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Abstract Background In patients with chronic obstructive pulmonary disease (COPD), a sensitization to A. fumigatus has been related to a decline in lung function, but the role of fungal agents in the disease pathogenesis remains unclear. The main purpose of the present study was to investigate whether cell inflammation could worsen after exposure to A. fumigatus spores in vitro and then, in mice, following chronic exposure to cigarette smoke mimicking COPD. Methods The inflammatory response to cigarette smoke alone or with A. fumigatus was investigated in cell culture models of murine macrophages and alveolar epithelial cells. In an animal model, mice were exposed daily to two cigarettes smoke over 14 weeks, and two intranasal instillations of 105 spores at weeks 7 and 14. Then, their lungs were recovered to perform inflammatory and histopathological analyses. Results In co-cultures of macrophages and epithelial cells treated with both cigarette smoke extracts (CSE) and A. fumigatus compared to CSE alone there were significant inductions in TNF-α (6.2-fold) and CXCL-2 (21.5-fold) gene expression, confirmed by significant increases in the corresponding protein secretion. In the murine model, histological analyses of the lung after chronic smoke exposure showed an increase in airspace enlargement. Moreover, a Bio-Plex approach on bronchoalveolar lavage of cigarette smoke and A. fumigatus-treated mice showed significant increases in multiple inflammatory proteins secreted in the lung. Conclusions There was a stronger inflammatory response after cigarette smoke exposure with A. fumigatus compared to cigarette smoke alone. These findings were correlated with histopathological changes in the mouse lung in vivo.

Background: Despite vaccination, patients receiving anti-CD20 monoclonal antibodies (mAbs) for multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD) have an increased risk of developing severe or protracted COVID-19. The aim of this study was to describe the effect of COVID-19 convalescent plasma (CCP) in patients with MS or NMOSD exposed to anti-CD20 and infected by SARS-CoV-2. Methods: This French national, retrospective cohort study was conducted between November 2020 and June 2023. Patients with MS or NMOSD, under anti-CD20 mAbs, with symptomatic COVID-19 and treated by CCP were screened. Protracted COVID-19 was defined by a duration of symptoms >21 days. The primary endpoint was the overall survival 30 days after CCP administration. Results: Ninety-two patients from 34 hospitals were included, 84 (91%) with MS and 8 (9%) with NMOSD. Overall, 30-day survival was 97% (IC95%: 91-99). SARS-CoV-2 viremia was positive in 47/75 (61%) patients before CCP versus 9/59 (15%) seven days post-CCP. In the 52 patients (57%) with protracted COVID-19, the duration of symptoms before CCP was 51 [28-69] days, including fever in 75% of cases, which disappeared in 100% of patients 7 days post-CCP. Conclusions: CCP could be a therapeutic option in patients exposed to anti-CD20 mAbs for inflammatory demyelinating disease, particularly in those with protracted COVID-19.

An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency. She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed. Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis. Insulin therapy rapidly corrected biochemical parameters, and clinical status improved. We propose that secondary Krebs cycle disturbances affecting pancreatic beta cells impaired glucose-stimulated insulin secretion, resulting in insulinopenia.

BackgroundCognitive functional ability affects the accessibility of IT and is thus something that should be controlled for in user experience (UX) research. However, many cognitive function assessment batteries are long and complex, making them impractical for use in conventional experimental time frames. Therefore, there is a need for a short and reliable cognitive assessment that has discriminant validity for cognitive functions needed for general IT tasks. One potential candidate is the Trail Making Test (TMT). ObjectiveThis study investigated the usefulness of a digital TMT as a cognitive profiling tool in IT-related UX research by assessing its predictive validity on general IT task performance and exploring its discriminant validity according to discrete cognitive functions required to perform the IT task. MethodsA digital TMT (parts A and B) named Axon was administered to 27 healthy participants, followed by administration of 5 IT tasks in the form of CAPTCHAs (Completely Automated Public Turing tests to Tell Computers and Humans Apart). The discrete cognitive functions required to perform each CAPTCHA were rated by trained evaluators. To further explain and cross-validate our results, the original TMT and 2 psychological assessments of visuomotor and short-term memory function were administered. ResultsAxon A and B were administrable in less than 5 minutes, and overall performance was significantly predictive of general IT task performance (F5,19=6.352; P=.001; Λ=0.374). This result was driven by performance on Axon B (F5,19=3.382; P=.02; Λ=0.529), particularly for IT tasks involving the combination of executive processing with visual object and pattern recognition. Furthermore, Axon was cross-validated with the original TMT (Pcorr=.001 and Pcorr=.017 for A and B, respectively) and visuomotor and short-term memory tasks. ConclusionsThe results demonstrate that variance in IT task performance among an age-homogenous neurotypical population can be related to intersubject variance in cognitive function as assessed by Axon. Although Axon’s predictive validity seemed stronger for tasks involving the combination of executive function with visual object and pattern recognition, these cognitive functions are arguably relevant to the majority of IT interfaces. Considering its short administration time and remote implementability, the Axon digital TMT demonstrates the potential to be a useful cognitive profiling tool for IT-based UX research.

A 2.5-month-old girl admitted for failure to thrive and severe pancytopenia was diagnosed with methylmalonic acidemia (MMA) secondary to transcobalamin II deficiency, an inborn error of vitamin B12 metabolism. Opportunistic Cytomegalovirus and Pneumocystis jirovecii pneumonia led to severe acute respiratory distress syndrome (ARDS) and immune reconstitution inflammatory syndrome (IRIS) after treatment initiation with vitamin B12 supplementation. In children with interstitial pneumonia-related ARDS, normal lymphocyte count should not delay invasive procedures required to document opportunistic infections. MMA can be associated with underlying lymphocyte dysfunction and vitamin B12 supplementation can fully reverse the associated immunodeficiency. IRIS may appear in highly treatment-responsive forms of pancytopenia in children and prompt treatment of dysregulated inflammation with high-dose corticosteroids should be initiated.

Objective: Lipreading, which plays a major role in the communication of the hearing impaired, lacked a French standardised tool. Our aim was to create and validate an audio-visual (AV) version of the French Matrix Sentence Test (FrMST). Design: Video recordings were created by dubbing the existing audio files. Sample: Thirty-five young, normal-hearing participants were tested in auditory and visual modalities alone (Ao, Vo) and in AV conditions, in quiet, noise, and open and closed-set response formats. Results: Lipreading ability (Vo) ranged from 1 % to 77%-word comprehension. The absolute AV benefit was 9.25 dB SPL in quiet and 4.6 dB SNR in noise. The response format did not influence the results in the AV noise condition, except during the training phase. Lipreading ability and AV benefit were significantly correlated. Conclusions: The French video material achieved similar AV benefits as those described in the literature for AV MST in other languages. For clinical purposes, we suggest targeting SRT80 to avoid ceiling effects, and performing two training lists in the AV condition in noise, followed by one AV list in noise, one Ao list in noise and one Vo list, in a randomised order, in open or close set-format.

Idiopathic pulmonary arterial hypertension (IPAH) is an uncommon and severe disease. We report the case of a 7-year-old boy investigated for cardiac murmur and exercise intolerance. Pulmonary hypertension (PH) was suspected at clinical examination and confirmed by echocardiography and cardiac catheterization. This case of pulmonary hypertension was classified as idiopathic given the negative etiological investigation. Vasoreactive testing with oxygen and nitric oxide was negative. Therefore, treatment with sildenafil (1.4 mg/kg/d) and bosentan (3 mg/kg/d) was initiated. This allowed the stabilization of, but not a decrease in, pulmonary artery pressure for the next 5 years, during which the patient’s quality of life was significantly reduced. At a later follow-up, the estimated pulmonary pressure was found to have increased and become supra-systemic, with a consequent deterioration in the child’s condition. This led to the decision to enter him into a clinical trial that is still ongoing. Idiopathic pulmonary arterial hypertension is a severe disease that can present with non-specific symptoms, such as asthenia and exercise limitation, which are important not to trivialize. The disease is associated with significantly decreased quality of life in affected children and carries a high burden in terms of mortality and morbidity. The current knowledge about IPAH in children is reviewed, with a particular focus on the future prospects for its treatment and the related quality of life of patients.

Summary: Detailed single-neuron modeling is widely used to study neuronal functions. While cellular and functional diversity across the mammalian cortex is vast, most of the available computational tools focus on a limited set of specific features characteristic of a single neuron. Here, we present a generalized automated workflow for the creation of robust electrical models and illustrate its performance by building cell models for the rat somatosensory cortex. Each model is based on a 3D morphological reconstruction and a set of ionic mechanisms. We use an evolutionary algorithm to optimize neuronal parameters to match the electrophysiological features extracted from experimental data. Then we validate the optimized models against additional stimuli and assess their generalizability on a population of similar morphologies. Compared to the state-of-the-art canonical models, our models show 5-fold improved generalizability. This versatile approach can be used to build robust models of any neuronal type. The bigger picture: Unraveling the complexity of information processing within individual neurons remains a hard task within neuroscience. Our work builds upon the advancements made in computational modeling, introducing a highly versatile and automated workflow for the construction of detailed and robust neuronal models that accurately reproduce experimentally observed electrophysiological behaviors. Utilizing open-source tools, our approach integrates 3D morphological reconstructions of neurons with specific ionic mechanisms. The resulting models offer novel insights into the diversity of neuronal responses observed in the rat somatosensory cortex. Furthermore, these models exhibit a 5-fold enhancement in generalizability compared to canonical models currently in use. Our universal workflow functions as a powerful tool to guide future experiments and enhance our comprehension of neuronal information processing and biophysical mechanisms across various neuronal types.

IntroductionMaladaptive behavior often results from poor decision-making and by extension poor control over decisions. Since maladaptive behavior in driving, such as excessive speed, can lead to dramatic consequences, identifying its causes is of particular concern. The present study investigated how risk-taking and executive functioning are related to driving performance and habits among the general population.MethodFive hundred and eighty-nine participants completed an on-road driving session with a professional driving instructor and a self-reported checklist of difficult driving situations typically avoided. Additionally, participants completed a set of experimental tasks assessing risk-taking tendencies, reactive adaptive mechanisms, and two distinct forms of inhibition: interference control and response inhibition.ResultsThe results of the present study revealed several significant findings. Firstly, poor driving performance was associated with a high avoidance of challenging driving situations. Secondly, neither form of inhibition studied (interference control or response inhibition) predicted driving performance. Thirdly, while greater involvement in reactive adaptive mechanisms did not predict better on-road performance, it was associated with a reduced tendency to avoid difficult situations. Surprisingly, a higher propensity for risk-taking predicted better on-road performance.DiscussionOverall, these results underline limited links between executive functioning and driving performance while highlighting a potentially more complex relationship between risk-taking tendencies and driving. Executive functioning, however, appears to be linked to driving habits.

Abstract Background Wolman disease (WD), the rapidly progressive phenotype of lysosomal acid lipase (LAL) deficiency, presents in neonates with failure to thrive and hepatosplenomegaly, and leads to multi-organ failure and death before 12 months of age. In clinical trials, enzyme replacement therapy (ERT) with sebelipase alfa led to improved survival, growth and biological parameters in WD patients followed up to 5 years. Long-term follow-up and health-related quality of life (HRQoL) evaluation are lacking. Results We performed a nationwide, retrospective study of sebelipase alfa in WD patients. Five patients with abolished LAL activity and bi-allelic LIPA mutations were included with a median follow-up of 7 years (1–10). ERT was initiated at a median age of 1 month (0–4). Infusion tolerance was excellent on the long-term with only one patient requiring systematic pre-medication. Cholestyramine, fat-soluble vitamin supplements and a specific diet (high in medium-chain triglycerides and low in long-chain fatty acids) were prescribed. Liver function tests, plasma lipid profiles, fat-soluble vitamin levels and growth parameters improved. Three patients transiently exhibited a neuromyopathic phenotype (footdrop gait, waddling walk or muscle fatigue) but electromyography and muscle strength testing were normal. At last follow-up, all patients were alive with normal growth parameters and a satisfactory HRQoL, no patient had special education needs, and one patient required parenteral nutrition since an acute gastroenteritis. Conclusions Early ERT initiation allowed 100% survival with positive outcomes. Very long-term follow-up and hematopoietic stem cell transplantation while on ERT should be evaluated to strengthen the benefits of sebelipase alfa.

Abstract Aim To test whether the occupancy of shorebirds has changed in the eastern Canadian Arctic, and whether these changes could indicate that shorebird distributions are shifting in response to long‐term climate change. Location Foxe Basin and Rasmussen Lowlands, Nunavut, Canada. Methods We used a unique set of observations, made 25 years apart, using general linear models to test if there was a relationship between changes in shorebird species' occupancy and their species temperature Index, a simple version of a species climate envelope. Results Changes in occupancy and density varied widely across species, with some increasing and some decreasing. This is despite that overall population trends are known to be negative for all of these species based on surveys during migration. The changes in occupancy that we observed were positively related to the species temperature index, such that the warmer‐breeding species appear to be moving into these regions, while colder‐breeding species appear to be shifting out of the regions, likely northward. Main Conclusions Our results suggest that we should be concerned about declining breeding habitat availability for bird species whose current breeding ranges are centered on higher and colder latitudes.

Knowledge of the cell-type-specific composition of the brain is useful in order to understand the role of each cell type as part of the network. Here, we estimated the composition of the whole cortex in terms of well characterized morphological and electrophysiological inhibitory neuron types (me-types). We derived probabilistic me-type densities from an existing atlas of molecularly defined cell-type densities in the mouse cortex. We used a well-established me-type classification from rat somatosensory cortex to populate the cortex. These me-types were well characterized morphologically and electrophysiologically but they lacked molecular marker identity labels. To extrapolate this missing information, we employed an additional dataset from the Allen Institute for Brain Science containing molecular identity as well as morphological and electrophysiological data for mouse cortical neurons. We first built a latent space based on a number of comparable morphological and electrical features common to both data sources. We then identified 19 morpho-electrical clusters that merged neurons from both datasets while being molecularly homogeneous. The resulting clusters best mirror the molecular identity classification solely using available morpho-electrical features. Finally, we stochastically assigned a molecular identity to a me-type neuron based on the latent space cluster it was assigned to. The resulting mapping was used to derive inhibitory me-types densities in the cortex. Author summary The computational abilities of the brain arise from its organization principles at the cellular level. One of these principles is the neuronal type composition over different regions. Since computational functions of neurons are best described by their morphological and electrophysiological properties, it is logical to use morpho-electrically defined cell types to describe brain composition. However, characterizing morpho-electrical properties of cells involve low-throughput techniques not very well suited to scan the whole brain. Thanks to recent progress on transcriptomic and immuno-staining techniques we are now able to get a more accurate snapshot of the mouse brain composition for molecularly defined cell types. How to link molecularly defined cell types with morpho-electrical cell types remains an open question. Several studies have explored this problem providing valuable three-modal datasets combining electrical, morphological and molecular properties of cortical neurons. The long-term goal of the Blue Brain Project (BBP) is to accurately model the mouse’s whole brain, which requires detailed biophysical models of neurons. Instead of going through the time-consuming process of producing detailed models from the three-modal datasets, we explored a time-saving method. We mapped the already available detailed morpho-electrical models from the BBP rat dataset to cells from a three-modal mouse dataset. We thus assigned a molecular identity to the neuron models allowing us to populate the whole mouse cortex with detailed neuron models.

According to the dual mechanisms of control (DMC), reactive and proactive control are involved in adjusting behaviors when maladapted to the environment. However, both contextual and inter-individual factors increase the weight of one control mechanism over the other, by influencing their cognitive costs. According to one of the DMC postulates, limited reactive control capacities should be counterbalanced by greater proactive control to ensure control efficiency. Moreover, as the flexible weighting between reactive and proactive control is key for adaptive behaviors, we expected that maladaptive behaviors, such as risk-taking, would be characterized by an absence of such counterbalance. However, to our knowledge, no studies have yet investigated this postulate. In the current study, we analyzed the performances of 176 participants on two reaction time tasks (Simon and Stop Signal tasks) and a risk-taking assessment (Balloon Analog Risk Taking, BART). The post-error slowing in the Simon task was used to reflect the spontaneous individuals' tendency to proactively adjust behaviors after an error. The Stop Signal Reaction Time was used to assess reactive inhibition capacities and the duration of the button press in the BART was used as an index of risk-taking propensity. Results showed that poorer reactive inhibition capacities predicted greater proactive adjustments after an error. Furthermore, the higher the risk-taking propensity, the less reactive inhibition capacities predicted proactive behavioral adjustments. The reported results suggest that higher risk-taking is associated with a smaller weighting of proactive control in response to limited reactive inhibition capacities. These findings highlight the importance of considering the imbalanced weighting of reactive and proactive control in the analysis of risk-taking, and in a broader sense, maladaptive behaviors.

Abstract The rapidly changing climate in the Arctic is expected to have a major impact on the foraging ecology of seabirds, owing to changes in the distribution and abundance of their prey but also that of competitors (e.g. southerly species expanding their range into the Arctic). Species can respond to interspecific competition by segregating along different niche axes. Here, we studied spatial, temporal and habitat segregation between two closely related seabird species: common guillemot Uria aalge (a temperate species) and Brünnich’s guillemot Uria lomvia (a true Arctic species), at two sympatric sites in Iceland that differ in their total population sizes and the availability of marine habitats. We deployed GPS and temperature-depth recorders to describe foraging locations and behaviour of incubating and chick-rearing adults. We found similar evidence of spatial segregation at the two sites (i.e. independent of population sizes), although segregation in environmental space was only evident at the site with a strong habitat gradient. Unexpectedly, temporal (and, to a limited extent, vertical) segregation appeared only at the least populated site. Overall, our results show complex relationships between the levels of inferred competition and that of segregation.

The airway exposure to Aspergillus fumigatus spores (AFsp) is associated with an inflammatory response, potentially leading to allergic and/or chronic pulmonary aspergillosis. The aim of our study is to better understand the host response, first in vitro, then in vivo, following the chronic exposure of mice to AFsp. We investigated the inflammatory response to AFsp in cell mono- and co-culture systems with murine macrophages and alveolar epithelial cells. The mice were subjected to two intranasal instillations using 105 AFsp. Their lungs were processed for inflammatory and histopathological analyses. In cell culture, the gene expressions significantly increased for TNF-α, CXCL-1, CXCL-2, IL-1β, IL-1α and GM-CSF in macrophages, with these increases being limited for TNF-α, CXCL-1 and IL-1α in epithelial cells. In co-culture, increases in the TNF-α, CXCL-2 and CXCL-1 gene expressions were observed to be associated with increased protein levels. The in vivo lung histological analyses of mice challenged by AFsp showed cellular infiltrates in the peribronchial and/or alveolar spaces. A Bio-Plex approach on the bronchoalveolar lavage revealed significant increases in the protein secretion of selected mediators of the challenged mice compared to the unchallenged mice. In conclusion, the exposure to AFsp resulted in a marked inflammatory response of macrophages and epithelial cells. These inflammatory findings were confirmed in mouse models associated with lung histologic changes.