Legionnaires’ Disease (LD) is a severe pneumonia mainly caused in Europe by Legionella pneumophila serogroup 1 (Lp1). Sequence-based typing methods reveal that some sequence types (ST) are overrepresented in clinical samples such as ST1 and ST47, suggesting that some strains are more fit for infection than others. In the present study, a collection of 108 Lp1 clinical isolates were used to evaluate the strain-dependent immune responses from human macrophages. Clinical Lp1 isolates induced differential TNFα secretion from macrophages. ST1 isolates induced a significantly higher TNF-α secretion than non-ST1, whereas ST47 isolates induced a significantly lower TNF-α secretion than non-ST47 isolates. ST1 isolates induced a significantly higher cell death than ST47 isolates evaluated by lactate dehydrogenase activity (cytotoxicity) and caspase-3 activity (apoptosis). Treatment of macrophages with anti-TNF-α antibodies significantly reduced the cell death in macrophages infected with ST1 or ST47 strains. The TNF-α secretion was neither explained by a differential bacterial replication nor by the number or type (bystander or infected) of TNF-α producing cells following infection but by a differential response from macrophages. The Paris ST1 reference strain elicited a significantly higher TNF-α gene transcription and a higher induction of NF-κB signaling pathway than the Lorraine ST47 reference strain. Clinical Lp1 isolates induce a diverse immune response and cell death, which could be related to the genotype. The two predominant sequence-types ST1 and ST47 trigger opposite inflammatory response that could be related to the host susceptibility.
Some cardiometabolic risk factors such as dyslipidemia and insulin resistance are known to be associated with low gut microbiota richness. A link between gut microbiota richness and the diversity of consumed dietary fibers (DF) has also been reported. We introduced a larger diversity of consumed DF by using a daily consumed bread in subjects at cardiometabolic risk and assessed the impacts on the composition and functions of gut microbiota as well as on cardiometabolic profile. Thirty-nine subjects at cardiometabolic risk were included in a double-blind, randomized, cross-over, twice 8-week study, and consumed daily 150 g of standard bread or enriched with a 7-dietary fiber mixture (5.55 g and 16.05 g of fibers, respectively). Before and after intervention, stool samples were collected for gut microbiota analysis from species determination down to gene-level abundance using shotgun metagenomics, and cardiometabolic profile was assessed. Multi-fiber bread consumption significantly decreased Bacteroides vulgatus, whereas it increased Parabacteroides distasonis, Fusicatenibacter saccharivorans, an unclassified Acutalibacteraceae and an unclassified Eisenbergiella (q < 0.1). The fraction of gut microbiota carrying the gene coding for five families/subfamilies of glycoside hydrolases (CAZymes) were also increased and negatively correlated with peaks and total/incremental area under curve (tAUC/iAUC) of postprandial glycemia and insulinemia. Compared to control bread, multi-fiber bread decreased total cholesterol (-0.42 mM; q < 0.01), LDL cholesterol (-0.36 mM; q < 0.01), insulin (-2.77 mIU/l; q < 0.05), and HOMA (-0.78; q < 0.05). In conclusion, increasing the diversity of DF in a daily consumed product modifies gut microbiota composition and function and could be a relevant nutritional tool to improve cardiometabolic profile.
Due to the potential role of the gut microbiota and bile acids in the pathogenesis of both inflammatory bowel disease (IBD) and sporadic colorectal cancer, we aimed to determine whether these factors were associated with colorectal cancer in IBD patients. 215 IBD patients and 51 non-IBD control subjects were enrolled from 10 French IBD centers between September 2011 and July 2018. Fecal samples were processed for bacterial 16S rRNA gene sequencing and bile acid profiling. Demographic, clinical, endoscopic, and histological outcomes were recorded. Characteristics of IBD patients included: median age: 41.6 (IQR 22); disease duration 13.2 (13.1); 47% female; 21.9% primary sclerosing cholangitis; 109 patients with Crohn's disease (CD); 106 patients with ulcerative colitis (UC). The prevalence of cancer was 2.8% (6/215: 1 CD; 5 UC), high-grade dysplasia 3.7% (8/215) and low-grade dysplasia 7.9% (17/215). Lachnospira was decreased in IBD patients with cancer, while Agathobacter was decreased and Escherichia-Shigella increased in UC patients with any neoplasia. Bile acids were not associated with cancer or neoplasia. Unsupervised clustering identified three gut microbiota clusters in IBD patients associated with bile acid composition and clinical features, including a higher risk of neoplasia in UC in two clusters when compared to the third (relative risk (RR) 4.07 (95% CI 1.6-10.3, P < .01) and 3.56 (95% CI 1.4-9.2, P < .01)). In this multicentre observational study, a limited number of taxa were associated with neoplasia and exploratory microbiota clusters co-associated with clinical features, including neoplasia risk in UC. Given the very small number of cancers, the robustness of these findings will require assessment and validation in future studies.
Objectives: Deliberative processes in Health Technologies Assessment (HTA) result in recommendations that determine the reimbursement of medicines, diagnostics or devices. These processes are governed by explicit criteria, but are also influenced by implicit factors. The objective of this work was to identify the implicit factors influencing HTA deliberative processes in five European countries (France, Germany, Italy, Spain and the UK). Methods: A systematic review of literature published between 2009 and 2019 was conducted. The search was performed in Pubmed, The Cochrane Database of Systematic Reviews, Google Scholar and Center for Reviews and Dissemination. The ISPOR database was searched manually. Results: Out of 100 eligible publications, eight articles were selected for data extraction and analysis. The implicit factors in the HTA deliberative process most frequently mentioned in the identified literature are value judgments, biases, preferences and subjectivity. Five out of the eight articles highlight the need to further improve the transparency of the process, and three provide recommendations on how to address the influence of implicit factors on the HTA deliberative process through a framework. Conclusion: Even in countries with a long HTA history, evidence on implicit factors is scarce. Some methods have been recommended for addressing these factors. Further research is required to characterize the implicit factors in the HTA deliberative process at a country level and explore potential ways to mitigate the influence of these factors on the HTA deliberative process.
Secondary organic aerosol (SOA) represents a major fraction of atmospheric fine particles. Both biogenic and anthropogenic volatile organic compounds (VOCs) can contribute to SOA through (photo-) oxidation. However, the current understanding of their combined, interactive effect on SOA formation and composition is still limited, challenging the accuracy in assessing global SOA budget, sources, and climate effect. Here we combine laboratory experiments and modelling to show that isoprene can suppress SOA formation from photo-oxidation of anthropogenic aromatics (toluene and p -xylene) with the presence of NO x , and similar SOA suppression phenomena are observed when replacing isoprene with propene. We find that the decreased SOA in such mixed-VOC conditions can be largely attributed to OH scavenging effect, resulting in reduced consumption of parent aromatics. However, various changes in SOA oxidation state (i.e., O/C) and oxidation pathways (i.e., more carbonyls formation) are observed following addition of isoprene, and the SOA chemical composition may not be similar to any single parent hydrocarbon, which implies the existence of complex interactions between the degradation chemistry for alkenes and aromatics. Under the conditions of this work, the OH scavenging effect is largely determined by gas-phase chemistry, which is expected to be widespread in binary or more complex systems in ambient air. More broadly, we infer that the global budget of anthropogenic SOA and its corresponding radiative forcing could be affected by biogenic emission of isoprene, particularly in urban environments with appreciable vegetation coverage.
Introduction In France, the cystic fibrosis (CF) care pathway is coordinated by multidisciplinary teams from specialised CF centres or transplant centres. It includes the care provided at home or out of hospital, risk prevention in daily life and adjustments to social life, which together contribute to the person’s quality of life. Patient experience is used to describe and evaluate the care and life of patients living with the disease. Objectives Our collaborative research aims to identify the most significant areas and criteria that characterise the CF pathway. It will lead to the development of a questionnaire to collect patients' experience, which can be administered to all patients or parents of children registered and followed in the centres. The article describes the protocol developed in partnership with patients and parents of children living with the disease. Method A multidisciplinary research group brings together researchers, patients, parents of children with CF and health care professionals. The patient partnership is involved in the 4 phases of the protocol: (1) setting up the study, recruiting patient and parent co-researchers, training them in qualitative research methods, defining the situations and profiles of patients in the study population, elaborating the protocol; (2) selecting the study sites, recruiting participants, carrying out semi-structured interviews, analysing verbatims using the grounded theory approach; (3) co-elaborating Patient-Reported Experience Measures (PREM) questionnaires adapted to the 4 types of participants: parents, adolescents, non-transplanted adults and transplanted adults; (4) validating the construct with participants and professionals from the study centres. Results The protocol obtained a favourable opinion from the Ethics Evaluation Committee of INSERM (IRB00003888—no. 20-700). Training was provided to the 5 patients and 2 parent co-researchers to enable them to participate effectively in the research. Eleven centres participated in the recruitment of participants in mainland France and Reunion Island. Eighty hours of interviews were conducted. Discussion The PREM questionnaires to be elaborated will have to undergo psychometric validation before being used by the actors of the CF network to assess the impact on the care pathways of quality approaches or new therapies available in cystic fibrosis. Trial Registration Registry : IRB00003888 – no. 20-700. Issue date: 06/09/2020.
We developed a new environment-sensing device based on the opto-ionic-electronic phenomena of an octahedral molybdenum metal (Mo6) cluster. When the Mo6 cluster is electrochemically deposited on a transparent electrode in an organic solvent containing a trace amount of water, the water permeates the deposited film. During the process, some ligand species that stabilize the frame structure of the Mo6 cluster are substituted with hydroxyl groups, and the negatively charged frame structure of the Mo6 cluster unit is stabilized by hydronium counterions. As a result, the transparent film of the Mo6 cluster fabricated by this method exhibits ionic-electronic mixed conduction of the hydronium ion. The ionic conduction greatly changes depending on the temperature and humidity in the atmosphere, and the electrical conductivity greatly changes depending on the wavelength and intensity of the irradiated light. These unique multisensing properties present new possibilities for environmental sensing applications.
Antibiotics released into the environment at low (sub-inhibitory) concentrations could select for antibiotic resistance that might disseminate to the human microbiome. In this case, low-level anthropogenic sources of antibiotics would have a significant impact on human health risk. In order to provide data necessary for the evaluation of this risk, we implemented river water microcosms at both sub-inhibitory and inhibitory concentrations of gentamicin as determined previously based on bacterial growth in enriched media. Using metagenomic sequencing and qPCR/RT-qPCR, we assessed the effects of gentamicin on water bacterial communities and their resistome. A change in the composition of total and active communities, as well as a gentamicin resistance gene selection identified via mobile genetic elements, was observed during a two-day exposure. We demonstrated the effects of sub-inhibitory concentrations of gentamicin on bacterial communities and their associated resistome in microcosms (simulating in situ conditions). In addition, we established relationships between antibiotic dose and the magnitude of the community response in the environment. The scope of resistance selection under sub-inhibitory concentrations of antibiotics and the mechanisms underlying this process might provide the basis for understanding resistance dispersion and associated risks in relatively low impacted ecosystems.
This paper presents two datasets obtained from laboratory experiments of urban flooding in a street network performed at the University of Liège. The experimental model represents a part of a synthetic urban district that consists of three inlets, three outlets and several three- and four- branches crossroads. The following experimental data was produced: (i) dataset 1: time-series of flow depths at model inlets and time-series of discharges at model outlets for a two-branch junction model, a two-branch bifurcation model and a district model. The datasets were generated by varying the upstream and downstream boundary conditions, i.e. flooding conditions; (ii) dataset 2 includes the same data type as dataset 1 complemented by 2D surface velocity measured using the non-intrusive LSPIV technique for eight urban form configurations in the district model. The collected data enable improving the understanding of the effect of urban forms on the urban flood processes. These two datasets are valuable for validating and improving numerical or analytical models of urban flooding and may contribute to flood risk management and flood-resilient urban design.
The cerebellum’s anatomical and functional organization and network interactions between the cerebellum and the cerebral cortex and subcortical structures are dynamic across the lifespan. Executive, emotional and social (EES) functions have likewise evolved during human development from contributing to primitive behaviors during infancy and childhood to being able to modulate complex actions in adults. In this review, we address how the importance of the cerebellum in the processing of EES functions might change across development. This evolution is driven by the macroscopic and microscopic modifications of the cerebellum that are occurring during development including its increasing connectivity with distant supra-tentorial cortical and sub-cortical regions. As a result of anatomical and functional changes, neuroimaging and clinical data indicate that the importance of the role of the cerebellum in human EES-related networks shifts from being crucial in newborns and young children to being only supportive later in life. In early life, given the immaturity of cortically mediated EES functions, EES functions and motor control and perception are more closely interrelated. At that time, the cerebellum due to its important role in motor control and sequencing makes EES functions more reliant on these computational properties that compute spatial distance, motor intent, and assist in the execution of sequences of behavior related to their developing EES expression. As the cortical brain matures, EES functions and decisions become less dependent upon these aspects of motor behavior and more dependent upon high-order cognitive and social conceptual processes. At that time, the cerebellum assumes a supportive role in these EES-related behaviors by computing their motor and sequential features. We suspect that this evolving role of the cerebellum has complicated the interpretation of its contribution to EES computational demands.
Background Artificial intelligence (AI) is defined as the study of algorithms that allow machines to reason and perform cognitive functions such as problem-solving, objects, images, word recognition, and decision-making. This study aimed to review the published articles and the comprehensive clinical relevance of AI-based tools used before, during, and after knee arthroplasty. Methods The search was conducted through PubMed, EMBASE, and MEDLINE databases from 2000 to 2021 using the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA). Results A total of 731 potential articles were reviewed, and 132 were included based on the inclusion criteria and exclusion criteria. Some steps of the knee arthroplasty procedure were assisted and improved by using AI-based tools. Before surgery, machine learning was used to aid surgeons in optimizing decision-making. During surgery, the robotic-assisted systems improved the accuracy of knee alignment, implant positioning, and ligamentous balance. After surgery, remote patient monitoring platforms helped to capture patients’ functional data. Conclusion In knee arthroplasty, the AI-based tools improve the decision-making process, surgical planning, accuracy, and repeatability of surgical procedures.
Background PEEP selection in severe COVID-19 patients under extracorporeal membrane oxygenation (ECMO) is challenging as no study has assessed the alveolar recruitability in this setting. The aim of the study was to compare lung recruitability and the impact of PEEP on lung aeration in moderate and severe ARDS patients with or without ECMO, using computed tomography (CT). Methods We conducted a two-center prospective observational case–control study in adult COVID-19-related patients who had an indication for CT within 72 h of ARDS onset in non-ECMO patients or within 72 h after ECMO onset. Ninety-nine patients were included, of whom 24 had severe ARDS under ECMO, 59 severe ARDS without ECMO and 16 moderate ARDS. Results Non-inflated lung at PEEP 5 cmH 2 O was significantly greater in ECMO than in non-ECMO patients. Recruitment induced by increasing PEEP from 5 to 15 cmH 2 O was not significantly different between ECMO and non-ECMO patients, while PEEP-induced hyperinflation was significantly lower in the ECMO group and virtually nonexistent. The median [IQR] fraction of recruitable lung mass between PEEP 5 and 15 cmH 2 O was 6 [4–10]%. Total superimposed pressure at PEEP 5 cmH 2 O was significantly higher in ECMO patients and amounted to 12 [11–13] cmH 2 O. The hyperinflation-to-recruitment ratio (i.e., a trade-off index of the adverse effects and benefits of PEEP) was significantly lower in ECMO patients and was lower than one in 23 (96%) ECMO patients, 41 (69%) severe non-ECMO patients and 8 (50%) moderate ARDS patients. Compliance of the aerated lung at PEEP 5 cmH 2 O corrected for PEEP-induced recruitment (C BABY LUNG ) was significantly lower in ECMO patients than in non-ECMO patients and was linearly related to the logarithm of the hyperinflation-to-recruitment ratio. Conclusions Lung recruitability of COVID-19 pneumonia is not significantly different between ECMO and non-ECMO patients, with substantial interindividual variations. The balance between hyperinflation and recruitment induced by PEEP increase from 5 to 15 cmH 2 O appears favorable in virtually all ECMO patients, while this PEEP level is required to counteract compressive forces leading to lung collapse. C BABY LUNG is significantly lower in ECMO patients, independently of lung recruitability.
Background Hereditary hemorrhagic telangiectasia (HHT) disease is a rare genetic disorder with symptoms and complications that can significantly affect patients’ daily lives. To date, no scale has been validated to assess the specific symptoms of this disease on the quality of life (QOL) of HHT patients. This makes it difficult for clinicians to accurately measure the quality of life of patients with HHT. The present study aims to develop and validate a QOL measurement tool specific to HHT disease: the QOL questionnaire in HHT (QoL-HHT). Methods A quantitative, non-interventional, multi-center study involving HHT patients in twenty French HHT expert centers was conducted. A calibration sample of 415 HHT patients and a validation sample of 228 HHT patients voluntarily participated in the study. Data were analyzed using exploratory factor analysis (EFA), confirmatory factor analysis (CFA), Exploratory Structural Equation Modeling (ESEM) analyses, reliability analyses, and correlational analyses. Results The EFA, CFA and ESEM results allowed us to provide evidence of the factorial structure of a questionnaire composed of 24 items measuring 6 domains of QOL: Physical limitations, social relationships, concern about bleeding, relationship with the medical profession, experience of symptoms, and concern about the evolution of the disease. Cronbach’s alpha coefficients (> 0.70) demonstrated reliable internal consistency of all the QoL-HHT scores (dimensions). The results of the test–retest provided further evidence of the reliability of the QOL-HHT scores over time. Correlational analyses provided evidence for the convergent validity of the QoL-HHT scores. Conclusions We developed a simple and quick self-assessment tool to measure quality of life specific to HHT disease. This study demonstrated reliability and validity of our QoL-HHT scores. It is a very promising tool to evaluate the impact of HHT disease on all aspects of the quality of life of HHT patients in order to offer them individualized medico-psycho-social support. Trial registration : ClinicalTrials, NCT03695874. Registered 04 October 2018, https://www.clinicaltrials.gov/ct2/show/NCT03695874
Organoids are 3D structures grown from pluripotent stem cells derived from human tissue and serve as in vitro miniature models of human organs. Organoids are expected to revolutionize biomedical research and clinical care. However, organoids are not seen as morally neutral. For instance, tissue donors may perceive enduring personal connections with their organoids, setting higher bars for informed consent and patient participation. Also, several organoid sub-types, e.g., brain organoids and human–animal chimeric organoids, have raised controversy. This systematic review provides an overview of ethical discussions as conducted in the scientific literature on organoids. The review covers both research and clinical applications of organoid technology and discusses the topics informed consent, commercialization, personalized medicine, transplantation, brain organoids, chimeras, and gastruloids. It shows that further ethical research is needed especially on organoid transplantation, to help ensure the responsible development and clinical implementation of this technology in this field.
We study a class of non-linear parabolic systems relevant in turbulence theory. Those systems can be viewed as simplified versions of the Prandtl one-equation and Kolmogorov two-equation models of turbulence. We restrict our attention to the case of one space dimension. We consider initial data for which the diffusion coefficients may vanish. We prove that, under this condition, those systems are locally well-posed in the class of Sobolev spaces of high enough regularity, but also that there exist smooth initial data for which the corresponding solutions blow up in finite time. We are able to put in evidence two different types of blow-up mechanism. In addition, the results are extended to the case of transport-diffusion systems, namely to the case when convection is taken into account.
The partition identities of Capparelli and Primc were originally discovered via representation theoretic techniques, and have since then been studied and refined combinatorially, but the question of giving a very broad generalisation remained open. In these two companion papers, we give infinite families of partition identities which generalise Primc's and Capparelli's identities, and study their consequences on the theory of crystal bases of the affine Lie algebra An−1(1). In this first paper, we focus on combinatorial aspects. We give a n2-coloured generalisation of Primc's identity by constructing a n2×n2 matrix of difference conditions, Primc's original identities corresponding to n=2 and n=3. While most coloured partition identities in the literature connect partitions with difference conditions to partitions with congruence conditions, in our case, the natural way to generalise these identities is to relate partitions with difference conditions to coloured Frobenius partitions. This gives a very simple expression for the generating function. With a particular specialisation of the colour variables, our generalisation also yields a partition identity with congruence conditions. Then, using a bijection from our new generalisation of Primc's identity, we deduce a large family of identities on (n2−1)-coloured partitions which generalise Capparelli's identity, also in terms of coloured Frobenius partitions. The particular case n=2 is Capparelli's identity and one of the cases where n=3 recovers an identity of Meurman and Primc. In the second paper, we will focus on crystal theoretic aspects. We will show that the difference conditions we defined in our n2-coloured generalisation of Primc's identity are actually energy functions for certain An−1(1) crystals. We will then use this result to retrieve the Kac-Peterson character formula and derive a new character formula as a sum of infinite products for all the irreducible highest weight An−1(1)-modules of level 1.
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