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Abstract Background Coronary microvascular dysfunction (CMD) refers to structural and functional abnormalities of the coronary microcirculation, which may be diagnosed using invasive coronary physiology. CMD is responsible for impaired diastolic cardiac function. It has recently been suggested that left atrial strain (LASr) represents a highly sensitive tool for detecting cardiac diastolic function abnormalities. Accordingly, the aim of this study was to investigate the relationship between CMD and LASr. Methods Consecutively enrolled patients with non-obstructed coronary arteries (NOCA) underwent CMD and LASr evaluation by invasive thermodilution and noninvasive echocardiography, respectively. Results Forty-two (42) patients were included, out of which 26 presented with CMD. There were no significant differences between CMD-positive and negative patients in terms of clinical and echocardiographic characteristics. LASr was significantly reduced in patients with CMD (24.6% ± 6.1 vs. 30.3 ± 7.8%, p = 0.01). A moderate correlation was observed between coronary flow reserve and LAsr (r = 0.47, p = 0.002). A multivariate logistic regression analysis demonstrated that CMD was independently associated with LASr (OR = 0.88, 95%CI 0.78–0.99.135, p = 0.04). A LASr cut-off of 25.5% enabled an optimal classification of patients with or without CMD. Conclusion Patients with NOCA and CMD had a significantly reduced LASr compared with patients without CMD, suggesting the early impairment of diastolic function in these patients.

Abstract Creativity is a key skill for the twenty-first century, where the individual and collective imperative to adapt is omnipresent. Yet, it is still unclear how to put creativity theories into practice, which signals a lacuna in our understanding of the pragmatic means by which we get creative. This paper starts from the identification of a number of gaps in the literature. In particular, individual and group creativity are usually treated separately, and the emphasis on the search for novelty seems to overshadow the importance experts give to the disruption of their habitual patterns of behavior. To overcome these gaps, we propose foundations for a unifying framework that takes the perspective of dynamical systems. Specifically, we suggest that de-synchronization, a hallmark of disruption, is an integral part of the creative processes that operate across individual and collective levels of analysis. We show that by conjuring uncertainty, de-synchronized states provide opportunities for creative reorganization. In order to ground this framework, we survey and discuss existing literature, and focus on group improvisation practices (in particular, music and dance improvisation), where partners use the dynamics of their interaction to bring forth a collective performance in real-time. In these practices, disruption by de-synchronization, termed here as ‘problematization of coordination’, is a pragmatic approach used to push the creative process forward. We suggest that this approach might also be relevant in other types of individual and collective creative processes.

Abstract Background The present analysis aimed to assess the mediating role of psychosocial and behavioural factors in socio-economic inequalities in health-related quality of life (HRQoL) among children and adolescents. Methods Cross-sectional data was drawn from the randomly selected SEROCoV-KIDS cohort study in Geneva, Switzerland. Associations of socio-economic conditions (parents’ highest education, household financial situation) with HRQoL, psychosocial (parent–child relationship, school difficulties, friends, extracurricular activities) and behavioural factors (screen time, physical activity, green spaces time, sleep duration), along with associations of psychosocial and behavioural factors with HRQoL, were evaluated with generalized estimating equations. Counterfactual mediation analyses were conducted to test pathways linking socio-economic conditions to HRQoL. Results Of 965 children and 816 adolescents, those with disadvantaged financial circumstances were more likely to have a poor HRQoL (adjusted Odds Ratio [aOR]: 3.80; 95% confidence interval [CI]: 1.96–7.36 and aOR: 3.66; 95%CI: 2.06–6.52, respectively). Psychosocial characteristics mediated 25% (95%CI: 5–70%) and 40% (95%CI: 18–63%) of financial disparities in HRQoL among children and adolescents, respectively. Health behaviours were weakly patterned by socio-economic conditions and did not contribute to financial differences in HRQoL. Conclusions These findings provide empirical evidence for mechanisms explaining socio-economic disparities in child HRQoL and could inform interventions aimed to tackle health inequalities.

Abstract This editorial outlines the outcome of an interdisciplinary session on collective sense-making through dance improvisation, which took place during the ‘Neural and Social Bases of Creative Movement’ workshop. We argue that joint improvisation practices place the scientist in a privileged position to reveal the nature of cognitive and creative behaviors.

Abstract Despite numerous efforts from numerical approaches to complement experimental measurements, several fundamental challenges have still hindered one’s ability to truly provide an atomistic picture of the nucleation process in nanocrystals. Among them, our study resolves three obstacles: (1) Machine-learning force fields including long-range interactions able to capture the finesse of the underlying atomic interactions, (2) Data-driven characterization of the local ordering in a complex structural landscape associated with several crystal polymorphs and (3) Comparing results from a large range of temperatures using both brute-force and rare-event sampling. Altogether, our simulation strategy has allowed us to study zinc oxide crystallization from nano-droplet melt. Remarkably, our results show that different nucleation pathways compete depending on the investigated degree of supercooling.

Abstract Long-read RNA sequencing is essential to produce accurate and exhaustive annotation of eukaryotic genomes. Despite advancements in throughput and accuracy, achieving reliable end-to-end identification of RNA transcripts remains a challenge for long-read sequencing methods. To address this limitation, we develop CapTrap-seq, a cDNA library preparation method, which combines the Cap-trapping strategy with oligo(dT) priming to detect 5’ capped, full-length transcripts. In our study, we evaluate the performance of CapTrap-seq alongside other widely used RNA-seq library preparation protocols in human and mouse tissues, employing both ONT and PacBio sequencing technologies. To explore the quantitative capabilities of CapTrap-seq and its accuracy in reconstructing full-length RNA molecules, we implement a capping strategy for synthetic RNA spike-in sequences that mimics the natural 5’cap formation. Our benchmarks, incorporating the Long-read RNA-seq Genome Annotation Assessment Project (LRGASP) data, demonstrate that CapTrap-seq is a competitive, platform-agnostic RNA library preparation method for generating full-length transcript sequences.

Abstract Freezing of gait (FOG) is a debilitating problem that markedly impairs the mobility and independence of 38-65% of people with Parkinson’s disease. During a FOG episode, patients report that their feet are suddenly and inexplicably “glued” to the floor. The lack of a widely applicable, objective FOG detection method obstructs research and treatment. To address this problem, we organized a 3-month machine-learning contest, inviting experts from around the world to develop wearable sensor-based FOG detection algorithms. 1,379 teams from 83 countries submitted 24,862 solutions. The winning solutions demonstrated high accuracy, high specificity, and good precision in FOG detection, with strong correlations to gold-standard references. When applied to continuous 24/7 data, the solutions revealed previously unobserved patterns in daily living FOG occurrences. This successful endeavor underscores the potential of machine learning contests to rapidly engage AI experts in addressing critical medical challenges and provides a promising means for objective FOG quantification.

Abstract Background Immunosuppression at intensive care unit (ICU) admission has been associated with a higher incidence of ICU-acquired infections, some of them related to opportunistic pathogens. However, the association of immunosuppression with the incidence, microbiology and outcomes of ICU-acquired bacterial bloodstream infections (BSI) has not been thoroughly investigated. Methods Retrospective single-centered cohort study in France. All adult patients hospitalized in the ICU of Lille University-affiliated hospital for > 48 h between January 1st and December 31st, 2020, were included, regardless of their immune status. Immunosuppression was defined as active cancer or hematologic malignancy, neutropenia, hematopoietic stem cell and solid organ transplants, use of steroids or immunosuppressive drugs, human immunodeficiency virus infection and genetic immune deficiency. The primary objective was to compare the 28-day cumulative incidence of ICU-acquired bacterial BSI between immunocompromised and non-immunocompromised patients. Secondary objectives were to assess the microbiology and outcomes of ICU-acquired bacterial BSI in the two groups. Results A total of 1313 patients (66.9% males, median age 62 years) were included. Among them, 271 (20.6%) were immunocompromised at ICU admission. Severity scores at admission, the use of invasive devices and antibiotic exposure during ICU stay were comparable between groups. Both prior to and after adjustment for pre‐specified baseline confounders, the 28-day cumulative incidence of ICU-acquired bacterial BSI was not statistically different between immunocompromised and non-immunocompromised patients. The distribution of bacteria was comparable between groups, with a majority of Gram-negative bacilli (~ 64.1%). The proportion of multidrug-resistant bacteria was also similar between groups. Occurrence of ICU-acquired bacterial BSI was associated with a longer ICU length-of-stay and a longer duration of invasive mechanical ventilation, with no significant association with mortality. Immune status did not modify the association between occurrence of ICU-acquired bacterial BSI and these outcomes. Conclusion The 28-day cumulative incidence of ICU-acquired bacterial BSI was not statistically different between patients with and without immunosuppression at ICU admission.

Abstract Mitochondrial dysfunctions are key features of Alzheimer’s disease (AD). The occurrence of these disturbances in the peripheral cells of AD patients and their potential correlation with disease progression are underinvestigated. We studied mitochondrial structure, function and mitophagy in fibroblasts from healthy volunteers and AD patients at the prodromal (AD-MCI) or demented (AD-D) stages. We carried out correlation studies with clinical cognitive scores, namely, (i) Mini-Mental State Examination (MMSE) and (ii) Dementia Rating-Scale Sum of Boxes (CDR-SOB), and with (iii) amyloid beta (Aβ) plaque burden (PiB-PET imaging) and (iv) the accumulation of peripheral amyloid precursor protein C-terminal fragments (APP-CTFs). We revealed alterations in mitochondrial structure as well as specific mitochondrial dysfunction signatures in AD-MCI and AD-D fibroblasts and revealed that defective mitophagy and autophagy are linked to impaired lysosomal activity in AD-D fibroblasts. We reported significant correlations of a subset of these dysfunctions with cognitive decline, AD-related clinical hallmarks and peripheral APP-CTFs accumulation. This study emphasizes the potential use of peripheral cells for investigating AD pathophysiology.

Background Uncertainties remain about the impact of white matter hyperintensity (WMH) on prognosis after mechanical thrombectomy. Methods In this retrospective study from a national prospective registry of patients with ischemic stroke due to large vessel occlusion treated with mechanical thrombectomy, we assessed WMH volume using a quantitative semi‐automatized segmentation on baseline magnetic resonance imaging. We determined the association between WMH volume and the prognosis of patients with ischemic stroke presenting between 2019 and 2022. Results Among 902 patients (mean age 70.4 years, 50% women) with a baseline magnetic resonance imaging, the median WMH volume was 2.79 (0.75–9.14) mL. In multivariate analyses, increasing WMH volume was associated with a reduced probability of favorable outcome (modified Rankin Scale score 0–2) (adjusted odds ratio per 1 log+1 increase = 0.66, 95% confidence interval 0.54–0.82) and an increased risk of mortality at 90 days (adjusted odds ratio per 1 log+1 increase = 1.53, 95% confidence interval 1.23–1.90), with the greatest risk in patients with the highest WMH volume (>11 mL) compared to those with the lowest WMH volume (

Abstract Background The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer’s disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls. Methods Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy. Results We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients. Conclusions The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.

Abstract Background The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrPC, which represents a candidate therapeutic target. How PrPC is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrPC expression and to shed light on the gene regulatory networks linked to PrPC. Methods We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients. Results In silico analyses combined with cell-based assays identified the Wnt-β-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, β-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence. Conclusions An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.

Abstract Data on the SARS-CoV-2 infection among primary health care workers (PHCWs) are scarce but essential to reflect on policy regarding prevention and control measures. We assessed the prevalence of PHCWs who have been infected by SARS-CoV-2 in comparison with modeling from the general population in metropolitan France, and associated factors. A cross-sectional study was conducted among general practitioners (GPs), pediatricians, dental and pharmacy workers in primary care between May and August 2021. Participants volunteered to provide a dried-blood spot for SARS-CoV-2 antibody assessment and completed a questionnaire. The primary outcome was defined as the detection of infection-induced antibodies (anti-nucleocapsid IgG, and for non-vaccinees: anti-Spike IgG and neutralizing antibodies) or previous self-reported infection (positive RT-qPCR or antigenic test, or positive ELISA test before vaccination). Estimates were adjusted using weights for representativeness and compared with prediction from the general population. Poisson regressions were used to quantify associated factors. The analysis included 1612 PHCWs. Weighted prevalences were: 31.7% (95% CI 27.5–36.0) for GPs, 28.7% (95% CI 24.4–33.0) for pediatricians, 25.2% (95% CI 20.6–31.0) for dentists, and 25.5% (95% CI 18.2–34.0) for pharmacists. Estimates were compatible with model predictions for the general population. PHCWs more likely to be infected were: GPs compared to pharmacist assistants (adjusted prevalence ratio [aPR] = 2.26; CI 95% 1.01–5.07), those living in Île-de-France (aPR = 1.53; CI 95% 1.14–2.05), South-East (aPR = 1.57; CI 95% 1.19–2.08), North-East (aPR = 1.81; CI 95% 1.38–2.37), and those having an unprotected contact with a COVID-19 case within the household (aPR = 1.48; CI 95% 1.22–1.80). Occupational factors were not associated with infection. In conclusion, the risk of SARS-CoV-2 exposure for PHCWs was more likely to have occurred in the community rather than at their workplace.

Objectives The objectives are to assess smoking abstinence and its effects on vascular risk and to report tobacco-cessation counselling and pharmacotherapy use in patients who had a recent minor stroke or transient ischaemic attack (TIA).Design and setting The TIA registry.org project is a prospective, observational registry of patients with TIA and minor stroke that occurred in the previous 7 days with a 5-year follow-up, involving 61 sites with stroke specialists in 21 countries (Europe, Asia, Latin America and Middle East). Of those, 42 sites had 5-year follow-up data on more than 50% of their patients and were included in the present study.Participants From June 2009 through December 2011, 3847 patients were eligible for the study (80% of the initial cohort).Outcomes Tobacco counselling and smoking-cessation pharmacotherapy use in smoking patients were reported at discharge. Association between 3-month smoking status and risk of a major cardiovascular event (MACE) was analysed with multivariable Cox regression model.Results Among 3801 patients included, 835 (22%) were smokers. At discharge, only 35.2% have been advised to quit and 12.5% had smoking-cessation pharmacotherapy prescription. At 3 months, 383/835 (46.9%) baseline smokers were continuers. Living alone and alcohol abuse were associated with persistent smoking; high level of education, aphasia and dyslipidaemia with quitting. The adjusted HRs for MACE at 5 years were 1.13 (95% CI 0.90 to 1.43) in former smokers, 1.31 (95% CI 0.93 to 1.84) in quitters and 1.31 (95% CI 0.94 to 1.83) in continuers. Using time-varying analysis, current smoking at the time of MACE non-significantly increased the risk of MACE (HR 1.31 (95% CI 0.97 to 1.78); p=0.080).Conclusion In the TIAregistry.org, smoking-cessation intervention was used in a minority of patients. Surprisingly, in this population in which, at 5 years, other vascular risk factors were well controlled and antithrombotic treatment maintained, smoking cessation non-significantly decreased the risk of MACE.

Introduction Intraoperative opioids have been used for decades to reduce negative responses to nociception. However, opioids may have several, and sometimes serious, adverse effects. Cardiac surgery exposes patients to a high risk of postoperative complications, some of which are common to those caused by opioids: acute respiratory failure, postoperative cognitive dysfunction, postoperative ileus (POI) or death. An opioid-free anaesthesia (OFA) strategy, based on the use of dexmedetomidine and lidocaine, may limit these adverse effects, but no randomised trials on this issue have been published in cardiac surgery.We hypothesised that OFA versus opioid-based anaesthesia (OBA) may reduce the incidence of major opioid-related complications after cardiac surgery.Methods and analysis Multicentre, randomised, parallel and single-blinded clinical trial in four cardiac surgical centres in France, including 268 patients scheduled for coronary artery bypass grafting under cardiac bypass, with or without aortic valve replacement. Patients will be randomised to either a control OBA protocol using remifentanil or an OFA protocol using dexmedetomidine/lidocaine. The primary composite endpoint is the occurrence of at least one of the following: (1) postoperative cognitive disorder evaluated by the Confusion Assessment Method for the Intensive Care Unit test, (2) POI, (3) acute respiratory distress or (4) death within the first 48 postoperative hours. Secondary endpoints are postoperative pain, morphine consumption, nausea–vomiting, shock, acute kidney injury, atrioventricular block, pneumonia and length of hospital stay.Ethics and dissemination This trial has been approved by an independent ethics committee (Comité de Protection des Personnes Ouest III–Angers on 23 February 2021). Results will be submitted in international journals for peer reviewing.Trial registration number NCT04940689, EudraCT 2020-002126-90.

Abstract Acting in concert with others, a key aspect of our social life, requires behavioral coordination between persons on multiple timescales. When zooming in on the kinematic properties of movements, it appears that small speed fluctuations, called submovements, are embedded within otherwise smooth end-point trajectories. Submovements, by occurring at a faster timescale than that of movements, offer a novel window upon the functional relationship between distinct motor timescales. In this regard, it has previously been shown that when partners visually synchronize their movements, they also coordinate the timing of their submovement by following an alternated pattern. However, it remains unclear whether the mechanisms behind submovement coordination are domain-general or specific to the visual modality, and whether they have relevance for interpersonal coordination also at the scale of whole movements. In a series of solo and dyadic tasks, we show that submovements are also present and coordinated across partners when sensorimotor interactions are mediated by auditory feedback only. Importantly, the accuracy of task-instructed interpersonal coordination at the movement level correlates with the strength of submovement coordination. These results demonstrate that submovement coordination is a potentially fundamental mechanism that participates in interpersonal motor coordination regardless of the sensory domain mediating the interaction.

Abstract In eastern Canada, Black spruce (Picea mariana Mill. B.S.P.) grows in a wide variety of climates, from maritime-oceanic conditions near the Labrador Sea, to more continental climates, inland. Along this gradient, timing and provenance of heat and moisture that support growth are uncertain, weakening our capacity to predict the response of boreal ecosystems to climate variability. Here, we measured the stable oxygen isotopic composition of black spruce tree-ring cellulose at three sites in eastern Canada and provide evidence of a rapid decrease of Labrador Sea’s influence on adjacent ecosystems. Our results report a landwards decrease in the oxygen isotope composition of both tree-ring cellulose (δ 18O T R C ) and precipitation water (δ 18O p ). We also reveal a rapid landwards decoupling between δ 18O T R C variability (1950-2013), maximum temperature and Sea Surface Temperature variations over the Northwest Atlantic. Thus, despite their apparent ecological homogeneity, eastern Canada’s black spruce ecosystems rely on heterogeneous sources of heat and moisture.

BACKGROUND AND OBJECTIVES: Pandemic-related life changes may have had a deleterious impact on suicidal behaviours. Early detection of suicidal ideation and identification of subgroups at increased risk could help prevent suicide, one of the leading causes of death among adolescents worldwide. Here, we aimed to investigate the prevalence of and risk factors for suicidal ideation in adolescents using a population-based sample from Switzerland, two years into the pandemic. METHODS: Between December 2021 and June 2022, adolescents aged 14 to 17 years already enrolled in a population-based cohort study (State of Geneva, Switzerland) were asked about suicidal ideation over the previous year. In addition to a regression model, we conducted a network analysis of exposures which identified direct and indirect risk factors for suicidal ideation (i.e. those connected through intermediate risk factors) using mixed graphical models. RESULTS: Among 492 adolescents, 14.4% (95% CI: 11.5–17.8) declared having experienced suicidal ideation over the previous year. Using network analysis, we found that high psychological distress, low self-esteem, identifying as lesbian, gay or bisexual, suffering from bullying, extensive screen time and a severe COVID-19 pandemic impact were major risk factors for suicidal ideation, with parent-adolescent relationship having the highest centrality strength in the network. CONCLUSION: Our results show that a significant proportion of adolescents experience suicidal ideation, yet these rates are comparable with pre-pandemic results. Providing psychological support is fundamental, with a focus on improving parent-adolescent relationships.

Summary: The role of T cell receptor (TCR) diversity in infectious disease susceptibility is not well understood. We use a systems immunology approach on three cohorts of herpes zoster (HZ) patients and controls to investigate whether TCR diversity against varicella-zoster virus (VZV) influences the risk of HZ. We show that CD4+ T cell TCR diversity against VZV glycoprotein E (gE) and immediate early 63 protein (IE63) after 1-week culture is more restricted in HZ patients. Single-cell RNA and TCR sequencing of VZV-specific T cells shows that T cell activation pathways are significantly decreased after stimulation with VZV peptides in convalescent HZ patients. TCR clustering indicates that TCRs from HZ patients co-cluster more often together than TCRs from controls. Collectively, our results suggest that not only lower VZV-specific TCR diversity but also reduced functional TCR affinity for VZV-specific proteins in HZ patients leads to lower T cell activation and consequently affects the susceptibility for viral reactivation.

Partial prostatectomy has been described as an alternative to focal ablation therapy for the management of localized low- to intermediate-risk prostate cancer. This report aims to describe the long-term outcomes in a series of 28 men (2000–2022) who underwent robotic-assisted anterior partial prostatectomy (APP) for anteriorly located tumors entirely or partially within the anterior fibromuscular stroma. The median follow-up is 7 yr (interquartile range [IQR]: 4.2–8). The median prostate-specific antigen (PSA) before APP was 9.6 (6–11). Continence remained uninterrupted in 92% of patients. Erectile function without drug remained uninterrupted in 69%. The median nadir PSA after APP was 0.36 ng/ml (IQR: 0.25–0.60). Cancer recurrence at biopsies at the margins of the primary cancer resected area in case of a PSA elevation was observed in eight patients and led to salvage completion robotic radical prostatectomy at a median time of 3.25 yr (IQR: 2.4–6). Freedom from post-APP cancer recurrence at 7 yr was 62.7% (35.0–81.3%). Pre-APP tumor volume at magnetic resonance imaging (MRI) and volume of grade 4/5 were predictive of recurrence. Freedom from biochemical recurrence after completion radical prostatectomy at 7 yr was 94.7% (68.1–99.3%). All 28 patients are alive. No one had systemic treatment or metastases. These results confirm our initial report of robotic APP with good functional results and acceptable oncological results. The use of the inclusion criteria of pre-APP tumor volume at MRI

To rapidly achieve ceftazidime target concentrations, a 2 g loading dose (LD) is recommended before continuous infusion, but its adequacy in critically ill patients, given their unique pharmacokinetics, needs investigation. This study included patients from six ICUs in Saint-Etienne and Paris, France, who received continuous ceftazidime infusion with plasma concentration measurements. Using MONOLIX and R, a pharmacokinetic (PK) model was developed, and the literature on ICU patient PK models was reviewed. Simulations calculated the LD needed to reach a 60 mg/L target concentration and assessed ceftazidime exposure for various regimens. Among 86 patients with 223 samples, ceftazidime PK was best described by a one-compartment model with glomerular filtration rate explaining clearance variability. Typical clearance and volume of distribution were 4.45 L/h and 88 L, respectively. The literature median volume of distribution was 37.2 L. Simulations indicated that an LD higher than 2 g was needed to achieve 60 mg/L in 80% of patients, with a median LD of 4.9 g. Our model showed a 4 g LD followed by 6 g/day infusion reached effective concentrations within 1 h, while a 2 g LD caused an 18 h delay in achieving target steady state.

Optical quantum information processing relies critically on Bell-state measurement, a ubiquitous operation for quantum communication and computing. Its practical realization involves the interference of optical modes and the detection of a single photon in an indistinguishable manner. Yet, in the absence of efficient photon-number-resolution capabilities, errors arise from multiphoton components, decreasing the overall process fidelity. Here, we introduce a hybrid detection scheme for Bell-state measurement, leveraging both on-off single-photon detection and quadrature conditioning via homodyne detection. We derive explicit fidelities for quantum teleportation and entanglement-swapping processes employing this strategy, demonstrating its efficacy. We also compare with photon-number-resolving detectors and find a strong advantage of the hybrid scheme in a wide range of parameters. This work provides a new tool for linear-optics schemes, with applications to quantum state engineering and quantum interconnects.

High temperature superconductors (HTSs) are enablers of extensive electrification for aircraft propulsion. Indeed, if used in electrical machines, HTS materials can drastically improve their performance in terms of the power-to-weight ratio. Among the different topologies of superconducting electrical machines, a flux modulation machine based on HTS bulks is of interest for its compactness and light weight. Such a machine is proposed in the FROST (Flux-barrier Rotating Superconducting Topology) project led by Airbus to develop new technologies as part of their decarbonization goals driven by international policies. The rotor of the machine will house large ring-segment-shaped HTS bulks in order to increase the output power. However, the properties of those bulks are scarcely known and have barely been investigated in the literature. In this context, the present work aims to fill out partially this scarcity within the framework of FROST. Thus, a thorough characterisation of the performances and homogeneity of 11 large REBaCuO bulks was carried out. Ten of the bulks are to be utilized in the machine prototype, originally keeping the eleventh bulk as a spare. A first set of characterisation was conducted on the eleven bulks. For this set, the trapped field mapping and the critical current were estimated. Then, a series of in-depth characterisations on the eleventh bulk followed. It included critical current measurement, X-ray diffraction, and scanning electron microscopy on different millimetre-size samples cut out from the bulk at various locations. The X-ray diffraction and scanning electron microscopy showed weakly oxygenated regions inside the bulk explaining the local drop or loss in superconducting properties. The objective was to determine the causes of the inhomogeneities found in the trapped field measured on all the bulks, sacrificing one of them, here the spare one. To help obtain a clearer picture, a numerical model was then elaborated to reproduce the field map of the eleventh bulk using the experimental data obtained from the characterisation of its various small samples. It is concluded that further characterisations, including the statistics on various bulks, are still needed to understand the underlying reasons for inhomogeneity in the trapped field. Nonetheless, all the bulks presented enough current density to be usable in the construction of the proposed machine.

Background: The origin of pre-existing cognitive impairment in stroke patients remains controversial, with a vascular or a degenerative hypothesis. Objective: To determine whether endothelial dysfunction is associated with pre-existing cognitive problems, lesion load and biological anomalies in stroke patients. Methods: Patients originated from the prospective STROKDEM study. The baseline cognitive state, assessed using the IQ-CODE, and risk factors for stroke were recorded at inclusion. Patients with an IQ-CODE score >64 were excluded. Endothelial function was determined 72 h after stroke symptom onset by non-invasive digital measurement of endothelium-dependent flow-mediated dilation and calculation of the reactive hyperemia index (RHI). RHI ≤ 1.67 indicated endothelial dysfunction. Different biomarkers of endothelial dysfunction were analysed in blood or plasma. All patients underwent MRI 72 h after stroke symptom onset. Results: A total of 86 patients were included (52 males; mean age 63.5 ± 11.5 years). Patients with abnormal RHI have hypertension or antihypertensive treatment more often. The baseline IQ-CODE was abnormal in 33 (38.4%) patients, indicating a pre-existing cognitive problem. Baseline IQ-CODE > 48 was observed in 15 patients (28.3%) with normal RHI and in 18 patients (54.6%) with abnormal RHI (p = 0.016). The RHI median was significantly lower in patients with abnormal IQ-CODE. Abnormal RHI was associated with a significantly higher median FAZEKAS score (2.5 vs. 2; p = 0.008), a significantly higher frequency of periventricular lesions (p = 0.015), more white matter lesions (p = 0.007) and a significantly higher cerebral atrophy score (p < 0.001) on MRI. Vascular biomarkers significantly associated with abnormal RHI were MCP-1 (p = 0.009), MIP_1a (p = 0.042), and homocysteinemia (p < 0.05). Conclusions: A vascular mechanism may be responsible for cognitive problems pre-existing stroke. The measurement of endothelial dysfunction after stroke could become an important element of follow-up, providing an indication of the functional and cognitive prognosis of stroke patients.

Background. Unfractionated heparin is administered in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Anticoagulation monitoring is recommended, with an anti-activated factor X (anti-Xa) targeting 0.3 to 0.7 IU/mL. Owing to heparin’s heterogeneous pharmacokinetic properties, anti-Xa is unpredictable, generating a challenge in anticoagulation practices. The aim of this study was to build a pharmacokinetic model of heparin accounting for potential confounders, and derive an optimized dosing regimen for a given anti-Xa target. Methods. Adult patients undergoing VA-ECMO were included between January 2020 and June 2021. Anticoagulation was managed with an initial 100 IU/kg heparin loading dose followed by a continuous infusion targeting 0.2 to 0.7 IU/mL anti-Xa. The data were split into model development and model validation cohorts. Statistical analysis was performed using a nonlinear mixed effects modeling population approach. Model-based simulations were performed to develop an optimized dosing regimen targeting the desired anti-Xa. Results. A total of 74 patients were included, with 1703 anti-Xa observations. A single-compartment model best fitted the data. Interpatient variability for distribution volume was best explained by body weight, C-reactive protein and ECMO indication (post-cardiotomy shock or medical cardiogenic shock), and interpatient variability for elimination clearance was best explained by serum creatinine and C-reactive protein. Simulations using the optimized regimen according to these covariates showed accurate anti-Xa target attainment. Conclusion. In adult patients on VA-ECMO, heparin’s effect increased with serum creatinine and medical indication, whereas it decreased with body weight and systemic inflammation. We propose an optimized dosing regimen accounting for key covariates, capable of accurately predicting a given anti-Xa target.

Abstract Gene fusions and MET exon skipping drive oncogenesis in 8–9% and 3% of non-small cell lung cancers (NSCLC) respectively. Their detection are essential for the management of patients since they confer sensitivity to specific targeted therapies with significant clinical benefit over conventional chemotherapy. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) account for historical reference techniques however molecular-based technologies (RNA-based sequencing and RT-PCR) are emerging as alternative or complementary methods. Here, we evaluated the analytical performance of the fully-automated RT-PCR Idylla GeneFusion assay compared to reference methods using 35 fixed NSCLC samples. Idylla demonstrated overall agreement, sensitivity and specificity of 100% compared to RNASeq. Interestingly, it succeeded in retrieving 10 out of 11 samples with inconclusive results due to insufficient RNA quality for sequencing. Idylla showed an overall agreement, sensitivity and specificity of 90.32%, 91.67% and 89.47% compared to IHC/FISH respectively. Using commercial standards, the limit of detection of the Idylla system for the most frequent fusions and exon skipping ranges between 5 and 10 ng RNA input. These results support that the Idylla assay is a reliable and rapid option for the detection of these alterations, however a particular attention is needed for the interpretation of the expression imbalance.

Introduction: Bone marrow adipose tissue (BMAT) is associated with aging, osteoporosis, and chronic kidney disease (CKD). To date, the association between BMAT and kidney function in postmenopausal women has not been thoroughly investigated. The main purpose of this study was to determine whether a relationship exists between proton density fat fraction (PDFF) and kidney function in postmenopausal women. Methods: We investigated the cross-sectional association between estimated glomerular filtration rate (eGFR) – calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation – and PDFF – measured at the lumbar spine and proximal femur using Water Fat Imaging (WFI) MRI – in 199 postmenopausal women from the ADIMOS cohort study. We also performed DXA scans and laboratory measurements of sclerostin and c-terminal Fibroblast Growth Factor 23 (cFGF23). Results: Participants' mean age was 67.5 (standard deviation, SD 10.0) years. Their median eGFR was 85.0 (interquartile range, IQR 72.2–95.0) ml/min/1.73 cm2, and their mean lumbar spine PDFF was 57.9 % (SD 9.6). When classified by eGFR-based CKD stages, 41.7 % of the cohort had an eGFR ≥ 90 (n = 83), 47.2 % had an eGFR of 60–89.9 (n = 94), and 11.1 % had an eGFR of 30–59.9 (n = 22). Participants with eGFR ≥ 90 had a lower lumbar spine PDFF than those with eGFR 60–89.9 (mean 55.8 % (9.8) vs. 58.9 % (9.0), p = 0.031) and those with eGFR 30–59.9 (55.8 % (9.8) vs. 60.8 % (9.8), p = 0.043). However, the differences did not remain significant after adjusting for predetermined confounders, including age, diabetes, Charlson comorbidity index, recent history of fragility fracture, appendicular lean mass, and lumbar spine BMD. The inclusion of sclerostin and/or cFGF23 as suspected mediators did not alter the findings. When proximal hip imaging-based PDFF was considered, no significant differences were found between the eGFR categories in the unadjusted and adjusted analyses. Conclusion: No evidence of an association between kidney function and bone marrow adiposity was found either in the lumbar spine or proximal femur in a cohort of postmenopausal women.

ABSTRACTThe SARS-CoV-2 pandemic still represents a threat for immunosuppressed and hematological malignancy (HM) bearing patients, causing increased morbidity and mortality. Given the low anti-SARSCoV-2 IgG titers post-vaccination, the COVID-19 threat prompted the prophylactic use of engineered anti-SARS-CoV-2 monoclonal antibodies. In addition, potential clinical significance of T cell responses has been overlooked during the first waves of the pandemic, calling for additional in-depth studies. We reported that the polarity and the repertoire of T cell immune responses govern the susceptibility to SARS-CoV-2 infection in health care workers and solid cancer patients. Here, we longitudinally analyzed humoral and cellular immune responses at each BNT162b2 mRNA vaccine injection in 47 HM patients under therapy. Only one-third of HM, mostly multiple myeloma (MM) bearing patients, could mount S1-RBD-specific IgG responses following BNT162b2 mRNA vaccines. This vaccine elicited a S1-RBD-specific Th1 immune response in about 20% patients, mostly in MM and Hodgkin lymphoma, while exacerbating Th2 responses in the 10% cases that presented this recognition pattern at baseline (mostly rituximab-treated patients). Performing a third booster barely improved the percentage of patients developing an S1-RBD-specific Th1 immunity and failed to seroconvert additional HM patients. Finally, 16 patients were infected with SARS-CoV-2, of whom 6 developed a severe infection. Only S1-RBD-specific Th1 responses were associated with protection against SARS-CoV2 infection, while Th2 responses or anti-S1-RBD IgG titers failed to correlate with protection. These findings herald the paramount relevance of vaccine-induced Th1 immune responses in hematological malignancies.

Abstract Binding antibody levels against SARS-CoV-2 have shown to be correlates of protection against infection with pre-Omicron lineages. This has been challenged by the emergence of immune-evasive variants, notably the Omicron sublineages, in an evolving immune landscape with high levels of cumulative incidence and vaccination coverage. This in turn limits the use of widely available commercial high-throughput methods to quantify binding antibodies as a tool to monitor protection at the population-level. Here we show that anti-Spike RBD antibody levels, as quantified by the immunoassay used in this study, are an indirect correlate of protection against Omicron BA.1/BA.2 for individuals previously infected by SARS-CoV-2. Leveraging repeated serological measurements between April 2020 and December 2021 on 1083 participants of a population-based cohort in Geneva, Switzerland, and using antibody kinetic modeling, we found up to a three-fold reduction in the hazard of having a documented positive SARS-CoV-2 infection during the Omicron BA.1/BA.2 wave for anti-S antibody levels above 800 IU/mL (HR 0.30, 95% CI 0.22-0.41). However, we did not detect a reduction in hazard among uninfected participants. These results provide reassuring insights into the continued interpretation of SARS-CoV-2 binding antibody measurements as an independent marker of protection at both the individual and population levels.

Abstract Background Monitoring the progression of Tau pathology makes it possible to study the clinical diversity of Alzheimer’s disease. In this 2-year longitudinal PET study, we aimed to determine the progression of [18F]-flortaucipir binding and of cortical atrophy, and their relationships with cognitive decline. Methods Twenty-seven AD patients at the mild cognitive impairment/mild dementia stages and twelve amyloid-negative controls underwent a neuropsychological assessment, 3 T brain MRI, and [18F]-flortaucipir PET imaging (Tau1) and were monitored annually over 2 years with a second brain MRI and tau-PET imaging after 2 years (Tau2). We analyzed the progression of tau standardized uptake value ratio (SUVr) and grey matter atrophy both at the regional and voxelwise levels. We used mixed effects models to explore the relations between the progression of SUVr values, cortical atrophy, and cognitive decline. Results We found an average longitudinal increase in tau SUVr values, except for the lateral temporoparietal cortex where the average SUVr values decreased. Individual analyses revealed distinct profiles of SUVr progression according to temporoparietal Tau1 uptake: high-Tau1 patients demonstrated an increase in SUVr values over time in the frontal lobe, but a decrease in the temporoparietal cortex and a rapid clinical decline, while low-Tau1 patients displayed an increase in SUVr values in all cortical regions and a slower clinical decline. Cognitive decline was strongly associated with the progression of regional cortical atrophy, but only weakly associated with SUVr progression. Conclusions Despite a relatively small sample size, our results suggest that tau-PET imaging could identify patients with a potentially “more aggressive” clinical course characterized by high temporoparietal Tau1 SUVr values and a rapid clinical progression. In these patients, the paradoxical decrease in temporoparietal SUVr values over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. They could particularly benefit from future therapeutic trials, the neuroimaging outcome measures of which deserve to be discussed.

Abstract Background Coevolution between pathogens and their hosts decreases host morbidity and mortality. Bats host and can tolerate viruses which can be lethal to other vertebrate orders, including humans. Bat adaptations to infection include localized immune response, early pathogen sensing, high interferon expression without pathogen stimulation, and regulated inflammatory response. The immune reaction is costly, and bats suppress high-cost metabolism during torpor. In the temperate zone, bats hibernate in winter, utilizing a specific behavioural adaptation to survive detrimental environmental conditions and lack of energy resources. Hibernation torpor involves major physiological changes that pose an additional challenge to bat-pathogen coexistence. Here, we compared bat cellular reaction to viral challenge under conditions simulating hibernation, evaluating the changes between torpor and euthermia. Results We infected the olfactory nerve-derived cell culture of Myotis myotis with an endemic bat pathogen, European bat lyssavirus 1 (EBLV-1). After infection, the bat cells were cultivated at two different temperatures, 37 °C and 5 °C, to examine the cell response during conditions simulating euthermia and torpor, respectively. The mRNA isolated from the cells was sequenced and analysed for differential gene expression attributable to the temperature and/or infection treatment. In conditions simulating euthermia, infected bat cells produce an excess signalling by multitude of pathways involved in apoptosis and immune regulation influencing proliferation of regulatory cell types which can, in synergy with other produced cytokines, contribute to viral tolerance. We found no up- or down-regulated genes expressed in infected cells cultivated at conditions simulating torpor compared to non-infected cells cultivated under the same conditions. When studying the reaction of uninfected cells to the temperature treatment, bat cells show an increased production of heat shock proteins (HSPs) with chaperone activity, improving the bat’s ability to repair molecular structures damaged due to the stress related to the temperature change. Conclusions The lack of bat cell reaction to infection in conditions simulating hibernation may contribute to the virus tolerance or persistence in bats. Together with the cell damage repair mechanisms induced in response to hibernation, the immune regulation may promote bats’ ability to act as reservoirs of zoonotic viruses such as lyssaviruses.

Abstract Backgrounds To investigate the relationship between obesity and 30-day mortality in a cohort of older hospitalized COVID-19 inpatients. Methods Included patients were aged 70 years or more; hospitalized in acute geriatric wards between March and December 2020; with a positive PCR for COVID-19; not candidate to intensive care unit admission. Clinical data were collected from patients electronic medical records. Data on 30-day mortality were retrieved from the hospital administrative database. Results Patients included (N = 294) were on average 83.4 ± 6.7 years old, 50.7% were women, and 21.7% were obese (BMI > 30 kg/m2). At 30-day, 85 (28.9%) patients were deceased. Compared to survivors in bivariable analysis, deceased patients were older (84.6 ± 7.6 vs 83.0 ± 6.3 years), more frequently with very complex health status (63.5% vs 39.7%, P

Abstract 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 β 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.

Abstract We explore the effective theory of an axion in a gauged baryon number symmetry extension of the Standard Model (SM), where the axion is realized from a Dine-Fischler-Srednicki-Zhitnitsky (DFSZ) model construction. Integrating out the anomalons realizes a pattern of effective Wilson coefficients reflecting the factorization between the anomalous Peccei-Quinn and gauged baryon number symmetries. We construct and analyze the chiral transformation invariance of the axion effective theory, accounting for possible flavor-violating axion couplings. We calculate and study the unique phenomenology of the axion and Z′ boson, and we present the current collider limits on these particles in the m Z ′ g B $$ \left\{{m}_{Z^{\prime }},{g}_B\right\} $$ , {m a , G aγγ }, and m a f a − 1 $$ \left\{{m}_a,{f}_a^{-1}\right\} $$ planes.

Existing models for the analysis of concurrent processes tend to focus on fail-stop failures, where processes are either working or permanently stopped, and their state (working/stopped) is known. In fact, systems are often affected by grey failures: failures that are latent, possibly transient, and may affect the system in subtle ways that later lead to major issues (such as crashes, limited availability, overload). We introduce a model of actor-based systems with grey failures, based on two interlinked layers: an actor model, given as an asynchronous process calculus with discrete time, and a failure model that represents failure patterns to inject in the system. Our failure model captures not only fail-stop node and link failures, but also grey failures (e.g., partial, transient). We give a behavioural equivalence relation based on weak barbed bisimulation to compare systems on the basis of their ability to recover from failures, and on this basis we define some desirable properties of reliable systems. By doing so, we reduce the problem of checking reliability properties of systems to the problem of checking bisimulation.

Background: Children and adolescents are highly vulnerable to the impact of sustained stressors during developmentally sensitive times. We investigated how demographic characteristics intersect with socioeconomic dimensions to shape the social patterning of quality of life and mental health in children and adolescents, two years into the COVID-19 pandemic. Methods: We used data from the prospective SEROCoV-KIDS cohort study of children and adolescents living in Geneva (Switzerland, 2022). We conducted an intersectional Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy by nesting participants within 48 social strata defined by intersecting sex, age, immigrant background, parental education and financial hardship in Bayesian multilevel logistic models for poor health-related quality of life (HRQoL, measured with PedsQL) and mental health difficulties (measured with the Strengths and Difficulties Questionnaire). Results: Among participants aged 2–17 years, 240/2096 (11.5%, 95%CI 10.1–12.9) had poor HRQoL and 105/2135 (4.9%, 95%CI 4.0–5.9) had mental health difficulties. The predicted proportion of poor HRQoL ranged from 3.4% for 6–11 years old Swiss girls with highly educated parents and no financial hardship to 34.6% for 12–17 years old non-Swiss girls with highly educated parents and financial hardship. Intersectional strata involving adolescents and financial hardship showed substantially worse HRQoL than their counterparts. Between-stratum variations in the predicted frequency of mental health difficulties were limited (range 4.4%–6.5%). Conclusions: We found considerable differences in adverse outcomes across social strata. Our results suggest that, post-pandemic, interventions to address social inequities in HRQoL should focus on specific intersectional strata involving adolescents and families experiencing financial hardship, while those aiming to improve mental health should target all children and adolescents.

Abstract Background The Syrian conflict has been responsible for the highest exodus of refugees, with Lebanon hosting the greatest number of refugees per capita, which placed a significant strain on an already overburdened healthcare system. Women are the most vulnerable group in times of conflict and displacement, with sexual and reproductive health and rights often neglected. This study focuses on the obstetric characteristics and pregnancy outcomes of Syrian Refugee (SR) women in Lebanon, in Comparison to their pre-displacement data. Methods This study is a secondary analysis of de-identified data from the Sijilli database. The data reported and analyzed were the refugees’ socio-demographics, obstetric history, pregnancy outcomes, experienced maternal and neonatal complications, breastfeeding history and duration, and contraception use and types. Data were reported in both frequencies and means/medians. Chi-square test, t-test, and ANOVA tests were used to compare pregnancies in Syria to those that happened in Lebanon. Results A total of 1065 female records were included in this study, with 634 ever-pregnant women and the total number of pregnancies being 3272. SR women were shown to get pregnant in Lebanon at a younger age compared to cases in Syria. The number of gravidities is equal in women who got pregnant in Syria and those who moved later to Lebanon. The mean spacing between pregnancies has decreased comparing SR women who got pregnant in Syria only versus those who got pregnant in Lebanon only. Among the mixed group, the mean spacing between pregnancies as well as the prevalence of spontaneous abortions significantly increased after displacing to Lebanon. C-section rate was higher among SR women after moving to Lebanon. Also, maternal complications and not breastfeeding have increased after moving to Lebanon. A prior pregnancy was significantly associated with higher contraception use rate. The most common methods of contraception were oral contraceptive pills and intra-uterine devices. Conclusion The C-section deliveries, spontaneous abortions and maternal complications have all increased among SR women after being displaced to Lebanon. While the age at first pregnancy, mean spacing between their pregnancies and breastfeeding rates have decreased after moving to Lebanon. SR women are less likely to use contraceptives after their displacement. It is necessary to address access to reproductive healthcare and antenatal care delivery among displaced refugee women living in informal tented settlements.

Abstract 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.

Abstract We construct a new framework to calculate the enhancement of axion masses and concomitant effects on axion-meson mixing arising from small size instantons (SSIs), which originate in models featuring an extended color gauge symmetry. The framework is based on an explicit evaluation of ‘t Hooft determinantal operators that partition into instanton amplitudes, affording a more precise determination of the axion-diphoton coupling than previous results. Using an explicit model first presented in ref. [1], we demonstrate that axions solving the strong CP problem can have electroweak scale masses and higher, driven by SSI effects. Such collider axions are prime targets for resonance searches at the Large Hadron Collider and afford a unique anchor for motivating extended color symmetries.

Objective Some patients with rheumatic diseases might be at higher risk for coronavirus disease 2019 (COVID‐19) acute respiratory distress syndrome (ARDS). We aimed to develop a prediction model for COVID‐19 ARDS in this population and to create a simple risk score calculator for use in clinical settings. Methods Data were derived from the COVID‐19 Global Rheumatology Alliance Registry from March 24, 2020, to May 12, 2021. Seven machine learning classifiers were trained on ARDS outcomes using 83 variables obtained at COVID‐19 diagnosis. Predictive performance was assessed in a US test set and was validated in patients from four countries with independent registries using area under the curve (AUC), accuracy, sensitivity, and specificity. A simple risk score calculator was developed using a regression model incorporating the most influential predictors from the best performing classifier. Results The study included 8633 patients from 74 countries, of whom 523 (6%) had ARDS. Gradient boosting had the highest mean AUC (0.78; 95% confidence interval [CI]: 0.67‐0.88) and was considered the top performing classifier. Ten predictors were identified as key risk factors and were included in a regression model. The regression model that predicted ARDS with 71% (95% CI: 61%‐83%) sensitivity in the test set, and with sensitivities ranging from 61% to 80% in countries with independent registries, was used to develop the risk score calculator. Conclusion We were able to predict ARDS with good sensitivity using information readily available at COVID‐19 diagnosis. The proposed risk score calculator has the potential to guide risk stratification for treatments, such as monoclonal antibodies, that have potential to reduce COVID‐19 disease progression.

Deposition of Siberian wildfire aerosols, which contained nitrogen, enhanced phytoplankton growth in the eastern Eurasian Basin of the Arctic Ocean in summer 2014, suggest satellite-based ocean color data and atmospheric transport modeling.

Abstract Background Ventilator-associated pneumonia (VAP) is common in patients with severe SARS-CoV-2 pneumonia. The aim of this ancillary analysis of the coVAPid multicenter observational retrospective study is to assess the relationship between adjuvant corticosteroid use and the incidence of VAP. Methods Planned ancillary analysis of a multicenter retrospective European cohort in 36 ICUs. Adult patients receiving invasive mechanical ventilation for more than 48 h for SARS-CoV-2 pneumonia were consecutively included between February and May 2020. VAP diagnosis required strict definition with clinical, radiological and quantitative microbiological confirmation. We assessed the association of VAP with corticosteroid treatment using univariate and multivariate cause-specific Cox’s proportional hazard models with adjustment on pre-specified confounders. Results Among the 545 included patients, 191 (35%) received corticosteroids. The proportional hazard assumption for the effect of corticosteroids on the incidence of VAP could not be accepted, indicating that this effect varied during ICU stay. We found a non-significant lower risk of VAP for corticosteroid-treated patients during the first days in the ICU and an increased risk for longer ICU stay. By modeling the effect of corticosteroids with time-dependent coefficients, the association between corticosteroids and the incidence of VAP was not significant (overall effect p = 0.082), with time-dependent hazard ratios (95% confidence interval) of 0.47 (0.17–1.31) at day 2, 0.95 (0.63–1.42) at day 7, 1.48 (1.01–2.16) at day 14 and 1.94 (1.09–3.46) at day 21. Conclusions No significant association was found between adjuvant corticosteroid treatment and the incidence of VAP, although a time-varying effect of corticosteroids was identified along the 28-day follow-up.