Medical hypnosis mitigates laboratory dyspnoea in healthy humans: a randomised, controlled experimental trial.

QUESTION: Dyspnoea persisting despite treatments of underlying causes requires symptomatic approaches. Medical hypnosis could provide relief without the untoward effects of pharmacological approaches. We addressed this question through experimentally induced dyspnoea in healthy humans (inspiratory threshold loading -excessive inspiratory effort- and carbon dioxide stimulation -air hunger-) MATERIAL AND METHODS: 20 volunteers (10 women, 21-40) were studied on 4 separate days. The order of the visits was randomised in two steps, firstly "inspiratory threshold loading first" versus "carbon dioxide first" group (n=10 in each group), secondly "medical hypnosis first" versus "visual distraction first" subgroup (n=5 in each subgroup). Each visit comprised three 5-minutes periods (reference, intervention, washout) during which participants used visual analog scales to rate dyspnoea's sensory and affective dimensions and after which they completed the Multidimensional Dyspnea Profile. RESULTS: Medical hypnosis reduced both dimensions of dyspnoea significantly more than visual distraction (inspiratory threshold loading: sensory reduction after 5 min 34% of full VAS versus 8% -p=0.0042-; affective reduction 17.6% versus 2.4% -p=0.044-; carbon dioxide; sensory reduction after 5 min 36.9% versus 3% -p=0.0015-; affective reduction 29.1% versus 8.7% -p=0.0023-). The Multidimensional Dyspnea Profile showed more marked sensory effects during inspiratory threshold loading and more marked affective effects during carbon dioxide stimulation. ANSWER TO THE QUESTION: Medical hypnosis was more effective than visual distraction at attenuating the sensory and affective dimensions of experimentally induced dyspnoea. This provides a strong rationale for clinical studies of hypnosis in persistent dyspnoea patients.

Increasing Sweep Gas Flow Reduces Respiratory Drive and Dyspnea in Nonintubated Venoarterial Extracorporeal Membrane Oxygenation Patients: A Pilot Study.

BACKGROUND: Data on assessment and management of dyspnea in patients on venoarterial extracorporeal membrane oxygenation (ECMO) for cardiogenic shock are lacking. The hypothesis was that increasing sweep gas flow through the venoarterial extracorporeal membrane oxygenator may decrease dyspnea in nonintubated venoarterial ECMO patients exhibiting clinically significant dyspnea, with a parallel reduction in respiratory drive. METHODS: Nonintubated, spontaneously breathing, supine patients on venoarterial ECMO for cardiogenic shock who presented with a dyspnea visual analog scale (VAS) score of greater than or equal to 40/100 mm were included. Sweep gas flow was increased up to +6 l/min by three steps of +2 l/min each. Dyspnea was assessed with the dyspnea-VAS and the Multidimensional Dyspnea Profile. The respiratory drive was assessed by the electromyographic activity of the alae nasi and parasternal muscles. RESULTS: A total of 21 patients were included in the study. Upon inclusion, median dyspnea-VAS was 50 (interquartile range, 45 to 60) mm, and sweep gas flow was 1.0 l/min (0.5 to 2.0). An increase in sweep gas flow significantly decreased dyspnea-VAS (50 [45 to 60] at baseline vs. 20 [10 to 30] at 6 l/min; P < 0.001). The decrease in dyspnea was greater for the sensory component of dyspnea (-50% [-43 to -75]) than for the affective and emotional components (-17% [-0 to -25] and -12% [-0 to -17]; P < 0.001). An increase in sweep gas flow significantly decreased electromyographic activity of the alae nasi and parasternal muscles (-23% [-36 to -10] and -20 [-41 to -0]; P < 0.001). There was a significant correlation between the sweep gas flow and the dyspnea-VAS (r = -0.91; 95% CI, -0.94 to -0.87), between the respiratory drive and the sensory component of dyspnea (r = 0.29; 95% CI, 0.13 to 0.44) between the respiratory drive and the affective component of dyspnea (r = 0.29; 95% CI, 0.02 to 0.54) and between the sweep gas flow and the alae nasi and parasternal (r = -0.31; 95% CI, -0.44 to -0.22; and r = -0.25; 95% CI, -0.44 to -0.16). CONCLUSIONS: In critically ill patients with venoarterial ECMO, an increase in sweep gas flow through the oxygenation membrane decreases dyspnea, possibly mediated by a decrease in respiratory drive.

Specific and Nonuniform Brain States during Cold Perception in Mice.

The quest to decode the complex supraspinal mechanisms that integrate cutaneous thermal information in the central system is still ongoing. The dorsal horn of the spinal cord is the first hub that encodes thermal input which is then transmitted to brain regions via the spinothalamic and thalamocortical pathways. So far, our knowledge about the strength of the interplay between the brain regions during thermal processing is limited. To address this question, we imaged the brains of adult awake male mice in resting state using functional ultrasound imaging during plantar exposure to constant and varying temperatures. Our study reveals for the first time the following: (1) a dichotomy in the response of the somatomotor-cingulate cortices and the hypothalamus, which was never described before, due to the lack of appropriate tools to study such regions with both good spatial and temporal resolutions. (2) We infer that cingulate areas may be involved in the affective responses to temperature changes. (3) Colder temperatures (ramped down) reinforce the disconnection between the somatomotor-cingulate and hypothalamus networks. (4) Finally, we also confirm the existence in the mouse brain of a brain mode characterized by low cognitive strength present more frequently at resting neutral temperature. The present study points toward the existence of a common hub between somatomotor and cingulate regions, whereas hypothalamus functions are related to a secondary network.

Dyspnoea relief as an inherent benefit of high flow nasal cannula therapy: A laboratory randomized trial in healthy humans.

BACKGROUND AND OBJECTIVE: Persistent dyspnoea is a public health issue for which the therapeutic arsenal is limited. This study tested high-flow nasal cannula therapy (HFNT) as a means to alleviate experimental dyspnoea. METHODS: Thirty-two healthy subjects underwent an experimental dyspnoea induced by thoracoabdominal elastic loading. HFNT was administered with alternately FiO2 of 100% (HFNT100) or 21% (HFNT21). The sensory (S-VAS) and affective (A-VAS) components of dyspnoea, transcutaneous CO2 pressure (PtcCO2 ), pulse-oximetry oxygen saturation (SpO2 ), heart rate, respiratory rate and skin galvanometry were monitored continuously. Three experimental sessions of 8 min were conducted: the first session consisted in familiarization with the experimental dyspnoea and the next two sessions tested the effects of HFNT100 and HFNT21 alternatively in a randomized order. RESULTS: HFNT21 and HFNT100 significantly reduced dyspnoea, respectively of ∆A-VAS = 0.80 cm [-0.02-1.5]; p = 0.007 and ∆A-VAS = 1.00 cm [0.08-1.75]; p < 0.0001; ∆S-VAS = 0.70 cm [-0.15-1.98]), p < 0.0001 and ∆S-VAS = 0.70 cm [0.08-1.95]), p = 0.0002) with no significant difference between HFNT21 and HFNT100. HFNT did not significantly alter the respiratory rate or the heart rate, reduced PtcCO2 only on room air and GSR under both experimental conditions. CONCLUSION: HFNT was associated with a statistically significant reduction in the intensity of the sensory and affective components of dyspnoea, independent of oxygen addition. This relief of laboratory dyspnoea could result from a reduction of afferent-reafferent mismatch.

Sensory interventions to relieve dyspnoea in critically ill mechanically ventilated patients.

BACKGROUND: In critically ill patients receiving mechanical ventilation, dyspnoea is frequent, severe and associated with an increased risk of neuropsychological sequelae. We evaluated the efficacy of sensory interventions targeting the brain rather than the respiratory system to relieve dyspnoea in mechanically ventilated patients. METHODS: Patients receiving mechanical ventilation for ≥48 h and reporting dyspnoea (unidimensional dyspnoea visual analogue scale (Dyspnoea-VAS)) first underwent increased pressure support and then, in random order, auditory stimulation (relaxing music versus pink noise) and air flux stimulation (facial versus lower limb). Treatment responses were assessed using Dyspnoea-VAS, the Multidimensional Dyspnea Profile and measures of the neural drive to breathe (airway occlusion pressure (P 0.1) and electromyography of inspiratory muscles). RESULTS: We included 46 patients (tracheotomy or intubation n=37; noninvasive ventilation n=9). Increasing pressure support decreased Dyspnoea-VAS by median 40 mm (p<0.001). Exposure to music decreased Dyspnoea-VAS compared with exposure to pink noise by median 40 mm (p<0.001). Exposure to facial air flux decreased Dyspnoea-VAS compared with limb air flux by median 30 mm (p<0.001). Increasing pressure support, but not music exposure and facial air flux, reduced P 0.1 by median 3.3 cmH2O (p<0.001). CONCLUSIONS: In mechanically ventilated patients, sensory interventions can modulate the processing of respiratory signals by the brain irrespective of the intensity of the neural drive to breathe. It should therefore be possible to alleviate dyspnoea without resorting to pharmacological interventions or having to infringe the constraints of mechanical ventilation lung protection strategies by increasing ventilatory support.

Coupling Between Posture and Respiration Among the Postural Chain: Toward a Screening Tool for Respiratory-Related Balance Disorders.

Alteration of posturo-respiratory coupling (PRC) may precede postural imbalance in patients with chronic respiratory disease. PRC assessment would be appropriate for early detection of respiratory-related postural dysfunction. PRC may be evaluated by respiratory emergence (REm), the proportion of postural oscillations attributed to breathing activity; assessed by motion analysis) as measured from the displacement of the center of pressure (CoP) (measured with a force platform). To propose a simplified method of PRC assessment (using motion capture only), we hypothesized that the REm can appropriately be measured derived from single body segment the postural oscillations of a single body segment rather than whole body postural oscillations. An optoelectronic system recorded the breathing pattern and the postural oscillations of six body segments in 50 healthy participants (22 women), 34 years [26; 48]. The CoP displacements were assessed using a force platform. One-minute recordings were made in standing position in four conditions by varying vision (eyes opened/closed) and jaw position (rest position/dental contact). The Sway Path and Mean Velocity of the CoP and of the representative point of each body segment were recorded. The REm was measured along the major and the minor axis of the 95% confidence ellipse of the CoP position (REm_MajorAxisCoP; REm_MinorAxisCoP) and of that of each body segment. SwayPathCoP and MVCoP varied widely across the four conditions (par< 0.000001). These changes were related to the visual condition ( [Formula: see text]) while the jaw position had no effect. The REm_MajorAxisCoP and the REm_MinorAxisCoP changed across conditions ( [Formula: see text]); this was related to vision while jaw induced changes only for the REm_MinorAxisCoP. The SwayPath, the Mean Velocity and the REm of all body segments were significantly correlated to the CoP, but the highest correlations were observed for the thorax, the pelvis and the shoulder. PRC may be assessed from the postural oscillations of thorax, pelvis and shoulder. This should simplify the evaluation of respiratory-related postural interactions in the clinical environment, by using a single device to simultaneously assess postural oscillations on body segments, and breathing pattern. In addition, this study provides reference data for PRC and its sensory-related modulations on body segments along the postural chain.

Decreased breathing variability is associated with poorer outcome in mechanically ventilated patients.

Rationale: Breathing is a cyclic activity that is variable by nature. Breathing variability is modified in mechanically ventilated patients. We aimed to evaluate whether decreased variability on the day of transition from assist-control ventilation to a partial mode of assistance was associated with a poorer outcome. Methods: This was an ancillary study of a multicentre, randomised, controlled trial comparing neurally adjusted ventilatory assist to pressure support ventilation. Flow and the electrical activity of the diaphragm (EAdi) were recorded within 48 h of switching from controlled ventilation to a partial mode of ventilatory assistance. Variability of flow and EAdi-related variables were quantified by the coefficient of variation, the amplitude ratio of the spectrum's first harmonic to its zero-frequency component (H1/DC) and two surrogates of complexity. Main results: 98 patients ventilated for a median duration of 5 days were included. H1/DC of inspiratory flow and EAdi were lower in survivors than in nonsurvivors, suggesting a higher breathing variability in this population (for flow, 37% versus 45%, p=0.041; for EAdi, 42% versus 52%, p=0.002). By multivariate analysis, H1/DC of inspiratory EAdi was independently associated with day-28 mortality (OR 1.10, p=0.002). H1/DC of inspiratory EAdi was lower in patients with a duration of mechanical ventilation <8 days (41% versus 45%, p=0.022). Noise limit and the largest Lyapunov exponent suggested a lower complexity in patients with a duration of mechanical ventilation <8 days. Conclusion: Higher breathing variability and lower complexity are associated with higher survival and lower duration of mechanical ventilation.

Increased plasma DYRK1A with aging may protect against neurodegenerative diseases.

Early markers are needed for more effective prevention of Alzheimer's disease. We previously showed that individuals with Alzheimer's disease have decreased plasma DYRK1A levels compared to controls. We assessed DYRK1A in the plasma of cognitively healthy elderly volunteers, individuals with either Alzheimer's disease (AD), tauopathies or Down syndrome (DS), and in lymphoblastoids from individuals with DS. DYRK1A levels were inversely correlated with brain amyloid ß burden in asymptomatic elderly individuals and AD patients. Low DYRK1A levels were also detected in patients with tauopathies. Individuals with DS had higher DYRK1A levels than controls, although levels were lower in individuals with DS and with dementia. These data suggest that plasma DYRK1A levels could be used for early detection of at risk individuals of AD and for early detection of AD. We hypothesize that lack of increase of DYRK1A at middle age (40-50 years) could be a warning before the cognitive decline, reflecting increased risk for AD.

Interventions Relieving Dyspnea in Intubated Patients Show Responsiveness of the Mechanical Ventilation-Respiratory Distress Observation Scale.

Rationale: Breathing difficulties are highly stressful. In critically ill patients, they are associated with an increased risk of posttraumatic manifestations. Dyspnea, the corresponding symptom, cannot be directly assessed in noncommunicative patients. This difficulty can be circumvented using observation scales such as the mechanical ventilation-respiratory distress observation scale (MV-RDOS). Objective: To investigate the performance and responsiveness of the MV-RDOS to infer dyspnea in noncommunicative intubated patients. Methods: Communicative and noncommunicative patients exhibiting breathing difficulties under mechanical ventilation were prospectively included and assessed using a dyspnea visual analog scale, MV-RDOS, EMG activity of alae nasi and parasternal intercostals, and EEG signatures of respiratory-related cortical activation (preinspiratory potentials). Inspiratory-muscle EMG and preinspiratory cortical activities are surrogates of dyspnea. Assessments were conducted at baseline, after adjustment of ventilator settings, and, in some cases, after morphine administration. Measurements and Main Results: Fifty patients (age, 67 [(interquartile interval [IQR]), 61-76] yr; Simplified Acute Physiology Score II, 52 [IQR, 35-62]) were included, 25 of whom were noncommunicative. Relief occurred in 25 (50%) patients after ventilator adjustments and in 21 additional patients after morphine administration. In noncommunicative patients, MV-RDOS score decreased from 5.5 (IQR, 4.2-6.6) at baseline to 4.2 (IQR, 2.1-4.7; P < 0.001) after ventilator adjustments and 2.5 (IQR, 2.1-4.2; P = 0.024) after morphine administration. MV-RDOS and alae nasi/parasternal EMG activities were positively correlated (ρ = 0.41 and 0.37, respectively). MV-RDOS scores were higher in patients with EEG preinspiratory potentials (4.9 [IQR, 4.2-6.3] vs. 4.0 [IQR, 2.1-4.9]; P = 0.002). Conclusions: The MV-RDOS seems able to detect and monitor respiratory symptoms reasonably well in noncommunicative intubated patients. Clinical trial registered with www.clinicaltrials.gov (NCT02801838).

Modifications of the endosomal compartment in fibroblasts from sporadic Alzheimer's disease patients are associated with cognitive impairment.

Morphological alterations of the endosomal compartment have been widely described in post-mortem brains from Alzheimer's disease (AD) patients and subjects with Down syndrome (DS) who are at high risk for AD. Immunostaining with antibodies against endosomal markers such as Early Endosome Antigen 1 (EEA1) revealed increased size of EEA1-positive puncta. In DS, peripheral cells such as peripheral blood mononuclear cells (PBMCs) and fibroblasts, share similar phenotype even in the absence of AD. We previously found that PBMCs from AD patients have larger EEA1-positive puncta, correlating with brain amyloid load. Here we analysed the endosomal compartment of fibroblasts from a very well characterised cohort of AD patients (IMABio3) who underwent thorough clinical, imaging and biomarkers assessments. Twenty-one subjects were included (7 AD with mild cognitive impairment (AD-MCI), 7 AD with dementia (AD-D) and 7 controls) who had amyloid-PET at baseline (PiB) and neuropsychological tests at baseline and close to skin biopsy. Fibroblasts isolated from skin biopsies were immunostained with anti-EEA1 antibody and imaged using a spinning disk microscope. Endosomal compartment ultrastructure was also analysed by electron microscopy. All fibroblast lines were genotyped and their AD risk factors identified. Our results show a trend to an increased EEA1-positive puncta volume in fibroblasts from AD-D as compared to controls (p.adj = 0.12) and reveal enhanced endosome area in fibroblasts from AD-MCI and AD-AD versus controls. Larger puncta size correlated with PiB retention in different brain areas and with worse cognitive scores at the time of biopsy as well as faster decline from baseline to the time of biopsy. Finally, we identified three genetic risk factors for AD (ABCA1, COX7C and MYO15A) that were associated with larger EEA1 puncta volume. In conclusion, the endosomal compartment in fibroblasts could be used as cellular peripheral biomarker for both amyloid deposition and cognitive decline in AD patients.

Moderate-to-severe obstructive sleep apnea syndrome is associated with altered tongue motion during wakefulness.

PURPOSE: Impairment of genioglossus control is a frequent "non-anatomical" cause of obstructive sleep apnea syndrome (OSAS) in non- or mildly obese patients. Although wake-related compensatory mechanisms prevent the occurrence of obstructive events, the genioglossus control is often impaired during wakefulness. We hypothesized that the lingual motion would be altered during wakefulness in this population in patients with moderate-to-severe OSAS. METHODS: We included non- or mildly obese participants with suspected OSAS. They underwent a Bucco-Linguo-Facial Motor Skills assessment using the MBLF ("Motricité Bucco-Linguo-Faciale"), which includes an evaluation of 13 movements of the tongue. This was followed by a night-attended polysomnography. We compared patients with moderate-to-severe OSAS (apnea-hypopnea index (AHI) ≥ 15/h; n = 15) to patients without or with mild OSAS (AHI < 15/h; n = 24). RESULTS: MBLF total and "tongue" sub-scores were lower in patients with moderate-to-severe OSAS: total z-score - 0.78 [- 1.31; 0.103] versus 0.20 [- 0.26; 0.31], p = 0.0011; "tongue" z-sub-score (- 0.63 [- 1.83; 0.41] versus 0.35 [0.26; 0.48], p = 0.014). There was a significant age-adjusted correlation between the "tongue" sub-score and AHI. The logistic regression model for the prediction of moderate-to-severe OSAS gave area under the curve ratio of 88.2% for MBLF score plus age. CONCLUSIONS: Myofunctional activity of the tongue is impaired during wakefulness in non- or mildly obese patients with moderate-to-severe OSAS. This study supports the lingual myofunctional assessment using the MBLF in screening of moderate-to-severe OSAS. This simple tool could help clinicians to select patients with suspected moderate-to-severe OSAS for polysomnography.

Screening of obstructive sleep apnea syndrome by the deep breathing technique.

STUDY OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) is associated with alterations in heart rate variability (HRV) in relation to chronic autonomic dysfunction. We tested the ability of the deep breathing technique-a simple way to evaluate HRV-to identify patients with OSAS. METHODS: Consecutive patients referred for suspected OSAS (without obesity, diabetes, and heart diseases) were included. They underwent a measure of HRV at rest and of heart rate oscillations during expiration vs inspiration (DeltaHRDB) when breathing deeply at the resonant frequency of 6 cycles per minute (deep breathing technique) while sitting awake, followed by a nighttime polysomnography. We measured DeltaHRDB and performed temporal and spectral HRV analysis. RESULTS: Of 31 included participants (77% male), 14 had mild to moderate OSAS (apnea-hypopnea index median [IQR]: 18 [12]) and 17 had no OSAS. The conventional HRV analysis did not reveal any difference between the groups with vs without OSAS. However, the DeltaHRDB was lower in those with than without OSAS. Lower DeltaHRDB correlated with higher apnea-hypopnea index, arousal index, and desaturation degree. A DeltaHRDB below 11 beats per minute (bpm) predicted OSAS with a sensitivity of 100% and specificity of 86%. CONCLUSIONS: The deep breathing technique accurately identifies a reduction in cardiac changes in patients with mild to moderate OSAS. It could be used as a simple screening tool to select patients for polysomnography. CITATION: Onanga M, Joanny S, Rivals I, et al. Screening of obstructive sleep apnea syndrome by the deep breathing technique. J Clin Sleep Med. 2023;19(2):293-302.

Prognostic Value of the Intensive Care Respiratory Distress Observation Scale on ICU Admission.

BACKGROUND: The association between dyspnea and mortality has not been demonstrated in the ICU setting. We tested the hypothesis that dyspnea (self-reported respiratory discomfort) or its observational correlates (5-item intensive care Respiratory Distress Observation Scale [IC-RDOS]) assessed on ICU admission would be associated with ICU mortality. METHODS: Ancillary analysis of single-center data prospectively collected from 220 communicative ICU subjects allocated to a derivation cohort of 120 subjects and a separate validation cohort of 100 subjects. Dyspnea was assessed dichotomously (yes/no), with a dyspnea visual analog scale (measured in mm), and IC-RDOS was calculated. Multivariate logistic regression was used to identify factors associated with ICU and hospital mortality. RESULTS: Dyspnea was reported by 69 (58%; median 45 [interquartile range [IQR] 32-60] mm) and 47 (47%; 38 [IQR 26-48] mm) subjects in the derivation and validation cohorts, respectively. IC-RDOS was 2.3 (1.2-3.1) and 2.4 (1.3-2.8), respectively. IC-RDOS values were higher in subjects with dyspnea than in subjects without dyspnea in both the derivation cohort (2.6 [2.2-4.6] vs 1.4 [0.9-2.4], P < .001) and the validation cohort (2.6 [2.3-4.4] vs 2.2 [1.0-2.8], P < .001). On multivariate analysis of the derivation cohort, admission for hemorrhagic shock (odds ratio 13.98), IC-RDOS (odds ratio 1.77), and Simplified Acute Physiology Score II (odds ratio 1.10) was associated with ICU mortality. Areas under the receiving operating characteristic curve of IC-RDOS to predict ICU mortality were 0.785 and 0.794 in the derivation and validation cohorts, respectively. CONCLUSIONS: IC-RDOS, an observational correlate of dyspnea, but not dyspnea itself, was associated with higher mortality in ICU subjects.

Ultrasound localization microscopy and functional ultrasound imaging reveal atypical features of the trigeminal ganglion vasculature.

The functional imaging within the trigeminal ganglion (TG) is highly challenging due to its small size and deep localization. This study combined a methodological framework able to dive into the rat trigeminal nociceptive system by jointly providing 1) imaging of the TG blood vasculature at microscopic resolution, and 2) the measurement of hemodynamic responses evoked by orofacial stimulations in anesthetized rats. Despite the small number of sensory neurons within the TG, functional ultrasound imaging was able to image and quantify a strong and highly localized hemodynamic response in the ipsilateral TG, evoked not only by mechanical or chemical stimulations of corneal nociceptive fibers, but also by cutaneous mechanical stimulations of the ophthalmic and maxillary orofacial regions using a von Frey hair. The in vivo quantitative imaging of the TG's vasculature using ultrasound localization microscopy combined with in toto labelling reveals particular features of the vascularization of the area containing the sensory neurons, that are likely the origin of this strong vaso-trigeminal response. This innovative imaging approach opens the path for future studies on the mechanisms underlying changes in trigeminal local blood flow and evoked hemodynamic responses, key mechanisms for the understanding and treatment of debilitating trigeminal pain conditions.

Reliability of B-mode ultrasound and shear wave elastography in evaluating sacral bone and soft tissue characteristics in young adults with clinical feasibility in elderly.

BACKGROUND: Physiologic aging is associated with loss of mobility, sarcopenia, skin atrophy and loss of elasticity. These factors contribute, in the elderly, to the occurrence of a pressure ulcer (PU). Brightness mode ultrasound (US) and shear wave elastography (SWE) have been proposed as a patient-specific, bedside, and predictive tool for PU. However, reliability and clinical feasibility in application to the sacral region have not been clearly established. METHOD: The current study aimed to propose a simple bedside protocol combining US and SWE. The protocol was first tested on a group of 19 healthy young subjects by two operators. The measurements were repeated three times. Eight parameters were evaluated at the medial sacral crest. Intraclass Correlation Coefficient (ICC) was used for reliability assessment and the modified Bland Altman plot analysis for agreement assessment. The protocol was then evaluated for clinical feasibility on a healthy older group of 11 subjects with a mean age of 65 ± 2.4 yrs. FINDINGS: ICC showed poor to good reliability except for skin SWE and hypodermis thickness with an ICC (reported as: mean (95%CI)) of 0.78 (0.50-0.91) and 0.98 (0.95-0.99) respectively. No significant differences were observed between the young and older group except for the muscle Shear Wave Speed (SWS) (respectively 2.11 ± 0.27 m/s vs 1.70 ± 0.17 m/s). INTERPRETATION: This is the first protocol combining US and SWE that can be proposed on a large scale in nursing homes. Reliability, however, was unsatisfactory for most parameters despite efforts to standardize the protocol and measurement definitions. Further studies are needed to improve reliability.

Tau-PET imaging predicts cognitive decline and brain atrophy progression in early Alzheimer's disease.

OBJECTIVES: To explore whether regional tau binding measured at baseline is associated with the rapidity of Alzheimer's disease (AD) progression over 2 years, as assessed by the decline in specified cognitive domains, and the progression of regional brain atrophy, in comparison with amyloid-positron emission tomography (PET), MRI and cerebrospinal fluid (CSF) biomarkers. METHODS: Thirty-six patients with AD (positive CSF biomarkers and amyloid-PET) and 15 controls underwent a complete neuropsychological assessment, 3T brain MRI, [11C]-PiB and [18F]-flortaucipir PET imaging, and were monitored annually over 2 years, with a second brain MRI after 2 years. We used mixed effects models to explore the relations between tau-PET, amyloid-PET, CSF biomarkers and MRI at baseline and cognitive decline and the progression of brain atrophy over 2 years in patients with AD. RESULTS: Baseline tau-PET was strongly associated with the subsequent cognitive decline in regions that are usually associated with each cognitive domain. No significant relationship was observed between the cognitive decline and initial amyloid load, regional cortical atrophy or CSF biomarkers. Baseline tau tracer binding in the superior temporal gyrus was associated with subsequent atrophy in an inferomedial temporal volume of interest, as was the voxelwise tau tracer binding with subsequent cortical atrophy in the superior temporal, parietal and frontal association cortices. CONCLUSIONS: These results suggest that tau tracer binding is predictive of cognitive decline in AD in domain-specific brain areas, which provides important insights into the interaction between tau burden and neurodegeneration, and is of the utmost importance to develop new prognostic markers that will help improve the design of therapeutic trials.

Biplanar Low-Dose Radiograph Is Suitable for Cephalometric Analysis in Patients Requiring 3D Evaluation of the Whole Skeleton.

BACKGROUND: The biplanar 2D/3D X-ray technology (BPXR) is a 2D/3D imaging system allowing simultaneous stereo-corresponding posteroanterior (PA) and lateral 2D views of the whole body. The aim of our study was to assess the feasibility of cephalometric analysis based on the BPXR lateral skull view to accurately characterize facial morphology. METHOD: A total of 17 landmarks and 11 angles were placed and/or calculated on lateral BPXR and lateral cephalograms of 13 patients by three investigators. Five methods of angle identification were performed: the direct construction of straight lines on lateral cephalograms (LC-A) and on BPXR (BPXR-A), as well as the calculation of angles based on landmark identification on lateral cephalograms (LA-L) and on BPXR with the PA image (BPXR-LPA) or without (BPXR-L). Intra- and interoperator reliability of landmark identification and angle measurement of each method were calculated. To determine the most reliable method among the BPXR-based methods, their concordance with the reference method, LC-A, was evaluated. RESULTS: Both imaging techniques had excellent intra- and interoperator reliability for landmark identification. On lateral BPXR, BPXR-A presented the best concordance with the reference method and a good intra- and interoperator reliability. CONCLUSION: BPXR provides a lateral view of the skull suitable for cephalometric analysis with good reliability.

Evaluation of distance-based approaches for forensic comparison: Application to hand odor evidence.

The issue of distinguishing between the same-source and different-source hypotheses based on various types of traces is a generic problem in forensic science. This problem is often tackled with Bayesian approaches, which are able to provide a likelihood ratio that quantifies the relative strengths of evidence supporting each of the two competing hypotheses. Here, we focus on distance-based approaches, whose robustness and specifically whose capacity to deal with high-dimensional evidence are very different, and need to be evaluated and optimized. A unified framework for direct methods based on estimating the likelihoods of the distance between traces under each of the two competing hypotheses, and indirect methods using logistic regression to discriminate between same-source and different-source distance distributions, is presented. Whilst direct methods are more flexible, indirect methods are more robust and quite natural in machine learning. Moreover, indirect methods also enable the use of a vectorial distance, thus preventing the severe information loss suffered by scalar distance approaches. Direct and indirect methods are compared in terms of sensitivity, specificity, and robustness, with and without dimensionality reduction, with and without feature selection, on the example of hand odor profiles, a novel and challenging type of evidence in the field of forensics. Empirical evaluations on a large panel of 534 subjects and their 1690 odor traces show the significant superiority of the indirect methods, especially without dimensionality reduction, be it with or without feature selection.

DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study.

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.