Per and poly-fluoroalkyl substances and respiratory health in an Inuit community.

BACKGROUND: Concentrations of plasma per and poly-fluoroalkyl substances (PFAS) are elevated in the Inuit population of Nunavik and may be causing adverse health effects. Respiratory health outcomes have been associated with PFAS, but have not been explored in Inuit communities. The aim of the study was to examine the association between PFAS and respiratory health outcomes, and the moderating role of nutritional biomarkers. METHODS: We included up to 1298 participants of the Qanuilirpitaa? 2017 survey aged 16-80 years. Generalized regression models were used to estimate the associations between six individual PFAS congeners and four self-reported symptoms, four spirometry measures, and physician-diagnosed asthma. Outcomes associated with PFAS from single chemical models were further explored using Bayesian Kernel Machine Regression (BKMR). The modifying effect of n-3 PUFA in red blood cell quartiles and vitamin D deficiency were examined on the associations between PFAS and respiratory outcomes. RESULTS: PFNA and PFOS were associated with asthma (odds ratio (OR) 1.61, 95% confidence interval (CI) 1.12, 2.32; OR 1.45 95% CI 1.04, 2.03). PFOA, PFNA, PFDA and PFHxS were associated with a decrease in the ratio between the forced expiratory volume in the first second and forced vital capacity (FEV1/FVC). No associations were observed with self-reported respiratory symptoms. No associations were observed between a PFAS mixture and asthma. Some associations were modified by nutritional factors, namely, stronger associations between PFOA and PFHxS and asthma with lower n-3 PUFA levels and stronger associations between PFDA, PFUnDA and PFOS and FEV1/FVC with vitamin D deficiency. CONCLUSION: These findings add to the growing literature on the impacts of PFAS on respiratory health, and the importance of their global regulation. Associations were modified by nutritional factors pointing to the nutritional value of traditional Inuit foods.

Tonsil explants as a human in vitro model to study vaccine responses.

Introduction: Vaccination is one of the most effective infection prevention strategies. Viruses with high mutation rates -such as influenza- escape vaccine-induced immunity and represent significant challenges to vaccine design. Influenza vaccine strain selection is based on circulating strains and immunogenicity testing in animal models with limited predictive outcomes for vaccine effectiveness in humans. Methods: We developed a human in vitro vaccination model using human tonsil tissue explants cultured in 3D perfusion bioreactors to be utilized as a platform to test and improve vaccines. Results: Tonsils cultured in bioreactors showed higher viability, metabolic activity, and more robust immune responses than those in static cultures. The in vitro vaccination system responded to various premanufactured vaccines, protein antigens, and antigen combinations. In particular, a multivalent in vitro immunization with three phylogenetically distant H3N2 influenza strains showed evidence for broader B cell activation and induced higher antibody cross-reactivity than combinations with more related strains. Moreover, we demonstrate the capacity of our in vitro model to generate de novo humoral immune responses to a model antigen. Discussion: Perfusion-cultured tonsil tissue may be a valuable human in vitro model for immunology research with potential application in vaccine candidate selection.

Linguistics-based formalization of the antibody language as a basis for antibody language models.

Apparent parallels between natural language and antibody sequences have led to a surge in deep language models applied to antibody sequences for predicting cognate antigen recognition. However, a linguistic formal definition of antibody language does not exist, and insight into how antibody language models capture antibody-specific binding features remains largely uninterpretable. Here we describe how a linguistic formalization of the antibody language, by characterizing its tokens and grammar, could address current challenges in antibody language model rule mining.

Evaluation of the Contrast Enhancement Performance of Gadopiclenol for Magnetic Resonance Angiography in Healthy Rabbits and Pigs.

OBJECTIVES: Unexpected accumulations of gadolinium in various organs were reported after the administration of gadolinium-based contrast agents, making desirable to reduce the dose while maintaining equivalent diagnostic performance. The aim of this study was to evaluate the contrast enhancement performance of high relaxivity gadopiclenol compared with gadoterate meglumine in abdominal contrast-enhanced magnetic resonance angiography (CE-MRA). MATERIALS AND METHODS: In a first study in healthy rabbits, axial 3D gradient echo sequences were applied at 4.7 T to study arterial enhancement as a function of gadopiclenol dose (0.025, 0.05, 0.075, and 0.1 mmol Gd/kg) or gadoterate meglumine at 0.1 mmol Gd/kg (n = 5-6/group). The increase in signal-to-noise ratio (ΔSNR) in the aorta at the first pass was measured and compared. In a second, crossover study in 6 healthy pigs, abdominal CE-MRA sequences were acquired at 3 T with gadopiclenol at 0.05 mmol Gd/kg or gadoterate meglumine at 0.1 mmol Gd/kg at a 1-week interval. Quantitatively on the maximum intensity projection (MIP) images, the mean MIP SNR within the aorta of both groups was compared. Qualitatively, a blinded comparison of the angiograms was performed by an experienced radiologist to determine the preferred contrast agent. RESULTS: In the rabbit, ∆SNR is linearly correlated with the gadopiclenol dose ( P = 0.0010). Compared with gadoterate meglumine 0.1 mmol Gd/kg, an increase in the ∆SNR is observed after 0.05, 0.075, and 0.1 mmol Gd/kg of gadopiclenol (+63% P = 0.0731, +78% P = 0.0081, and +72% P = 0.0773, respectively), whereas at 0.025 mmol Gd/kg, ∆SNR is in the same range as with gadoterate meglumine 0.1 mmol Gd/kg (+15% P > 0.9999). In pigs, contrast enhancement after gadopiclenol at 0.05 mmol/kg is +22% superior to MIP SNR after gadoterate meglumine at 0.1 mmol Gd/kg ( P = 0.3095). Qualitatively, a preference was shown for gadopiclenol images (3/6) over the gadoterate meglumine examinations (1/6), with no preference being shown for the remainder (2/6). CONCLUSIONS: First-pass CE-MRA is feasible with gadopiclenol at 0.05 mmol Gd/kg with at least the same arterial signal enhancement and image quality as gadoterate meglumine at 0.1 mmol Gd/kg.

A Decision-Making Algorithm for Remote Digital Assessments of Alzheimer's Disease.

INTRODUCTION: Remote digital assessments (RDAs) such as voice recording, video and motor sensors, olfactory, hearing, and vision screenings are now starting to be employed to complement classical biomarker and clinical evidence to identify patients in the early AD stages. Choosing which RDA can be proposed to individual patients is not trivial and often time-consuming. This position paper presents a decision-making algorithm for using RDA during teleconsultations in memory clinic settings. METHOD: The algorithm was developed by an expert panel following the Delphi methodology. RESULTS: The decision-making algorithm is structured as a series of yes-no questions. The resulting questionnaire is freely available online. DISCUSSION: We suggest that the use of screening questionnaires in the context of memory clinics may help accelerating the adoption of RDA in everyday clinical practice.

Assessing the feasibility of statistical inference using synthetic antibody-antigen datasets.

Simulation frameworks are useful to stress-test predictive models when data is scarce, or to assert model sensitivity to specific data distributions. Such frameworks often need to recapitulate several layers of data complexity, including emergent properties that arise implicitly from the interaction between simulation components. Antibody-antigen binding is a complex mechanism by which an antibody sequence wraps itself around an antigen with high affinity. In this study, we use a synthetic simulation framework for antibody-antigen folding and binding on a 3D lattice that include full details on the spatial conformation of both molecules. We investigate how emergent properties arise in this framework, in particular the physical proximity of amino acids, their presence on the binding interface, or the binding status of a sequence, and relate that to the individual and pairwise contributions of amino acids in statistical models for binding prediction. We show that weights learnt from a simple logistic regression model align with some but not all features of amino acids involved in the binding, and that predictive sequence binding patterns can be enriched. In particular, main effects correlated with the capacity of a sequence to bind any antigen, while statistical interactions were related to sequence specificity.

Somatic and Posttraumatic Stress Symptoms in Children and Adolescents in France.

Importance: Somatic symptoms are a major concern among the pediatric population because of frequency and burden. The association between adverse childhood experiences and somatic symptoms in adults is well established but less is known concerning somatic symptoms in young people. Objective: To explore the frequency and intensity of somatic symptoms in children and adolescents exposed to traumatic events. Design, Setting, and Participants: This cross-sectional study was conducted from January 1 to December 31, 2021, at the Nice Pediatric Psychotrauma Referral Center in Nice, France. Participants included pediatric outpatients, aged 7 to 17 years, who were referred to the center. Statistical analysis was performed in January 2022. Exposure: All participants experienced at least 1 traumatic event during life. Main Outcome and Measure: Somatic and posttraumatic stress symptoms were assessed using the Patient Health Questionnaire-13 (PHQ-13) and Child PTSD Checklist (CPC). Posttraumatic stress disorder (PTSD) and non-PTSD groups were defined based on CPC symptoms severity score. In the hypothesized association between somatic symptoms and posttraumatic stress symptoms (PTSS), PTSD and non-PTSD groups were compared, correlations between PTSS and severity of CPC were analyzed, and a regression model was performed. Results: There were 363 participants included (mean [SD] age, 13.58 [0.25] years; 174 [47.9%] female, 189 [52.1%] male). Compared with the non-PTSD group, the PTSD group presented with a higher mean (SD) number of somatic symptoms (7.0 [2.5] vs 4.0 [2.5] symptoms; t360 = 11.7; P < .001), and higher mean (SD) intensity (10.4 [4.6] vs 4.8 [3.7] points; t360 = 12.6; P < .001). Most of the explored somatic symptoms positively correlated with the intensity of PTSS and their functional alterations (eg, PTSS intensity correlated with stomach pain symptoms [r = .30; P < .001]; and with headaches symptoms [r = .44; P < .001]). In the regression model, the combination of migraines, palpitation, nausea, tiredness, and sleep disorders explained 6.5% of the variance in the PTSD group. (F1,341 = 22.651; P < .001). Conclusions and Relevance: In this cross-sectional study, somatic symptoms were positively correlated with PTSS both in frequency and intensity among youths. These results suggest that the systematic screening for somatic symptoms in youths with traumatic exposure should be a routine evaluation procedure.

Productive art engagement in a hybrid format: effects on emotions of older adults during COVID-19 pandemic.

Introduction: Previous studies have shown benefits of productive art-activity on frail older adults' mental and physical health. In this study, we investigated the effects of art-producing activities in a hybrid format (in-person and online) in a context of lockdown compared with previous studies taking place in museums and their effects on wellbeing, quality of life, physical frailty, and apathy in older adults. Methods: We conducted a randomized unicentric control trial on a sample of 126 seniors older than 65 years (mean age 71.9 ± 2.3, 81% women) living in Nice (France). Participants were randomized in two parallel groups (intervention group with n = 62 vs. control group with n = 64) conducted during pandemic, between March and May 2021. The intervention group involved participatory art-based activities conducted in a hybrid format, either in-person or online, once a week for 2 h over a 12-week period. No specific intervention was proposed to the control group. The main aim was to evaluate how this hybrid format would impact the wellbeing, quality of life, and physical frailty of participants. The secondary aim was to compare our results with the previous studies conducted by Beauchet et al., and the third aim was to evaluate the impact of the intervention on apathy. Validated scales were implemented in RedCap and administered at baseline (M0) and at the end of the third month (M3). Results: The intervention group showed significant improvement in their quality of life (p = 0.017) and their level of apathy (p = 0.016) after intervention. Emotional blunting increased significantly in the control group (p = 0.016) while it remained stable in the intervention group. No significant improvement was observed on the frailty, and wellbeing scores remained constant in both groups. Conclusion: This randomized control trial confirmed emotional effects on seniors practicing an art-based activity in a hybrid format during pandemic on a weekly basis for 3 months. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04570813.

Blocked-flow vs. free-flow cyanoacrylate glue embolization: Histological differences in an in vivo rabbit renal artery model.

PURPOSE: The purpose of this in vivo animal study was to compare the acute histological effects on the arterial vessel wall of free-flow vs. blocked-flow embolization with metacryloxysulfolane-n­butyl cyanoacrylate (MS-NBCA) in several concentrations. MATERIALS AND METHODS: A total of 42 rabbit renal arteries were embolized using MS-NBCA mixed with ethiodized oil. The MS-NBCA concentration was 12.5%, 25%, or 50%. All mixtures were injected under both free-flow and blocked-flow conditions. The rabbits were euthanised 30 min after arterial embolization. Arterial-lumen distension, intimal inflammation and necrosis, peri­arterial edema, and distality of MS-NBCA penetration were assessed histologically. Multivariable regression analyses were performed using a manual backward procedure, with linear, ordinal and logistic regression to search for factors associated with these outcomes RESULTS: Marked or severe dilatation was observed in 36 out of 42 arteries (86%) and marked or transmural intimal arteritis in all 42 arteries (42/42; 100%). Lumen dilatation caused focal vessel-wall flattening, which resulted in intimal necrosis. Multifocal necrosis extending from the intima to the media occurred in 23 out of 42 kidneys (55%) and peri­arterial edema with multifocal vascular leakage in 19 out of 42 kidneys (45%). At multivariable analysis, blocked-flow MS-NBCA injection was associated with greater severity of vessel-wall lesions, including intimal arteritis (P = 0.003) and intimal necrosis (P = 0.014), compared to free-flow injection. Blocked-flow injection was also associated with peri­arterial edema (P = 0.008) and greater distality of MS-NBCA penetration (P = 0.001). CONCLUSION: Blocked-flow MS-NBCA injection during renal artery embolization is significantly associated with more acute arterial-wall damage and greater distality of glue penetration compared to free-flow injection in a rabbit model. These preliminary findings may have clinical implications, as blocked-flow injection is routinely used to treat specific vascular diseases or malformations in human.

Respiratory health and its determinants among Nunavimmiut: results from the Qanuilirpitaa? 2017 Nunavik Health Survey.

OBJECTIVES: Respiratory diseases are the leading cause of hospitalization in Nunavik (northern Québec, Canada) and contribute to disparities in life expectancy with the rest of Canada. As part of Qanuilirpitaa? 2017, a cross-sectional population-based health survey, we sought to describe the prevalence of respiratory health indicators, including the first estimate of airway obstruction based on spirometry in an Inuit population, and explore their associated characteristics. METHODS: We analyzed data from 1296 participants aged 16 years and older, using multivariate logistic regression to assess characteristics associated with spirometry-determined airway obstruction and self-reported respiratory symptoms, i.e., wheezing in the last year and chronic cough during at least 3 months. RESULTS: In this relatively young population (83% aged 16 to 54), the prevalences of wheezing, chronic cough, and airway obstruction were, respectively, 27% (95% CI 24-30), 21% (18-23), and 17% (14-20). These estimates are prone to biases due to the relatively low participation rate (about 37%). The most consistent associations were with smoking (≥ 15 pack-years; odds ratio [OR] 3.13, 3.39, and 2.86 for the three indicators, respectively) and food security (OR 0.55 with wheezing and OR 0.26 with chronic cough), as defined in the Household Food Security Survey Module. Wheezing was also associated with allergic sensitization to dogs (2.60) and obesity (2.18). Chronic cough was associated with respiratory infections during childhood (2.12), housing in need of major repairs (1.72), and housing crowding (1.50), and was negatively associated with participation to traditional activities (0.62) and going on the land (0.64). Airway obstruction was associated with being underweight (3.84) and post-secondary education (0.40). Among young adults and women, wheezing was also associated with any inhalation of solvents for recreational purposes during their lifetime (2.62 and 1.56, respectively), while airway obstruction was associated with regular marijuana use (2.22 and 1.84, respectively). CONCLUSION: Smoking and food insecurity are both highly prevalent and strongly associated with respiratory symptoms in Nunavik. Together with essential smoking prevention and cessation programs, our findings suggest that solving food security and housing crises, improving socioeconomic conditions, and promoting traditional lifestyle may improve respiratory health in Nunavik.

RéSUMé: OBJECTIFS: Les maladies respiratoires sont la première cause d'hospitalisation au Nunavik (Nord-du-Québec, Canada) et contribuent aux écarts d'espérance de vie avec le reste du Canada. Dans le cadre de l'enquête transversale et populationnelle Qanuilirpitaa? 2017, cette étude décrit la prévalence d'indicateurs de santé respiratoire et explore les caractéristiques qui leur sont associées. Elle fournit le premier estimé de la prévalence d'obstruction respiratoire par spirométrie dans la population inuite. MéTHODES: Les données de 1 296 participants âgés de 16 ans et plus ont été analysées par régression logistique multivariée pour évaluer les caractéristiques associées avec le wheezing (dans la dernière année), la toux chronique (durant au moins 3 mois) et l'obstruction bronchique (mesurée par spirométrie). RéSULTATS: Dans cette population relativement jeune (83 % entre 16 et 54 ans), les prévalences de wheezing, de toux chronique et d'obstruction bronchique étaient de 27 % (IC95% 24-30), 21 % (18-23) et 17 % (14-20). Ces estimés pourraient être biaisés puisque le taux de participation à l'enquête était relativement faible (environ 37 %). Les associations les plus fortes et consistantes sont observées avec le tabagisme (≥ 15 paquets-années; RC 3,13, 3,39 et 2,86 pour les trois indicateurs, respectivement) et avec la sécurité alimentaire (RC 0,55 avec le wheezing et 0,26 avec la toux chronique), définie à partir du Module d'enquête sur la sécurité alimentaire des ménages. Le wheezing était notamment associé avec la sensibilisation allergique aux chiens (2,60) et l'obésité (2,18). La toux chronique était associée avec les infections respiratoires sévères dans l'enfance (2,12), un logement ayant besoin de réparations majeures (1,72) et un logement surpeuplé (1,50); tandis que participer aux activités traditionnelles (0,62) et aller souvent dans la nature (0,64) semblaient protecteurs. L'obstruction bronchique était associée avec un faible indice de masse corporelle (3,84) et un niveau de scolarité postsecondaire (0,40). Le wheezing était aussi associé avec le fait d'avoir déjà inhalé des solvants chez les jeunes adultes (2,62) et chez les femmes (1,56), tandis que l'obstruction bronchique était associée avec la consommation régulière de cannabis chez les jeunes adultes (2,22) et chez les femmes (1,84). CONCLUSION: Le tabagisme et l'insécurité alimentaire sont fort prévalents et fortement associés avec des symptômes respiratoires au Nunavik. En plus de rappeler l'importance de la prévention du tabagisme, ces résultats supportent la pertinence des efforts communautaires et gouvernementaux pour résoudre les crises de l'insécurité alimentaire et du logement, améliorer les conditions socioéconomiques et promouvoir la culture inuite afin d'améliorer la santé respiratoire au Nunavik.

Administration of oxathridine, a first-in-class histamine-3 receptor partial agonist in healthy male volunteers: Central nervous system depression and pseudo-hallucinations.

AIMS: To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first-in-class histamine-3 receptor partialagonist, in healthy male volunteers. METHODS: A randomised, double-blind, placebo-controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution. After dosing, safety and NeuroCart tests (adaptive tracking [AT], body sway [BS], saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], pharmaco-electroencephalogram [pEEG], Sustained Attention to Response Task [SART]) were performed at set times. RESULTS: Forty volunteers completed the study. Given doses were: 0.5, 2.5, 5, 0.25 and 1.5 mg. At 5 mg, unacceptable and unanticipated adverse events (AEs) of (orthostatic) hypotension and pseudo-hallucinations were reported. Statistically significant effects ([CI]; p-value) of 2.5 mg and 5 mg oxathridine were observed on AT ([-8.28, -1.60]; p = 0.0048), ([-8.10, -1.51]; p = 0.00530), BS ([0.6, 80.2]; p = 0.0455), ([5.9, 93.1]; p = 0.0205) and SPV ([-59.0, -15.9]; p = 0.0011), ([-43.9, -1.09]; p = 0.0399), respectively. Oxathridine 5 mg significantly increased all three VAS Bowdle subscale scores; VAS external ([0.183, 0.476]; p = <.0001), VAS internal ([0.127, 0.370]; p = 0.0001) and VAS feeling high ([0.263, 0.887]; p = 0.0006). CONCLUSION: NeuroCart tests indicated central nervous system (CNS) depressant effects. Oxathridine also unexpectedly caused pseudohallucinations. Although this led to the decision to stop further development of oxathridine, these observations suggest that the H3R system could be an interesting new target for the development of novel antipsychotics.

Detection of Brain Metastases by Contrast-Enhanced MRI: Comparison of Gadopiclenol and Gadobenate in a Mouse Model.

OBJECTIVES: The aim of this study was to evaluate the capacity of gadopiclenol, a high-relaxivity gadolinium-based contrast agent to detect brain metastases in mice as a function of dose (0.08 mmol/kg or 0.1 mmol/kg) compared with gadobenate at 0.1 mmol/kg. MATERIALS AND METHODS: Brain metastases were induced by ultrasound-guided intracardiac implantation of 1.10 5 MDA-MB-231Br cells in the left ventricle of 18 anesthetized Balb/c Nude nu/nu female mice. At day 28 ± 3 after cell injection, each mouse received 2 crossover intravenous injections at 24-hour intervals, randomly selected from 2 doses of gadopiclenol (0.08 mmol/kg or 0.1 mmol/kg) and gadobenate (0.1 mmol/kg) with n = 6 mice/group (3 groups). Brain magnetic resonance imaging sessions were performed at 4 weeks on a 2.35 T magnet with a 3-dimensional T1-weighted high-resolution gradient echo sequence, before and after each injection. Images were blindly and randomly analyzed to detect enhancing lesions. Contrast-to-noise ratio between the metastases and the surrounding healthy parenchyma was calculated, based on region-of-interest signal measurements. In 2 animals per group, an early time point was added to the protocol (day 22 ± 3) to evaluate the sensitivity of detection as a function of time. After the last imaging session, the presence and location of whole-brain metastases were confirmed by histology in 4 mice. RESULTS: After gadopiclenol, approximately twice as many metastases were detected compared with gadobenate, regardless of the dose. Contrast-to-noise ratios of the detected metastases were 2.3 and 3.3 times higher with gadopiclenol at 0.08 mmol/kg and 0.1 mmol/kg, respectively, compared with gadobenate at 0.1 mmol/kg ( P < 0.0001). Gadopiclenol at the dose of 0.1 mmol/kg resulted in a 1.4-fold higher contrast compared with gadopiclenol at 0.08 mmol/kg ( P < 0.02). In a subset of mice that were imaged 1 week earlier, 2 metastases were detected with gadopiclenol and not with gadobenate. CONCLUSIONS: The high-relaxivity macrocyclic gadolinium-based contrast agent gadopiclenol allowed higher diagnostic performance for detecting brain enhancing metastases in terms of contrast-to-noise ratio and number of detected metastases compared with gadobenate, at both equal (0.1 mmol/kg) dose and 20% lower Gd dose (0.08 mmol/kg). Tumor detection was higher after gadopiclenol at the dose of 0.1 mmol/kg compared with 0.08 mmol/kg.

July 14th 2016 Nice Terrorist Attack Court Trial: A Protocol on Sleep Quality and Somatic Symptoms as Markers of Risk for Traumatic Reactivation in Adolescents Exposed to This Attack.

The court trial of the 14th of July 2016 terrorist attack in Nice (France) opened in September 2022 and ended in December 2022. Engaging in court proceedings, whether as a victim or a witness, can lead to a significant risk of traumatic reactivation (i.e., the re-emergence of post-traumatic stress symptoms). The present protocol aimed to improve knowledge of the pathophysiology of traumatic reactivation due to the media coverage of the trial by assessing sleep disturbances and somatic symptoms that could reappear if there is a traumatic reactivation. Method and Analysis: This is a monocentric longitudinal study, with recruitment solely planned at the Nice Pediatric Psychotrauma Center (NPPC). We intended to include 100 adolescents aged 12 to 17 years who were directly or indirectly exposed to the attack and included in the "14-7" program). Assessments began one month before the trial, in August 2022, and were scheduled once a month until the end of the trial. A smartwatch recorded sleep activity. Somatic and PTSD symptoms and sleep were assessed through validated questionnaires. The main analyses comprised the variance and regression analyses of predictors of clinical evolution over time. Ethics and Dissemination: The National Ethics Committee "NORD OUEST III" approved the "14-7" program protocol (number 2017-A02212-51). The specific amendment for this research was approved in April 2022 by the same national ethical committee. Inclusions started in August 2022.

Validation study of the apathy motivation index in French adults.

Objective: Apathy is present in many brain disorders, but it is also prevalent to varying degrees in healthy people. While many tools have been developed to assess levels of apathy in pathology, no standardized measure of apathy in healthy people exists. Method: Therefore, this study aimed to validate the French version of the Apathy Motivation Index (f-AMI). The results of 729 participants were analyzed using an exploratory factorial analysis. Results: Preliminary analyses suggested that the three domains of apathy extracted in the original AMI scale-behavioral activation (BA), social motivation (SM), and emotional sensitivity (ES)-could be found also in the f-AMI. A further exploratory analysis showed that a higher number of factors could be extracted, particularly for women. Specifically, both social and emotional factors could be divided into two sub-factors: (1) social motivation toward strangers or toward an acquaintance and (2) self-directed emotional sensitivity directed toward others. Regarding construct validity, the scores of f-AMI were correlated with the French Dimensional Apathy Scale results. Concerning the divergent validity, emotional sensitivity in apathy is different from depression, anhedonia, and fatigue levels. Conclusion: These results suggest that the f-AMI can be used to assess levels of apathy in healthy adults.

How does apathy impact exploration-exploitation decision-making in older patients with neurocognitive disorders?

Apathy is a pervasive clinical syndrome in neurocognitive disorders, characterized by a quantitative reduction in goal-directed behaviors. The brain structures involved in the physiopathology of apathy have also been connected to the brain structures involved in probabilistic reward learning in the exploration-exploitation dilemma. This dilemma in question involves the challenge of selecting between a familiar option with a more predictable outcome, and another option whose outcome is uncertain and may yield potentially greater rewards compared to the known option. The aim of this study was to combine experimental procedures and computational modeling to examine whether, in older adults with mild neurocognitive disorders, apathy affects performance in the exploration-exploitation dilemma. Through using a four-armed bandit reinforcement-learning task, we showed that apathetic older adults explored more and performed worse than non-apathetic subjects. Moreover, the mental flexibility assessed by the Trail-making test-B was negatively associated with the percentage of exploration. These results suggest that apathy is characterized by an increased explorative behavior and inefficient decision-making, possibly due to weak mental flexibility to switch toward the exploitation of the more rewarding options. Apathetic participants also took longer to make a choice and failed more often to respond in the allotted time, which could reflect the difficulties in action initiation and selection. In conclusion, the present results suggest that apathy in participants with neurocognitive disorders is associated with specific disturbances in the exploration-exploitation trade-off and sheds light on the disturbances in reward processing in patients with apathy.

Teleconsultations for mental health: Recommendations from a Delphi panel.

Introduction: The use of teleconsultations for mental health has drastically increased since 2020 due to the Covid19 pandemic. In the present paper, we aimed to analyze the advantages and disadvantages of teleconsultations for mental health compared to face-to-face consultations, and to provide recommendations in this domain. Methods: The recommendations were gathered using a Delphi methodology. The expert panel (N = 21) included professionals from the health and ICT domains. They answered questions via two rounds of web surveys, and then discussed the results in a plenary meeting. Some of the questions were also shared with non-experts (N = 104). Results: Both the experts and the non-experts with teleconsultation experience reported a general satisfaction concerning teleconsultations. A SWOT analysis revealed several strengths and opportunities of teleconsultations for mental health, but also several weaknesses and threats. The experts provided a set of practical recommendations for the preparation and organization of teleconsultations for mental health. Discussion: Teleconsultations for mental health have the potential to allow access to care for patients in remote and isolated areas. Thus, their use will unlikely be discontinued after the end of the pandemic. In this context, we suggest that the collaboration among clinicians, researchers, and interface designers is crucial to improve usability and user experience for both clinicians and patients. The importance of teaching teleconsultation skills and informing the public on the features of teleconsultations (e.g., data privacy/security) is also highlighted.

Stochastic models of regulation of transcription in biological cells.

In this paper we study an important global regulation mechanism of transcription of biological cells using specific macro-molecules, 6S RNAs. The functional property of 6S RNAs is of blocking the transcription of RNAs when the environment of the cell is not favorable. We investigate the efficiency of this mechanism with a scaling analysis of a stochastic model. The evolution equations of our model are driven by the law of mass action and the total number of polymerases is used as a scaling parameter. Two regimes are analyzed: exponential phase when the environment of the cell is favorable to its growth, and the stationary phase when resources are scarce. In both regimes, by defining properly occupation measures of the model, we prove an averaging principle for the associated multi-dimensional Markov process on a convenient timescale, as well as convergence results for "fast" variables of the system. An analytical expression of the asymptotic fraction of sequestrated polymerases in stationary phase is in particular obtained. The consequences of these results are discussed.

Mild cognitive impairment identification based on motor and cognitive dual-task pooled indices.

OBJECTIVE: This study investigates the possibility of adopting motor and cognitive dual-task (MCDT) approaches to identify subjects with mild cognitive impairment (MCI) and subjective cognitive impairment (SCI). METHODS: The upper and lower motor performances of 44 older adults were assessed using the SensHand and SensFoot wearable system during three MCDTs: forefinger tapping (FTAP), toe-tapping heel pin (TTHP), and walking 10 m (GAIT). We developed five pooled indices (PIs) based on these MCDTs, and we included them, along with demographic data (age) and clinical scores (Frontal Assessment Battery (FAB) scores), in five logistic regression models. RESULTS: Models which consider cognitively normal adult (CNA) vs MCI subjects have accuracies that range from 67% to 78%. The addition of clinical scores stabilised the accuracies, which ranged from 85% to 89%. For models which consider CNA vs SCI vs MCI subjects, there are great benefits to considering all three regressors (age, FAB score, and PIs); the overall accuracies of the three-class models range between 50% and 59% when just PIs and age are considered, whereas the overall accuracy increases by 18% when all three regressors are utilised. CONCLUSION: Logistic regression models that consider MCDT PIs and age have been effective in distinguishing between CNA and MCI subjects. The inclusion of clinical scores increased the models' accuracy. Particularly high performances in distinguishing among CNA, SCI, and MCI subjects were obtained by the TTHP PI. This study suggests that a broader framework for MCDTs, which should encompass a greater selection of motor tasks, could provide clinicians with new appropriate tools.

Alzheimer's early detection in post-acute COVID-19 syndrome: a systematic review and expert consensus on preclinical assessments.

Introduction: The risk of developing Alzheimer's disease (AD) in older adults increasingly is being discussed in the literature on Post-Acute COVID-19 Syndrome (PACS). Remote digital Assessments for Preclinical AD (RAPAs) are becoming more important in screening for early AD, and should always be available for PACS patients, especially for patients at risk of AD. This systematic review examines the potential for using RAPA to identify impairments in PACS patients, scrutinizes the supporting evidence, and describes the recommendations of experts regarding their use. Methods: We conducted a thorough search using the PubMed and Embase databases. Systematic reviews (with or without meta-analysis), narrative reviews, and observational studies that assessed patients with PACS on specific RAPAs were included. The RAPAs that were identified looked for impairments in olfactory, eye-tracking, graphical, speech and language, central auditory, or spatial navigation abilities. The recommendations' final grades were determined by evaluating the strength of the evidence and by having a consensus discussion about the results of the Delphi rounds among an international Delphi consensus panel called IMPACT, sponsored by the French National Research Agency. The consensus panel included 11 international experts from France, Switzerland, and Canada. Results: Based on the available evidence, olfaction is the most long-lasting impairment found in PACS patients. However, while olfaction is the most prevalent impairment, expert consensus statements recommend that AD olfactory screening should not be used on patients with a history of PACS at this point in time. Experts recommend that olfactory screenings can only be recommended once those under study have reported full recovery. This is particularly important for the deployment of the olfactory identification subdimension. The expert assessment that more long-term studies are needed after a period of full recovery, suggests that this consensus statement requires an update in a few years. Conclusion: Based on available evidence, olfaction could be long-lasting in PACS patients. However, according to expert consensus statements, AD olfactory screening is not recommended for patients with a history of PACS until complete recovery has been confirmed in the literature, particularly for the identification sub-dimension. This consensus statement may require an update in a few years.

Optimizing detection of Alzheimer's disease in mild cognitive impairment: a 4-year biomarker study of mild behavioral impairment in ADNI and MEMENTO.

BACKGROUND: Disease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding MBI would better identify AD, we interrogated associations between MBI in MCI, and cerebrospinal fluid biomarkers [ß-amyloid (Aß), phosphorylated-tau (p-tau), and total-tau (tau)-ATN], cross-sectionally and longitudinally. METHODS: Data were from two independent referral-based cohorts, ADNI (mean[SD] follow-up 3.14[1.07] years) and MEMENTO (4.25[1.40] years), collected 2003-2021. Exposure was based on three-group stratification: 1) NPS meeting MBI criteria; 2) conventionally measured NPS (NPSnotMBI); and 3) noNPS. Cohorts were analyzed separately for: 1) cross-sectional associations between NPS status and ATN biomarkers (linear regressions); 2) 4-year longitudinal repeated-measures associations of MBI and NPSnotMBI with ATN biomarkers (hierarchical linear mixed-effects models-LMEs); and 3) rates of incident dementia (Cox proportional hazards regressions). RESULTS: Of 510 MCI participants, 352 were from ADNI (43.5% females; mean [SD] age, 71.68 [7.40] years), and 158 from MEMENTO (46.2% females; 68.98 [8.18] years). In ADNI, MBI was associated with lower Aß42 (standardized ß [95%CI], -5.52% [-10.48-(-0.29)%]; p = 0.039), and Aß42/40 (p = 0.01); higher p-tau (9.67% [3.96-15.70%]; p = 0.001), t-tau (7.71% [2.70-12.97%]; p = 0.002), p-tau/Aß42 (p < 0.001), and t-tau/Aß42 (p = 0.001). NPSnotMBI was associated only with lower Aß42/40 (p = 0.045). LMEs revealed a similar 4-year AD-specific biomarker profile for MBI, with NPSnotMBI associated only with higher t-tau. MBI had a greater rate of incident dementia (HR [95%CI], 3.50 [1.99-6.17; p < 0.001). NPSnotMBI did not differ from noNPS (HR 0.96 [0.49-1.89]; p = 0.916). In MEMENTO, MBI demonstrated a similar magnitude and direction of effect for all biomarkers, but with a greater reduction in Aß40. HR for incident dementia was 3.93 (p = 0.004) in MBI, and 1.83 (p = 0.266) in NPSnotMBI. Of MBI progressors to dementia, 81% developed AD dementia. CONCLUSIONS: These findings support a biological basis for NPS that meet MBI criteria, the continued inclusion of MBI in NIA-AA ATN clinical staging, and the utility of MBI criteria to improve identification of patients for enrollment in disease-modifying drug trials or for clinical care.