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Michael Quiquempoix,1,2 Fabien Sauvet,1,2 Mégane Erblang,1– 3 Pascal Van Beers,1,2 Mathias Guillard,1,2 Catherine Drogou,1,2 Aurélie Trignol,1,2 Anita Vergez,1,2 Damien Léger,2,4 Mounir Chennaoui,1,2 Danielle Gomez-Merino,1,2 Arnaud Rabat1,2 1Department of Operational Environments, Fatigue and Vigilance Team, French Armed Forces Biomedical Research Institute (IRBA), Paris, France; 2VIFASOM Team (EA 7330), University of Paris - Hôtel Dieu AP-HP Hospital, Paris, France; 3LBEPS, Univ Evry, IRBA, University of Paris-Saclay, Paris, France; 4Centre du sommeil et de la vigilance, Hôpital Hôtel Dieu AP-HP, Paris, 75004, FranceCorrespondence: Michael Quiquempoix, Department of operational environments, Fatigue and Vigilance Team, Armed Forces Biomedical Research Institute (IRBA), 1, avenue du Général Valérie André, BP 73, Brétigny sur Orge, Paris, 91223, France, Email michael.quiquempoix@def.gouv.frIntroduction: It is widely admitted that both total sleep deprivation (TSD) and extended task engagement (Time-On-Task, TOT) induce a cognitive fatigue state in healthy subjects. Even if EEG theta activity and adenosine both increase with cognitive fatigue, it remains unclear if these modifications are common mechanisms for both sustained attention and executive processes.Methods: We performed a double-blind counter-balanced (placebo (PCBO) and caffeine (CAF) - 2× 2.5 mg/kg/24 h)) study on 24 healthy subjects (33.7 ± 5.9 y). Subjects participated in an experimental protocol including an habituation/training day followed by a baseline day (D0 and D1) and a total sleep deprivation (TSD) day beginning on D1 at 23:00 until D2 at 21:00. Subjects performed the psychomotor vigilance test (PVT) assessing sustained attention, followed by the executive Go-NoGo inhibition task and the 2-NBack working memory task at 09:15 on D1 and D2.Results: We showed differential contributions of TSD and TOT on deficits in sustained attention and both executive processes. An alleviating effect of caffeine intake is only observed on sustained attention deficits related to TSD and not at all on TOT effect. The caffeine dose slows down the triggering of sustained attention deficits related to TOT effect.Discussion: These results suggest that sustained attention deficits induced by TSD rely on the adenosinergic mechanism whereas TOT effect observed for both sustained attention and executive would not.Keywords: total sleep deprivation, time on task, caffeine, sustained attention, inhibition, working memory, cognitive fatigue, mental fatigue, healthy subjects

Aircraft pilots face a high mental workload (MW) under environmental constraints induced by high altitude and sometimes sleep restriction (SR). Our aim was to assess the combined effects of hypoxia and sleep restriction on cognitive and physiological responses to different MW levels using the Multi-Attribute Test Battery (MATB)-II with an additional auditory Oddball-like task. Seventeen healthy subjects were subjected in random order to three 12-min periods of increased MW level (low, medium, and high): sleep restriction (SR, 6 h TST), hypoxia (HY, 2 h, FIO2 = 13.6%, ~3500 m vs. normoxia, NO, FIO2 = 21%). Following each MW level, participants completed the NASA-TLX subjective MW scale. Increasing MW decreases performance on the MATB-II Tracking task (p = 0.001, MW difficulty main effect) and increases NASA-TLX (p = 0.001). In the combined HY/SR condition, MATB-II performance was lower, and the NASA-TLX score was higher compared with the NO/HS condition, while no effect of hypoxia alone was observed. In the accuracy of the auditory task, there is a significant interaction between hypoxia and MW difficulty (F(2–176) = 3.14, p = 0.04), with lower values at high MW under hypoxic conditions. Breathing rate, pupil size, and amplitude of pupil dilation response (PDR) to auditory stimuli are associated with increased MW. These parameters are the best predictors of increased MW, independently of physiological constraints. Adding ECG, SpO2, or electrodermal conductance does not improve model performance. In conclusion, hypoxia and sleep restriction have an additive effect on MW. Physiological and electrophysiological responses must be taken into account when designing a MW predictive model and cross-validation.

Abstract Background NADPH oxidase (NOX), a primary source of endothelial reactive oxygen species (ROS), is considered a key event in disrupting the integrity of the blood-retinal barrier. Abnormalities in neurovascular-coupled immune signaling herald the loss of ganglion cells in glaucoma. Persistent microglia-driven inflammation and cellular innate immune system dysregulation often lead to deteriorating retinal degeneration. However, the crosstalk between NOX and the retinal immune environment remains unresolved. Here, we investigate the interaction between oxidative stress and neuroinflammation in glaucoma by genetic defects of NOX2 or its regulation via gp91ds-tat. Methods Ex vivo cultures of retinal explants from wildtype C57BL/6J and Nox2 −/− mice were subjected to normal and high hydrostatic pressure (Pressure 60 mmHg) for 24 h. In vivo, high intraocular pressure (H-IOP) was induced in C57BL/6J mice for two weeks. Both Pressure 60 mmHg retinas and H-IOP mice were treated with either gp91ds-tat (a NOX2-specific inhibitor). Proteomic analysis was performed on control, H-IOP, and treatment with gp91ds-tat retinas to identify differentially expressed proteins (DEPs). The study also evaluated various glaucoma phenotypes, including IOP, retinal ganglion cell (RGC) functionality, and optic nerve (ON) degeneration. The superoxide (O2 -) levels assay, blood-retinal barrier degradation, gliosis, neuroinflammation, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative PCR were performed in this study. Results We found that NOX2-specific deletion or activity inhibition effectively attenuated retinal oxidative stress, immune dysregulation, the internal blood-retinal barrier (iBRB) injury, neurovascular unit (NVU) dysfunction, RGC loss, and ON axonal degeneration following H-IOP. Mechanistically, we unveiled for the first time that NOX2-dependent ROS-driven pro-inflammatory signaling, where NOX2/ROS induces endothelium-derived endothelin-1 (ET-1) overexpression, which activates the ERK1/2 signaling pathway and mediates the shift of microglia activation to a pro-inflammatory M1 phenotype, thereby triggering a neuroinflammatory outburst. Conclusions Collectively, we demonstrate for the first time that NOX2 deletion or gp91ds-tat inhibition attenuates iBRB injury and NVU dysfunction to rescue glaucomatous RGC loss and ON axon degeneration, which is associated with inhibition of the ET-1/ERK1/2-transduced shift of microglial cell activation toward a pro-inflammatory M1 phenotype, highlighting NOX2 as a potential target for novel neuroprotective therapies in glaucoma management.

Abstract Background & aims Despite its high prevalence in the western world metabolic dysfunction-associated steatotic liver disease (MASLD) does not benefit from targeted pharmacological therapy. We measured healthcare utilisation and identified factors associated with high-cost MASLD patients in France. Methods The prevalent population with MASLD (including non-alcoholic steatohepatitis) in the CONSTANCES cohort, a nationally representative sample of 200,000 adults aged between 18 and 69, was linked to the French centralised national claims database (SNDS). Study participants were identified by the fatty liver index (FLI) over the period 2015–2019. MASLD individuals were classified according as “high-cost” (above 90th percentile) or “non-high cost” (below 90th percentile). Factors significantly associated with high costs were identified using a multivariate logistic regression model. Results A total of 14,437 predominantly male (69%) participants with an average age of 53 ± SD 12 years were included. They mainly belonged to socially deprived population groups with co-morbidities such as diabetes, high blood pressure, mental health disorders and cardiovascular complications. The average expenditure was €1860 ± SD 4634 per year. High-cost MASLD cost €10,863 ± SD 10,859 per year. Conditions associated with high-cost were mental health disorders OR 1.79 (1.44–2.22), cardiovascular diseases OR 1.54 (1.21–1.95), metabolic comorbidities OR 1.50 (1.25–1.81), and respiratory disease OR 1.50 (1.11–2.00). The 10% high-cost participants accounted for 58% of the total national health care expenditures for MASLD. Conclusion Our results emphasize the need for comprehensive management of the comorbid conditions which were the major cost drivers of MASLD. Graphical Abstract

Introduction Membranopathies encompass haemolytic disorders arising from genetic variants in erythrocyte membrane proteins, including hereditary spherocytosis and stomatocytosis. Congenital dyserythropoietic anaemia type II (CDA II) is associated with the SEC23B gene and can exhibit phenotypic similarities to membranopathies. Current treatment options for these conditions, apart from splenectomy, are primarily supportive. Mitapivat, a novel pyruvate kinase (PK) activator, has demonstrated efficacy in increasing haemoglobin levels and reducing haemolysis in patients with PK deficiency, thalassemia, sickle cell disease and a mouse model of hereditary spherocytosis.Methods and analyses Safety and efficacy of mitapivat sulfate in adult patients with erythrocyte membranopathies (SATISFY) is a prospective, multicentre, single-arm phase two trial involving approximately 25 adult patients (≥18 years) diagnosed with a membranopathy or CDA II. During the 8-week dose escalation period, subjects will receive an initial dose of 50 mg mitapivat two times per day and may increase to 100 mg two times per day at week 4 based on the safety and changes in haemoglobin levels. Patients tolerating mitapivat well may be eligible to continue in two consecutive 24-week fixed dose periods.The primary objective of this study is to evaluate the safety of mitapivat, assessed through the occurrence of treatment-emergent adverse events. Secondary objectives include assessing the effects of mitapivat on haemoglobin levels, haemolysis, erythropoiesis, patient-reported outcome measures and spleen size.SATISFY aims to assess the safety and efficacy of mitapivat in adult patients with red blood cell membranopathies and CDA II, with the aim of establishing proof-of-concept in patients living with these rare conditions.Ethics and dissemination NCT05935202/CTIS:2023-503271-24-01. Findings will be published in peer-reviewed journals.Trial registration number Clinicaltrials.gov, NCT05935202. CTIS:2023-503271-24-01. Registered 07-July-2023. Protocol number: 2.1. https://clinicaltrials.gov/study/NCT05935202.

IntroductionThe unique red blood cell (RBC) properties that characterize the rare neuroacanthocytosis syndromes (NAS) have prompted the exploration of osmotic gradient ektacytometry (Osmoscan) as a diagnostic tool for these disorders. In this exploratory study, we assessed if Osmoscans can discriminate NAS from other neurodegenerative diseases.MethodsA comprehensive assessment was conducted using Osmoscan on a diverse group of patients, including healthy controls (n = 9), neuroacanthocytosis syndrome patients (n = 6, 2 VPS13A and 4 XK disease), Parkinson’s disease patients (n = 6), Huntington’s disease patients (n = 5), and amyotrophic lateral sclerosis patients (n = 4). Concurrently, we collected and analyzed RBC indices and patients’ characteristics.ResultsStatistically significant changes were observed in NAS patients compared to healthy controls and other conditions, specifically in osmolality at minimal elongation index (Omin), maximal elongation index (EImax), the osmolality at half maximal elongation index in the hyperosmotic part of the curve (Ohyper), and the width of the curve close to the osmolality at maximal elongation index (Omax-width).DiscussionThis study represents an initial exploration of RBC properties from NAS patients using osmotic gradient ektacytometry. While specific parameters exhibited differences, only Ohyper and Omax-width yielded 100% specificity for other neurodegenerative diseases. Moreover, unique correlations between Osmoscan parameters and RBC indices in NAS versus controls were identified, such as osmolality at maximal elongation index (Omax) vs. mean cellular hemoglobin content (MCH) and minimal elongation index (EImin) vs. red blood cell distribution width (RDW). Given the limited sample size, further studies are essential to establish diagnostic guidelines based on these findings.

Abstract Exposure to both oxidative and shear stress, a condition that the red blood cell (RBC) continuously experiences in the circulation in vivo can be mimicked in a Couette type viscometer and monitored by ektacytometry. RBCs maintain their deformation and orientation under shear stress and oxidative stress until a threshold is reached at which these conditions appear to overwhelm the elaborate and complex pathways that maintain a proper redox environment in the cell. Oxidative stress under shear alters the ability of the cell to deform, changes cell morphology, its orientation in the shear stress field, and appears to alter intracellular and membrane characteristics. The application of the RoxyScan technology allows the comparison of oxidant effects and the role of antioxidant systems. This provides the opportunity to study the ability of RBC to deal with oxidative stress in various conditions, including RBC disorders such as sickle cell disease (SCD).

Abstract Background Total laryngectomy (TL) is a surgical procedure commonly performed on patients with advanced laryngeal or hypopharyngeal carcinoma. One of the most common postoperative complications following TL is the development of a pharyngocutaneous fistula (PCF), characterized by a communication between the neopharynx and the skin. PCF can lead to extended hospital stays, delayed oral feeding, and compromised quality of life. The use of a myofascial pectoralis major flap (PMMF) as an onlay technique during pharyngeal closure has shown potential in reducing PCF rates in high risk patients for development of PCF such as patients undergoing TL after chemoradiation and low skeletal muscle mass (SMM). Its impact on various functional outcomes, such as shoulder and neck function, swallowing function, and voice quality, remains less explored. This study aims to investigate the effectiveness of PMMF in reducing PCF rates in patients with low SMM and its potential consequences on patient well-being. Methods This multicenter study adopts a randomized clinical trial (RCT) design and is funded by the Dutch Cancer Society. Eligible patients for TL, aged ≥ 18 years, mentally competent, and proficient in Dutch, will be enrolled. One hundred and twenty eight patients with low SMM will be centrally randomized to receive TL with or without PMMF, while those without low SMM will undergo standard TL. Primary outcome measurement involves assessing PCF rates within 30 days post-TL. Secondary objectives include evaluating quality of life, shoulder and neck function, swallowing function, and voice quality using standardized questionnaires and functional tests. Data will be collected through electronic patient records. Discussion This study’s significance lies in its exploration of the potential benefits of using PMMF as an onlay technique during pharyngeal closure to reduce PCF rates in TL patients with low SMM. By assessing various functional outcomes, the study aims to provide a comprehensive understanding of the impact of PMMF deployment. The anticipated results will contribute valuable insights into optimizing surgical techniques to enhance patient outcomes and inform future treatment strategies for TL patients. Trial registration NL8605, registered on 11-05-2020; International Clinical Trials Registry Platform (ICTRP).

Students involved in social justice activist groups and activities encounter several potentially negative consequences in advocating for issues that are important to them. Through duo ethnographic interviews with scholar-activists, former youth activists describe the barriers they experienced as socially engaged young people, including dealing with pushback from their cultural, school, and even activist communities. Without adult allies to help mentor them through these processes, the negative emotions associated with these encounters can lead youth to burn out and leave activism altogether. The findings of this study remind educators that they have an important role to play in providing meaningful activist training, apprenticeship opportunities, and supports for youth who are passionately engaged in progressive social and political action.

The immunomodulating chemotherapeutic drugs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) have the ablity to pass the placenta during pregnancy and might affect the development of the immune system of exposed infants. In particular rituximab causes a transient and almost complete depletion of CD20 expressing B cells and can remain detectable in the infant several months after birth.In this case series we report on the clinical and immunological outcomes of 3 infants exposed to R-CHOP during pregnancy because of maternal B-cell lymphoma and review other cases that have been published. We show that R-CHOP in pregnancy has a profound effect on the immune system in the first year of life, including B-cell lymphopenia, hypogammaglobinemia, neutropenia and decreased response to immunization. Immune monitoring of exposed infants is warranted.

Background: Therapeutic drug monitoring of biological Tumor Necrosis Factor (TNF)-alpha inhibitors is of critical importance. In this study, the performance of practically advantageous chemiluminescent immunoassays of Theradiag, assessing Infliximab and Adalimumab serum concentrations and anti-drug antibodies (ADA) against these biologics, were compared to the Enzyme-Linked Immuno-Sorbent Assays (ELISAs) from Sanquin Diagnostics. Methods: Leftover serum samples (n = 80 for each parameter) from patients treated with Infliximab or Adalimumab were collected. Correlation and agreement analyses for serum concentration and ADAs, respectively, were performed. Both Theradiag ADA assays, an assay targeting both free and bound ADAs and an assay targeting solely free ADAs, were investigated and compared to the Sanquin Diagnostics ADA assay, targeting both free and bound ADAs. Results: Strong positive correlations were observed between the biologic concentration assessment of Infliximab (Spearman’s Rho = 0.91) and Adalimumab (Spearman’s Rho = 0.94). However, there appeared to be significant bias in the Theradiag assay when compared to Sanquin (Infliximab median (Confidence Interval (CI)) = 2.1 (1.7–2.6) µg/mL; Adalimumab median (CI) = 0.8 (0.5–0.9) µg/mL). Agreement analyses showed moderate to good agreement for the Theradiag and Sanquin Diagnostics ADA assays, when detecting both free and bound ADAs, for Infliximab (Cohen’s k = 0.717) and Adalimumab (Cohen’s k = 0.802). In contrast, the Theradiag ADA assay detecting solely free ADAs had zero to poor agreement for Infliximab (Cohen’s k = 0.458) and Adalimumab (Cohen’s k = 0.119), respectively. Conclusions: This study demonstrated strong correlations and good agreement between the Theradiag and Sanquin Diagnostics assays measuring Infliximab and Adalimumab serum concentrations and ADAs, both free and bound, against these biologics. Discordance analyses showed significantly decreased drug concentrations in the solely free assays, indicating that the combined detection of free and bound ADAs better aligns with drug levels.

ObjectiveComorbid post-traumatic stress disorder in patients with anorexia nervosa may negatively affect the course of anorexia nervosa treatment, which is already challenging. There are currently no guidelines or recommendations on concurrent treatment approaches for both anorexia nervosa and post-traumatic stress disorder. This systematic scoping review aims to explore the feasibility, acceptability and effectiveness of psychological trauma-focused treatment concurrently offered to underweight patients receiving anorexia nervosa treatment.MethodA multi-step literature search, according to an a priori protocol was performed. Databases PubMed, Embase, APA PsycINFO, Web of Science, Scopus and Cochrane Central were searched up to September 19th 2022, and the search was rerun June 19th 2023. For quality assessment, Risk of Bias in Non-randomised Studies-of Interventions tool was used.ResultsThe extensive search yielded 1769 reports, out of which only three observational pilot studies, both English and German, published between 2004 and 2022, could be included. The included studies reported on a total of 13 female participants between 16 and 58 years old, with anorexia nervosa or otherwise specified feeding or eating disorder, baseline BMI ranging between 14.6 and 16.5, who received concurrent anorexia and post-traumatic stress disorder treatment. In all participants, the emotional and cognitive functioning was sufficient to process the offered trauma-focused interventions, despite their significantly low body weight.DiscussionThe findings of this review identify a dearth of treatment research on knowledge of concurrent trauma-focused treatments for patients with anorexia nervosa. Refraining patients with anorexia nervosa from trauma-focused treatment may not be warranted.

Binge-eating disorder (BED) is a psychiatric disorder characterized by recurrent episodes of eating a large amount of food in a discrete period of time while experiencing a loss of control. Cognitive behavioral therapy-enhanced (CBT-E) is a recommended treatment for binge-eating disorder and is typically offered through 20 sessions. Although binge-eating disorder is highly responsive to CBT-E, the cost of treating these patients is high. Therefore, it is crucial to evaluate the efficacy of low-intensity and low-cost treatments for binge-eating disorder that can be offered as a first line of treatment and be widely disseminated. The proposed noninferiority randomized controlled trial aims to determine the efficacy of web-based guided self-help CBT-E compared to treatment-as-usual CBT-E. Guided self-help will be based on a self-help program to stop binge eating, will be shorter in duration and lower intensity, and will require fewer therapist hours. Patients with binge-eating disorder (N = 180) will be randomly assigned to receive guided self-help or treatment-as-usual. Assessments will take place at baseline, mid-treatment, at the end of treatment, and at 20- and 40-weeks post-treatment. Treatment efficacy will be measured by examining the reduction in binge-eating days in the previous 28 days between baseline and the end of treatment between groups, with a noninferiority margin (Δ) of 1 binge-eating day. Secondary outcomes will include full remission, body shape dissatisfaction, therapeutic alliance, clinical impairment, health-related quality of life, attrition, and an economic evaluation to assess cost-effectiveness and cost-utility. The moderators examined will be baseline scores, demographic variables, and body mass index. It is expected that guided self-help is noninferior in efficacy compared to treatment-as-usual. The proposed study will be the first to directly compare the efficacy and economically evaluate a low-intensity and low-cost binge-eating disorder treatment compared to treatment-as-usual. If guided self-help is noninferior to treatment-as-usual in efficacy, it can be widely disseminated and used as a first line of treatment for patients with binge-eating disorder. The Dutch trial register number is R21.016. The study has been approved by the Medical Research Ethics Committees United on May 25th, 2021, case number NL76368.100.21.

Background and purpose: To date, the mid- and long-term outcomes of the Collum Femoris Preserving (CFP) stem compared with conventional straight stems are unknown. We aimed to compare physical function at a 5-year follow-up and implant survival at an average of 10-year follow-up in an randomized controlled trial (RCT). Methods: This is a secondary report of a double-blinded RCT in 2 hospitals. Patients aged 18–70 years with hip osteoarthritis undergoing an uncemented primary THA were randomized to a CFP or a Zweymüller stem. Patient-reported outcomes, clinical tests, and radiographs were collected at baseline, 2, 3, 4, and 5 years postoperatively. Primary outcome was the Hip disability and Osteoarthritis Outcome Score (HOOS) function in activities of daily living (ADL) subscale. Secondary outcomes were other patient-reported outcomes, clinical tests, adverse events, and implant survival. Kaplan–Meier and competing risk survival analyses were performed with data from the Dutch Arthroplasty Registry. Results: We included 150 patients. Mean difference between groups on the HOOS ADL subscale at 5 years was –0.07 (95% confidence interval –5.1 to 4.9). Overall survival was 92% for the CFP and 96% for the Zweymüller stem. No significant difference was found. Conclusion: No significant differences were found in physical function at 5-year and implant survival at 10-year follow-up between the CFP and Zweymüller stems. When taking cup revisions into account, the CFP group showed clinically inferior survival.