University of Angers

This paper describes a time-evolving digital twin and its application to a proof-of-concept engineering dynamics example. In this work, the digital twin is constructed by combining physics-based and data-based models of the physical twin, using a weighting technique. The resulting model combination enables the temporal evolution of the digital twin to be optimised based on the data recorded from the physical twin. This is achieved by creating digital twin output functions that are optimally-weighted combinations of physics- and/or data-based model components that can be updated over time to reflect the behaviour of the physical twin as accurately as possible. The engineering dynamics example is a system consisting of two cascading tanks driven by a pump. The data received by the digital twin is segmented so that the process can be carried out over relatively short time-scales. The weightings are computed based on error and robustness criteria. It is also shown how the error and robustness weights can be used to make a combined weighting. The results show how the time-varying water level in the tanks can be captured with the digital twin output functions, and a comparison is made with three different weighting choice criteria.

The COVID-19 pandemic remains hugely challenging, but its impact on emotional experience, especially over time, has often been neglected. The French Government imposed three COVID lockdowns with varying degrees of strictness that induced different types of emotional discomfort and emotion regulation. The present longitudinal study explored affect and emotion regulation strategies in each of these lockdowns, comparing samples assessed before and during the pandemic. The objective was to understand how government measures influenced subjective experience and how people adjusted their emotion regulation accordingly. The longitudinal lockdown sample comprised 164 participants (M age = 37.60 years, SD = 12.50). Affect and emotion regulation were assessed in the first week of each of the three lockdowns (20-). The 120 participants in the prepandemic (control) sample were drawn from previous studies focusing on affect and regulation strategies in natural everyday situations. Results indicated that affect deteriorated considerably, compared with prepandemic levels. Whereas activated negative affect (nervous and worried) tended to decrease, deactivated negative affect (sad and bored) increased. Regarding emotion regulation strategies, negative emotion expression was associated with more negative affect and less positive affect, while positive emotion expression and proactive behaviour were associated with a better emotional experience. A multivariate growth curve showed that in the absence of psychological support, stressful situations and repeated lockdowns do not induce people to make better emotion regulation strategy choices. As government restrictions had a negative impact on individuals' emotional experience, support programs should be implemented in future pandemics to promote emotion regulation.

Background Proportional assist ventilation with load-adjustable gain factors (PAV+) is a mechanical ventilation mode that delivers assistance to breathe in proportion to the patient’s effort. The proportional assistance, called the gain, can be adjusted by the clinician to maintain the patient’s respiratory effort or workload within a normal range. Short-term and physiological benefits of this mode compared to pressure support ventilation (PSV) include better patient-ventilator synchrony and a more physiological response to changes in ventilatory demand. Methods The objective of this multi-centre randomized controlled trial (RCT) is to determine if, for patients with acute respiratory failure, ventilation with PAV+ will result in a shorter time to successful extubation than with PSV. This multi-centre open-label clinical trial plans to involve approximately 20 sites in several continents. Once eligibility is determined, patients must tolerate a short-term PSV trial and either (1) not meet general weaning criteria or (2) fail a 2-min Zero Continuous Positive Airway Pressure (CPAP) Trial using the rapid shallow breathing index, or (3) fail a spontaneous breathing trial (SBT), in this sequence. Then, participants in this study will be randomized to either PSV or PAV+ in a 1:1 ratio. PAV+ will be set according to a target of muscular pressure. The weaning process will be identical in the two arms. Time to liberation will be the primary outcome; ventilator-free days and other outcomes will be measured. Discussion Meta-analyses comparing PAV+ to PSV suggest PAV+ may benefit patients and decrease healthcare costs but no powered study to date has targeted the difficult to wean patient population most likely to benefit from the intervention, or used consistent timing for the implementation of PAV+. Our enrolment strategy, primary outcome measure, and liberation approaches may be useful for studying mechanical ventilation and weaning and can offer important results for patients. Trial registration ClinicalTrials.gov NCT02447692. Prospectively registered on May 19, 2015.

Haematopoietic stem cell reinjection may be a curative option for poor graft function after haematopoietic stem cell transplantation; however, literature supporting its use remains limited. We conducted a multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, including 55 patients. We demonstrated response rates of nearly 40% and two-year survival of more than 60% in the context of an otherwise deadly complication and we observed that the timing of injection and the degree of cytopenia are strongly associated with outcomes. This study shows the feasibility of the procedure informing on its epidemiology, outcomes and prognostic factors, setting the stage for future guidelines.

Background: There is a lack of real-life data regarding the frequency and predictive factors of hypoglycemia in older patients with type 2 diabetes (T2D). This study aimed to determine the frequency and predictors of hypoglycemia in older patients with insulin-treated T2D. Methods: This prospective multicenter study included 155 insulin-treated T2D patients aged 75 years and older with ≥2 self-monitoring of blood glucose (SMBG) daily controls. Participants underwent a geriatric and diabetic assessment and received ambulatory blinded continuous glucose monitoring (CGM) for 28 consecutive days with FreeStyle Libre Pro® sensor. Study population (n = 141) has >70% CGM active time. Multivariable logistic regressions were used to identify factors associated with SMBG confirmed hypoglycemia (≥70 mg/dL) and with nocturnal level 2 time below range (glucose concentration <54 mg/dL during ≥15 consecutive min between 0.00 and 6.00 am). Results: The mean age of the 141 analyzed patients was 81.5 ± 5.3 years and 56.7% were male. The mean baseline HbA1c was 7.9% ± 1.0%. After geriatric assessment, 102 participants (72.3%) were considered as complex and 39 (27.7%) as healthy. The primary endpoint (confirmed SMBG <70 mg/dL) occurred in 37.6% patients. In multivariable analysis, the risk of SMBG-confirmed hypoglycemia was positively associated with a longer duration of diabetes (OR (+1 year) =1.04, (1.00-1.08), p = 0.04) and glycemic variability assessed by CGM (CV %) (OR (+1%) = 1.12, [1.05-1.19], p = <0.001). Nighty-two patients (65.2%) experienced nocturnal time in hypoglycemia (i.e., <54 mg/dL during ≥15 consecutive min between midnight and 6 a.m.). In multivariable analyses, cognitive impairment (OR: 9.31 [2.59-33.4]), heart failure (OR: 4.81 [1;48-15.6]), and depressive disorder (OR: 0.19 [0.06-0.53]) were associated with nocturnal time in hypoglycemia. Conclusion: Nocturnal hypoglycemia is very common and largely underdiagnosed in older patients with insulin-treated T2D. CGM is a promising tool to better identify hypoglycemia and adapt diabetes management in this population.

The aim of this study was to evaluate how comorbidities and molecular landscape relate to outcome in patients with acute myeloid leukemia (AML) aged 60 years or older who received intensive induction therapy. In 91 patients, 323 mutations were identified in 77 genes by next-generation sequencing, with a median of four mutations per patient, with NPM1, FLT3, TET2, and DNMT3A being the most frequently mutated genes. A multistate model identified FLT3, IDH2, RUNX1, and TET2 mutations as associated with a higher likelihood of achieving complete remission while STAG2 mutations were associated with primary refractory disease, and DNMT3A, FLT3, IDH2, and TP53 mutations with mortality after relapse. Ferrara unfitness criteria and performance status were the best predictors of short-term outcome (AUC=82 for 2-month survival for both parameters), whereas genomic classifications better predicted long-term outcome, with the Patel risk stratification performing the best over the 5-year follow-up period (C-index=0.63 for event-free and overall survival). We show that most genomic prognostic classifications, mainly used in younger patients, are useful for classifying older patients, but to a lesser extent, because of different mutational profiles. Specific prognostic classifications, incorporating performance status, comorbidities, and cytogenetic/molecular data, should be specifically designed for patients over 60 years. This article is protected by copyright. All rights reserved.

Labeling plant material such as detached leaves with 15NH4+ is a very instrumental method for the characterization of metabolic pathways of mineral nitrogen assimilation and incorporation into amino acids. A procedure of labeling, followed by amino acid extraction, purification, and derivatization for gas chromatography coupled to mass spectrometry (GC/MS) analysis, is presented. The rationale of heavy isotope abundance calculations and amino acid quantification is detailed. This method is adaptable to various plant species and various kinds of investigations, such as elucidating physiological changes occurring as a result of gene mutations (overexpression or inhibition) in natural variants or genetically modified crops, or characterization of metabolic fluxes in genotypes exhibiting contrasted physiological or developmental adaptive responses to biotic and/or abiotic environmental stresses. Furthermore, the benefit of working on detached organs or pieces of organs is to investigate finely the metabolism of species that are not amenable to laboratory work, such as plants growing in natural environments or under agricultural conditions in the field.

Tetrodotoxin (TTX) poisoning through the consumption of contaminated fish leads to lethal symptoms, including severe hypotension. This TTX-induced hypotension is likely due to the downfall of peripheral arterial resistance through direct or indirect effects on adrenergic signaling. TTX is a high-affinity blocker of voltage-gated Na + (NaV) channels. In arteries, NaV channels are expressed in sympathetic nerve endings, both in the intima and media. In this present work, we aimed to decipher the role of NaV channels in vascular tone using TTX. We first characterized the expression of NaV channels in the aorta, a model of conduction arteries, and in mesenteric arteries (MA), a model of resistance arteries, in C57Bl/6J mice, by Western blot, immunochemistry, and absolute RT-qPCR. Our data showed that these channels are expressed in both endothelium and media of aorta and MA, in which scn2a and scn1b were the most abundant transcripts, suggesting that murine vascular NaV channels consist of NaV1.2 channel subtype with NaVβ1 auxiliary subunit. Using myography, we showed that TTX (1 µM) induced complete vasorelaxation in MA in the presence of veratridine and cocktails of antagonists (prazosin and atropine with or without suramin) that suppressed the effects of neurotransmi er release. In addition, TTX (1 µM) strongly potentiated the flow-mediated dilation response of isolated MA. Altogether, our data showed that TTX blocks NaV channels in resistance arteries and consecutively decreases vascular tone. This could explain the drop in total peripheral resistance observed during mammal tetrodotoxications.

Background Breast cancer (BC) treatments and related symptoms may affect return to work (RTW). The objective of this study was to investigate the impact of BC care pathways (timing and sequence of treatments) and related symptoms on RTW. Methods The study population included working-age women with BC who were enrolled in the French CONSTANCES cohort from 2012 to 2018. BC treatments, antidepressant/anxiolytic and antalgic drug deliveries (used as proxies of depression and pain, respectively) and statutory sick pay (used to estimate RTW and time to RTW) were assessed monthly using data from the French national healthcare system database. BC care pathways were identified with the sequence analysis method. Cox models with time-dependent covariates were used to investigate the impact of BC care pathways and related symptoms on RTW and time to RTW, after adjusting for age and socioeconomic characteristics. Results 73.2% (231/303) of women returned to work within 2 years after BC diagnosis. Five BC care pathway patterns were identified: (i) BC surgery only, (ii) BC surgery and radiotherapy, (iii) BC surgery and chemotherapy, (iv) BC surgery and chemotherapy and radiotherapy, and (v) BC surgery and long-term alternative chemotherapy/radiotherapy. The hazards ratios of non-RTW were significantly higher for women who received BC surgery and long-term alternative chemotherapy/radiotherapy and for > 55-year-old women. Time to RTW was significantly longer in women who received chemotherapy (patterns iii to v) and in women with antidepressant/anxiolytic and antalgic drug deliveries. Conclusion This study highlights the value of considering the dynamic, cumulative and temporal features of BC care pathways and related symptoms to facilitate the RTW of women with BC.

Pediatric chronic immune thrombocytopenia (cITP) is a heterogeneous condition in terms of bleeding severity, second‐line treatment use, association with clinical and/or biological immunopathological manifestations (IMs), and progression to systemic lupus erythematosus (SLE). No risk factors for these outcomes are known. Specifically, whether age at ITP diagnosis, sex and IMs impact cITP outcomes is unknown. We report the outcomes of patients with pediatric cITP from the French nationwide prospective cohort OBS'CEREVANCE. We used multivariate analyses to investigate the effect of age at ITP diagnosis, sex and IMs on cITP outcomes. We included 886 patients with a median (min‐max) follow‐up duration of 5.3 (1.0–29.3) years. We identified an age cutoff that dichotomized the outcomes risk and defined two risk groups: patients with ITP diagnosed <10 years (children) and ≥ 10 years (adolescents). Adolescents had a two to four‐fold higher risk of grade ≥3 bleeding, second‐line treatment use, clinical and biological IMs, and SLE diagnosis. Moreover, female sex and biological IMs were independently associated with higher risks of biological IMs and SLE diagnosis, and second‐line treatment use and SLE diagnosis, respectively. The combination of these three risk factors defined outcome‐specific risk groups. Finally, we showed that patients clustered in mild and severe phenotypes, more frequent in children and adolescents, respectively. In conclusion, we identified that age at ITP diagnosis, sex, and biological IMs impacted the long‐term outcomes of pediatric cITP. We defined risk groups for each outcome, that will help clinical management and further studies. This article is protected by copyright. All rights reserved.

Purpose: Machine learning (ML) methods showed a higher accuracy in identifying individuals without cancer who were unable to return to work (RTW) compared to the classical methods (e.g. logistic regression models). We therefore aim to discuss the value of these methods in relation to RTW for cancer survivors. Methods: Breast cancer (BC) survivors who were working at diagnosis within the CONSTANCES cohort were included in the study. RTW was assessed five years after the BC diagnosis (early retirement was considered as non-RTW). Age and occupation at diagnosis, and physical occupational job exposures assessed using the Job Exposure Matrix, JEM-CONSTANCES, were evaluated as predictors of RTW five years after BC diagnosis. The following four ML methods were used: (i) k-nearest neighbors; (ii) random forest; (iii) neural network; and (iv) elastic net. Results: The training sample included 683 BC survivors (RTW: 85.7%), and the test sample 171 (RTW: 85.4%). The elastic net method had the best results despite low sensitivity (accuracy = 76.6%; sensitivity = 31.7%; specificity = 90.8%), and the random forest model was the most accurate (= 79.5%) but also the least sensitive (= 14.3%). Conclusion: This study takes a first step towards opening up new possibilities for identifying the occupational determinants of cancer survivors’ RTW. Further work, including a larger sample size, and more predictor variables, is now needed.

Background Pediatric magnetic resonance imaging (MRI) and computed tompgraphy (CT) require patient immobility and therefore often require sedation or general anesthesia of patients. Consensus on these procedures is lacking in France. Objective Thus, the aim of this study was to describe the current sedation practices for pediatric MRI and CT in France. Material and methods From January 2019 to December 2019, an online questionnaire was delivered by electronic mail to a representative radiologist in 60 pediatric radiology centers registered by the French-speaking pediatric and prenatal imaging society. Questions included protocols, drugs used, monitoring and side effects. Results Representatives of 40 of the 60 (67%) radiology centers responded to the survey. Among them, 31 performed sedation including 17 (55%) centers where radiologists performed sedation without anesthesiologists present during the procedure. The premedication drugs were hydroxyzine (n = 8, 80%) and melatonin (n = 2, 20%), Sedation drugs used for children ages 0 to 6 years old were pentobarbital (n = 9, 60%), midazolam (n = 2, 13%), chloral hydrate (n = 2, 13%), diazepam (n = 1, 6.5%) and chlorpromazine (n = 1, 6.5%). A written sedation protocol was available in 10/17 (59%) centers. In 6/17 (35%) centers, no monitoring was used during the procedures. Blood pressure monitoring and capnography were rarely used (< 10%) and post-sedation monitoring was heterogeneous. No life-threatening adverse effect was reported, but 6 centers reported at least one incident per year. Conclusion For half of the responding radiology centers, radiologists performed sedation alone in agreement with the local anesthesiology team. Sedation procedures and monitoring were heterogenous among centers. Adjustment and harmonization of the practices according to the capacity of each center may be useful.

The present paper deals with the development of a new and original hexadecyltrimethylammonium bromide (CTAB)-modified carbon paste electrode (CPE) dedicated for the direct analysis of nitrites in aquaculture and rat blood. The surface morphologies and contact angles of unmodified and modified CPEs were performed using Scanning Electron Microscopy (SEM), Optical Microscopy (OM) and sessile drop techniques, respectively. Cyclic Voltammetry (CV) was used to study the electrochemical behaviour of nitrites, whilst Differential Pulse Voltammetry (DPV) and Linear Sweep Voltammetry (LSV) techniques were used to investigate their quantitative analysis. DPV operating parameters were optimized and the optimum values were pulse height 0.4 V, scan increment 0.015 V, pulse width 0.01 s and step time 0.5 s. The repeatability and reproducibility of the CPE were studied, and the effect of some interfering ions was evaluated to highlight the selectivity of the electrode. The modified CTAB/CPE showed a good stability and proved to be more sensitive, leading to a Limit of Detection (LOD) of 0.034 mg L⁻¹ and a Limit of Quantification (LQ) of 0.152 mg L⁻¹. The elaborated sensors were applied with success for nitrites analysis in aquaria with CPE and in rat blood with CTAB/CPE, preparing human blood measurements in near future work. Graphical abstract

Background: We evaluated the diagnostic accuracy of simple non-invasive tests(NITs) in NAFLD patients with type 2 diabetes(T2D). Methods: This was an individual patient data meta-analysis of 1780 patients with biopsy-proven NAFLD and T2D. The index tests of interest were FIB-4, NAFLD Fibrosis Score(NFS), APRI, liver stiffness measurement(LSM) by vibration-controlled transient elastography(VCTE) and AGILE 3+. The target conditions were advanced fibrosis, nonalcoholic steatohepatitis(NASH) and fibrotic NASH(NASH plus F2-F4 fibrosis). The diagnostic performance of NITs individually or in sequential combination was assessed by area under receiver operating characteristic curve(AUROC) and by decision curve analysis(DCA). Comparison with 2278 NAFLD patients without T2D was also made. Results: In NAFLD with T2D LSM and AGILE 3+ outperformed both NFS and FIB-4 for advanced fibrosis(AUROC:LSM 0.82,AGILE 3+ 0.82,NFS 0.72,FIB-4 0.75,APRI 0.68;p < 0.001 of LSM-based versus simple serum tests), with an uncertainty area of 12%-20%.The combination of serum-based with LSM-based tests for advanced fibrosis led to a reduction of 40% to 60% in necessary LSM tests. DCA showed that all scores had modest net benefit for ruling-out advanced fibrosis at the risk threshold of 5%-10% of missing advanced fibrosis. LSM and AGILE 3+ outperformed both NFS and FIB-4 for fibrotic NASH(AUROC LSM 0.79,AGILE 3+ 0.77,NFS 0.71,FIB-4 0.71;p < 0.001 of LSM-based versus simple serum tests). All noninvasive scores were sub-optimal for diagnosing NASH. Conclusions: LSM and AGILE 3+ individually or in low availability setting in sequential combination after FIB-4 or NFS have a similar good diagnostic accuracy for advanced fibrosis and an acceptable diagnostic accuracy for fibrotic NASH in NAFLD patients with T2D.

Plasma membrane-derived vesicles, also referred to as large extracellular vesicles (lEVs), are implicated in several pathophysiological situations, including cancer. However, to date, no studies have evaluated the effects of lEVs isolated from patients with renal cancer on the development of their tumors. In this study, we investigated the effects of three types of lEVs on the growth and peritumoral environment of xenograft clear cell renal cell carcinoma in a mouse model. Xenograft cancer cells were derived from patients’ nephrectomy specimens. Three types of lEVs were obtained from pre-nephrectomy patient blood (cEV), the supernatant of primary cancer cell culture (sEV) and from blood from individuals with no medical history of cancer (iEV). Xenograft volume was measured after nine weeks of growth. Xenografts were then removed, and the expression of CD31 and Ki67 were evaluated. We also measured the expression of MMP2 and Ca9 in the native mouse kidney. lEVs from kidney cancer patients (cEV and sEV) tend to increase the size of xenografts, a factor that is related to an increase in vascularization and tumor cell proliferation. cEV also altered organs that were distant from the xenograft. These results suggest that lEVs in cancer patients are involved in both tumor growth and cancer progression.

Background Following myocardial infarction, left ventricular remodeling (LVR) is associated with heart failure and cardiac death. At the same time, left atrial (LA) remodeling (LAR) is an essential part of the outcome of a wide spectrum of cardiac conditions. The authors sought to evaluate the correlates of LAR and its relationships with LVR after myocardial infarction. Methods and Results This is a retrospective analysis of 320 of 443 patients enrolled for study of LVR after ST‐elevation myocardial infarction. Left ventricular (LV) volumes, infarct size and LA volume index were assessed by cardiac magnetic resonance imaging during index hospitalization (day 6 [interquartile range, 4–8]) and after a 3‐month follow‐up. LAR was studied using a linear mixed model for repeated measurements. Overall, there was a decrease in LA volume index between 6 days and 3 months (43.9±10.4 mL versus 42.8±11.1 mL, P =0.003). Patients with changes in LA volume index >8% over time were older, with greater body mass index, lower LV ejection fraction, and larger infarct size. Unadjusted predictors of LAR were age older than 70 years, infarct size, anterior infarction, time to reperfusion, history of hypertension, LV end‐diastolic volume, and heart failure at day 6. Independent correlates were age older than 70 years (3.24±1.33, P =0.015) and infarct size (2.16±0.72 per 10% LV, P <0.001). LA remodeling was correlated with LV remodeling ( r =0.372, P <0.001), but neither LA nor LV volumes at day 6 were related to LVR or LAR, respectively. Conclusions The authors found LA changes to occur in the months after myocardial infarction, with an overall decrease in LA volumes. While LAR coincided with LVR, the correlates for LAR were age older than 70 years and larger infarct size.

Sucrose and its derivative hexoses are key metabolites of the plant metabolism, structural units of cell walls and stored reserves (e [...]

Background It is unclear whether hybrid closed-loop therapy (HCL) attenuates the metabolic impact of missed or suboptimal meal insulin bolus compared with sensor-augmented pump therapy (SAP) in children with type 1 diabetes in free-living conditions. Methods This is an ancillary study from a multicenter randomized controlled trial that compared 24/7 HCL to evening and night (E/N) HCL for 36 weeks in children between 6 and 12 years old. In the present study, the 60 children from the E/N arm underwent a SAP phase, an evening and night (E/N) HCL for 18 weeks, then a 24/7 phase for 18 weeks, extended for 36 more weeks. The last 28-30 days of each of the four phases was analyzed according to meal bolus management (cumulated 6817 days). The primary endpoint was the percentage of time that the sensor glucose was in the target range (TIR, 70 to 180 mg/dl) according to the number of missed boluses per day. Findings TIR was 54±10% with SAP, 63± 7% with E/N HCL, and steadily 67±7% with 24/7 HCL. From the SAP phase to 72 weeks of HCL, the percentage of days with at least one missed meal bolus increased from 12% to 22%. Estimated marginal (EM) mean TIR when no bolus was missed was 54% (95% CI 53-56) in SAP and it was 13% higher (95% CI 11-15) in the 24/7 HCL phase. EM mean TIR with 1 and ≥ 2 missed boluses/day was 49.5% (95% CI 46-52) and 45% (95% CI 39-51) in SAP, and it was 15% (95% CI 14-16) and 17% higher (95% CI 6 to 28), respectively in 24/7 HCL phase (p<0.05 for all comparisons vs. SAP). Interpretation HCL persistently improves glycemic control compared to SAP, even in case of meal bolus omission.