high compliance. Future research should assess how regular night monitoring may optimize devices settings and patient management. Trial registration The OTRLASV study is registered on ClinicalTrials.gov (Identifier: NCT02429986) on 1 April 2015.

Aluminum samples have been exposed to a hydrogen plasma generated by a low-pressure – high-density microwave reactor. Aluminum has been chosen as a surrogate for Beryllium. The fluence was kept below 4 × 1024 ions/m2, in order to study the first steps of nucleation and growth of surface and bulk defects, i.e. blisters and bubbles. Experimental analyzes and macroscopic rate equation (MRE) modeling on poly- and single- crystals were made to investigate the role played by grains boundaries in the hydrogen retention. Temperature programmed desorption (TPD) on Al poly-crystals revealed the production of aluminum hydrides (alanes) as majority species in the desorption flux. Comparison of microscopy observations for three different single-crystal orientations (〈100〉, 〈110〉 and 〈111〉) allowed to determine preferential orientations able to attenuate the formation of blisters. Keywords: Blistering, Aluminum, Hydrogen inventory

NIA-AA diagnostic criteria include volumetric or visual rating measures of hippocampal atrophy (HA) as a diagnostic biomarker of Alzheimer's disease (AD). We aimed to determine its utility as a diagnostic biomarker for early onset Alzheimer's disease (EOAD) by assessing Medial Temporal Atrophy (MTA) and hippocampal volume (HV) determination. MTA score and HV quantified by FreeSurfer were assessed in 140 (aged ≤65) subjects with biomarker supported diagnosis: 38 amnesic (A-EOAD), 20 non-amnesic (NA-EOAD), 30 late onset AD (LOAD), 20 fronto-temporal dementia (FTD) and 32 healthy controls (HC). The results showed that the proportion of MTA ≥ 1.5 was higher on LOAD and FTD than EOAD and HC but none of the MTA thresholds (≥1, ≥1.5 and ≥ 2) showed acceptable diagnostic accuracy. LOAD had lower HV than the other groups. A-EOAD HV was lower than NA-EOAD and HC but equal to FTD. The 6258 mm3 cut-off showed good diagnostic accuracy between A-EOAD and HC. Both tools showed a moderate inverse correlation. In conclusion, MTA has a limited diagnostic utility as an EOAD biomarker as it does not discriminate AD from FTD or HC in initial symptomatic stages. HV may discriminate A-EOAD from HC but not from FTD., Highlights • FTD had higher MTA scores than AD patients. • MTA scores visual assessment had low diagnostic performance in EOAD. • Amnesic EOAD patients had lower hippocampal volume than the non-amnesic ones. • Quantitative assessment only discriminate between amnesic EOAD from controls.