Marine Aliaga
email: marinealiaga@hotmail.com

Jean-Marie Forel

Sophie De Bourmont

Boris Jung

Guillemette Thomas

Martin Mahul

Magali Bisbal

Stéphanie Nougaret

Sami Hraiech

Antoine Roch

Jean-Marie Forel

Stephanie Nougaret

Kathia Chaumoitre

Samir Jaber

Marc Gainnier

Laurent Papazian

J.-M Forel

Á G Thomas

Á S Hraiech

Á A Roch

Á L Papazian Re

J.-M Forel

Á L Papazian

Á M Bisbal

Á M Gainnier

Á M Mahul

Á S Jaber De ´part D'

S Nougaret

Diagnostic yield and safety of CT scans in ICU

Keywords: CT scan, Tomography, Intra-hospital transport, Intensive care unit, Critically ill, Complications, Adverse events, Diagnostic yield, Therapeutic yield, Safety

Abstract Purpose: Critically ill patients often require CT scans. Adverse events (AE) can occur during intra-hospital transport (IHT). The aim of this prospective study was to determine the diagnostic and therapeutic yield and the safety of CT scans in ICU patients. Methods: All ICU patients having a CT scan for diagnostic purposes were eligible. Diagnostic yield was evaluated by the agreement (full, partial or disagreement) between the physician main diagnostic hypothesis before the CT scan and the diagnosis established after the CT scan. Therapeutic yield was assessed by therapeutic changes after the CT scan. The safety was determined by the AE rate during IHT. Results: A total of 533 CT scans were performed on 359 patients in three teaching hospital ICUs. The diagnostic yield of CT scan showed 40.7 % of full agreement, 5.6 % of partial agreement and 53.7 % of disagreement with the main diagnostic hypothesis formulated before the CT scan. The CT-scan brought new elements to the diagnosis in 22.9 % of the cases. There was 54.4 % of therapeutic change after CT scan, while 22.3 % of AE occurred during IHT, including 6.7 % of life-threatening events. AE occurred more frequently in the first 48 h after ICU admission, in the most severely ill patients (higher SAPS II at admission), and when there was a large amount of equipment required for transport. Conclusions: The CT scan as a diagnostic procedure invalidated a diagnostic hypothesis and led to a therapeutic change in more than half of the cases.

Introduction

Critically ill patients hospitalised in the intensive care unit (ICU) often require diagnostic procedures, mainly CT scans, which lead to repeated intra-hospital transports (IHT) [START_REF] Warren | American College of Critical Care Medicine: guidelines for the inter-and intrahospital transport of critically ill patients[END_REF][START_REF] Lakhal | AzuRe ´a network for the RadioDay study group (2012) Chest radiographs in 104 French ICUs: current prescription strategies and clinical value[END_REF][START_REF] Quenot | Intrahospital transport of critically ill patients (excluding newborns) recommandations of the Socie ´te ´de Re ´animation de Langue Franc ¸aise (SRLF), the Socie ´te Franc ¸aise d'Anesthe ´sie et de Re ´animation (SFAR), and the Socie ´te Franc ¸aise de Me ´decine d'Urgence (SFMU)[END_REF]. ICU patients are usually clinically unstable, requiring heavy therapeutic support such as mechanical ventilation, vasopressors and fluid expansion, and continuous sedation, complicating IHT. These factors are sometimes responsible for adverse events (AE) and may worsen the prognosis. Numerous studies in critically ill adults have reported patient-related or life support equipment-related AE during IHT for diagnostic testing, with an overall rate up to 70 % [START_REF] Day | Keeping patients safe during intrahospital transport[END_REF][START_REF] Beckmann | Incidents relating to the intra-hospital transfer of critically ill patients. An analysis of reports submitted to the Australian Incident Monitoring Study in Intensive Care[END_REF][START_REF] Waydhas | Intrahospital transport of critically ill patients[END_REF][START_REF] Zuchelo | Intrahospital transport of patients on invasive ventilation: cardiorespiratory repercussions and adverse events[END_REF][START_REF] Damm | Complications during the intrahospital transport in critically ill patients[END_REF][START_REF] Lahner | Incidence of complications in intrahospital transport of critically ill patients-experience in an Austrian university hospital[END_REF][START_REF] Papson | Unexpected events during the intrahospital transport of critically ill patients[END_REF][START_REF] Kue | Adverse clinical events during intrahospital transport by a specialized team: a preliminary report[END_REF]. IHT complications from respiratory or haemodynamic issues can be life threatening. Indeed, Beckmann et al. [START_REF] Beckmann | Incidents relating to the intra-hospital transfer of critically ill patients. An analysis of reports submitted to the Australian Incident Monitoring Study in Intensive Care[END_REF] report a 2 % mortality rate associated with the IHT of critically ill patients. Therefore, evaluation of the risk/benefit ratio of IHT for CT scan is necessary [START_REF] Marques | Avoiding harm during intra-and inter-hospital transport[END_REF]. Only a few single-centre studies [START_REF] Caruana | Intrahospital transport of the critically ill adult: a research review and implications[END_REF][START_REF] Indeck | Risk, cost, and benefit of transporting ICU patients for special studies[END_REF][START_REF] Hurst | Cost and complications during in-hospital transport of critically ill patients: a prospective cohort study[END_REF] report therapeutic changes following a diagnostic procedure with an IHT (more than 80 % were CT scans), varying from 24 to 39 %, with a global AE rate up to 68 % during transport. However, these retrospective studies had a limited number of patients (100 or fewer patients), included only trauma and surgical patients, and did not focus on IHT for CT scan as a diagnostic procedure. To our knowledge, there is no prospective study that specifically evaluates the CT scan risk/benefit ratio as a diagnostic procedure in ICU patients. The main objective of this study was to evaluate the CT scan diagnostic and therapeutic yield. A secondary objective was to assess its safety during transport and during the exam.

Methods

This prospective, observational multicentre cohort study was conducted in two 14-and 12-bed medical ICU's and one 16-bed medical-surgical ICU in three teaching hospitals. Admissions occurred between January, 2012 and November, 2013. The local ethics committee approval was obtained for this study.

Inclusion criteria

All consecutive patients over 18 years of age were included when a CT scan for diagnostic purposes was performed. The decision to perform a CT scan was made by the senior physician in charge of the patient.

CT scans performed for systematic monitoring or interventional imagery, such as a CT scan-guided percutaneous aspiration or drainage, were not included.

IHT for CT scan procedure

We defined IHT as transportation of a patient to and from his ICU bed to the radiology department located outside the ICU, but within the hospital, with a priority path. The initiation and completion times for the CT scan were counted in the IHT. Each participating ICU had a written procedure for IHTs. IHTs occurred under medical supervision of at least one ICU staff member (junior or senior physician) and a second person (med student or porter). Recommendations for IHT were followed to limit AE [START_REF] Warren | American College of Critical Care Medicine: guidelines for the inter-and intrahospital transport of critically ill patients[END_REF].

Study protocol

Clinical patients' characteristics, CT scan and IHT characteristics were prospectively recorded. Data were collected through a case report form (CRF) by the physician in charge of the daily care of the patient. This CRF included three parts.

The first part was related to the period prior to the CT scan. The physician recorded the diagnostic hypotheses to be tested by the CT scan and classified them by order of relevance. There was a pre-established list of hypotheses: infectious cause, intracranial disease, extra cranial bleeding, venous thromboembolism (pulmonary embolism or deep venous thrombosis), pleural effusion or lung atelectasis, malignant tumour or another diagnosis (specification of this diagnosis was required). Expected therapeutic changes were also stipulated, whether medical (treatment initiation or withholding) or interventional (any change concerning surgery, drainage, interventional radiology or endoscopy).

Data concerning IHT were recorded in the second part of the CRF, starting with the patient's equipment: invasive mechanical ventilation (MV) with or without severe hypoxemia criteria (PEEP C 10 cm H 2 O or FiO 2 C 60 %), any type of vasopressor support, continuous sedation, drains (chest tube or surgical drainage) and extra corporeal life support (ECLS). We predefined different types of AE [START_REF] Fanara | Recommandations for the intra-hospital transport of critically ill patients[END_REF] and prospectively recorded them for all IHT: respiratory AE (oxygen desaturation: pulse oximetry (SpO 2 ) \95 % or a decrease of more than 5 % in baseline SpO 2 for more than 1 min [START_REF] Damm | Complications during the intrahospital transport in critically ill patients[END_REF][START_REF] Parmentier-Decrucq | Adverse envents during intrahospital transport of critically ill patients: incidence and risk factors[END_REF]; bronchospasm; pneumothorax; accidental extubation; selective intubation; patient-ventilator asynchrony), cardiocirculatory AE (severe hypotension defined as a systolic blood pressure \90 or 20 mmHg decrease in systolic or diastolic blood pressure more than 1 min [START_REF] Waydhas | Intrahospital transport of critically ill patients[END_REF][START_REF] Papson | Unexpected events during the intrahospital transport of critically ill patients[END_REF][START_REF] Parmentier-Decrucq | Adverse envents during intrahospital transport of critically ill patients: incidence and risk factors[END_REF]; arrhythmia; cardiac arrest), neurological AE (agitation, intracranial hypertension) and material malfunction AE (any intravenous or intra-arterial catheter disconnection, dislodgment or thrombosis, accidental dislodging of urinary catheter or nasogastric tube; incidents with airway equipment: disconnection of endotracheal tube, alarms or transport ventilator malfunction, or problems with oxygen supply; electric syringe battery down; bed electric command or elevator out of order). In addition, the physician in charge of the IHT was asked about his/her perception of the difficulty of IHT after CT scan (safe or difficult) and, when an AE occurred, they were asked about its potential or proved major consequences for the patient's stay. The final clinical impact of AE was assessed at day 3.

Serum creatinine was recorded on the CT scan day and the 2 days following the procedure, as was the presence of renal replacement therapy.

Three days later, the physician filled in the last part of the CRF concerning diagnostic yield (main diagnostic hypothesis confirmed or invalidated by CT scan) and therapeutic yield after CT scan: effective therapeutic change: medical (treatment initiation or withholding) or intervention (any change concerning surgery, drainage, interventional radiology or endoscopy). Effective therapeutic changes were evaluated on the same principle as the proposed changes before CT scan.

Data analysis and statistics

Diagnostic yield was defined by the agreement between the main diagnostic hypothesis proposed by the physician (before CT scan) and the effective diagnosis established by the CT scan. Diagnostic yield was classified as full agreement when the main hypothesis before CT scan was confirmed by the scan, partial agreement when the main hypothesis before CT scan was confirmed but new diagnostic elements were determined by the scan and disagreement when the main hypothesis before CT scan was completely different than effective diagnosis established by the scan. In case of disagreement, there were two possibilities, either new diagnostic elements unanticipated by the clinician were found or no diagnosis was established by the CT scan. Therapeutic yield was evaluated by therapeutic changes after the CT scan and compared to what was expected by the physician before the CT scan, in cases where the main diagnostic hypothesis is confirmed by CT scan. Safety was evaluated by the AE occurrence rate and its association with equipment and timing of the CT scan after ICU admission. Concordance between difficulty of IHT and the rate of AE, the number of equipment and severity was analysed. We counted one point for each item (except MV with severe hypoxemia criteria, two points) to evaluate the influence of the amount of equipment on transport perception or AE occurrence. The Acute Kidney Injury Network (AKIN) definition for ICM-associated acute kidney injury was used [START_REF] Mccullough | Acute kidney injury with iodinated contrast[END_REF][START_REF] Lakhal | Acute Kidney Injury Network definition of contrast-induced nephropathy in the critically ill: incidence and outcome[END_REF][START_REF] Ehrmann | Acute kidney injury in the critically ill: is iodinated contrast medium really harmful?[END_REF][START_REF] Azoulay | Year in review in Intensive Care Medicine 2013: II. Sedation, invasive and noninvasive ventilation, airways, ARDS, ECMO, family satisfaction, end-of-life care, organ donation, informed consent, safety, hematological issues in critically ill patients[END_REF]: C25 % increase in serum creatinine over 48 h. The day-28 ICU-free days were calculated by subtracting the actual ICU length of stay in days from 28. The day-28 ICU-free days was considered as 0 if a patient died before hospital discharge or stayed in ICU for [28 days. The variable distribution was evaluated using the Kolmogorov-Smirnov test. According to the distribution, quantitative variables were expressed as the median and interquartile range (IQR) or mean (±standard deviation) and qualitative variables as the percentage. Qualitative variables and proportions were compared using the Pearson v 2 test. For the contingence tables with more than 2 9 2, we used the v 2 test for trend. When possible, the diagnostic accuracy of the CT-scan was reported in accordance with the guidelines of the Standards for the Reporting of Diagnostic accuracy studies (STARD) [22]. The degree of agreement between the main diagnostic hypothesis before CT scan and effective diagnosis after CT scan was quantified by Cohen's kappa (j). A p value \0.05 was considered to be significant. Statistical analysis was conducted using SPSS v.20.0 (IBM, NY, USA).

Results

Patients

During the study period, 359 patients were included. Of these, 32.6 % had more than one CT scan. Table S1 (electronic supplementary material) presents patients' characteristics in the three participating ICUs. Causes of ICU admission were: surgical emergency or complications from a scheduled surgery in 92 cases (25.6 %), respiratory failure in 76 cases (21.2 %), neurological failure in 75 cases (20.9 %), septic shock in 62 cases (17.3 %) and haemodynamic failure (cardiogenic shock or cardiac arrest) in 33 cases (9.2 %).

CT scans and IHT characteristics

CT scan characteristics

A total of 533 CT scans were included. Figure 1 presents the flow chart of CT scans inclusion. Anatomical regions explored by CT scan are shown in Table 1. A total of 39.2% (209) of the CT scans were performed within the first 48 h of ICU stay and 60.8 % (324) after 48 h. The prescriber was a single senior intensivist in 80.1 % of the cases, and a staff decision was made in 19.9 % of the cases.

IHT characteristics

A total of 81.6% of transports to and from the ICU to the radiology department were performed with patients who had one or more pieces of the equipment listed in Table 1, while 18% (98) of IHTs were performed with patients who had no equipment listed, 25.1 % (134) with one piece, 22.7 % (121) with two pieces, 16.7 % (89) with three pieces, 11.6 % (62) with four pieces and 5.4 % (29) with five or six pieces of the equipment listed.

Diagnostic and therapeutic hypotheses before CT scan

The main diagnostic hypotheses formulated by senior physicians before the CT scan are presented in Table 2. In 42.6 % (227) of the CT scans, a second diagnostic hypothesis was formulated: intracranial disease in 26.8 % (61) of those CT scans, infectious cause in 22.5 % (51) of CTs, pleural effusion or lung atelectasis in 22 % (50) of CTs, venous thromboembolism in 13.2 % (30) of CTs, extra-cranial bleeding in 7.9 % (18) of CTs, malignant tumour in 1.8 % (4) of CTs and other varied causes in 5.7 % (13) of CTs.

Expected therapeutic changes (before CT scan) concerned interventional procedures in 69.8 % (372) of the CT scans and medical treatment in 30.2 % (161) of the CT scans.

Diagnostic and therapeutic yields after CT scan

Diagnostic yield

There was a full agreement between the main diagnostic hypothesis formulated before CT scan and the diagnosis 92) of them were found after CT scans invalidating the main diagnostic hypothesis and 5.6 % (30) in addition to the main diagnostic hypothesis. These results are summarized in Fig. 1. The Cohen's kappa coefficient (j = 0.29) indicated a low level of agreement between the main diagnostic hypothesis formulated before CT scan and the effective diagnosis established after CT scan.

Therapeutic yield

There was a therapeutic change within 3 days after CT scan in 54.4 % (290) of the cases. An interventional procedure (surgery, drainage, interventional radiology or endoscopy) occurred in 28.7 % (153) of the cases, and a medical change (treatment initiation or withholding) was made in 25.7 % (137) of the cases. Table 3 shows the comparison between before CT scan expected therapeutic change and after CT scan effective change. Among the 290 CT scans that induced therapeutic change, the modification was in accordance with the one that was expected before the CT scan in 207 (71.4 %) of the cases. As presented in Figure S1 (electronic supplementary material), therapeutic change differed depending on whether the main diagnostic hypothesis was confirmed by the CT scan. Among the 122 CT scans which discovered new elements, 68.9 % (84) led to a therapeutic change.

Safety

Transport difficulty perception

In 55.5 % (296) of the cases, IHT was estimated as safe by the physician. Among the 44.5 % (237) IHTs that were estimated as difficult, 24.1 % (57) were felt to be very difficult. As presented in Fig. 2, IHT difficulty perception significantly increased with the amount of equipment. Among the 170 patients having a CT scan within 48 h after ICU admission (209 CT scans), the patient's admission severity, assessed by SAPS II score at admission, was higher when transport was perceived to be difficult (56.2 ± 17.7 when transport was difficult and 49.2 ± 17.0 when transport was safe, p = 0.011).

Adverse events

An adverse event happened in 22.3 % (119) of the IHTs for CT scan. A detailed list is shown in Figure S2 (electronic supplementary material). Of these AEs, 37 % were considered by the clinicians to alter ICU duration of stay or hospital mortality, including almost 7 % considered life threatening. Among them, two cardiac arrests occurred, one fatal. Mean day-28 ICU-free days and mortality in patients having an AE considered by the clinicians to alter ICU duration of stay and/or mortality were respectively 4.7 ± 8.9 days and 50 % as compared to 7.4 ± 9.9 days and 34 % when AE was not considered to have consequences (p = 0.22 for ICU-free days and p = 0.16 for ICU mortality). As shown in Fig. 2, the amount of equipment had an influence on AE occurrence (p trend = 0.006). Patients transported with continuous sedation or with vasopressor support had an increased risk of AE. Indeed, 27.5 % (64) of patients with sedation had an AE, compared to 18.3 % (55) of AEs in patients who were not sedated (p = 0.012). Of patients with vasopressors, 29% (69) had an AE, compared to 19.1 % (69) in patients without vasopressors (p = 0.008). No There was a more significant AE rate during IHT in the first 48 h after ICU admission, 27.8 % (58) compared to 18.8 % when IHT was performed after 48 h (61), p = 0.016. In addition, in the first 48 h after ICU admission, the mean amount of equipment was more significant in IHT with AE occurrence (2.5 ± 1.5) than without AE (1.9 ± 1.4), p = 0.005. Among the patients having an IHT for CT scan within 48 h after ICU admission, the SAPS II score at admission was higher when an AE occurred (57.4 ± 18.6) during IHT compared to the SAPS II of patients having an IHT without AE (50.2 ± 16.9), p = 0.018.

Serum creatinine

An iodinated contrast medium (ICM) was injected in 82 % (437) of the CT scans. After those 437 CT scans, 13 % (57) of the patients met AKIN criteria for CIN. Among them, 15 patients had renal replacement therapy for the first time in the 48 h following CT scan.

Risk benefit ratio of CT scans

An AE happened in 14.9 % (29 of 194) of IHTs for CT scans with no diagnosis established as compared with 26.5 % (90 of 339) when a diagnosis was established (p = 0.002). There was a higher rate of CT scans providing radiological diagnosis when there was an AE during IHT than when there was not (75.1 vs. 60.1 %, respectively; p = 0.002). There was also a higher rate of CT scans leading to a therapeutic change when there was an AE during IHT than when there was not (67.2 vs. 50.7 %, respectively; p = 0.002).

Discussion

In this multicentre, prospective observational cohort study, CT scan contributed to diagnosis by a disagreement in 53.7 % (286) of the cases, a partial agreement in 5.6 % (30) of the cases and a full agreement in 40.7 % (217) of the cases with the main diagnostic hypothesis formulated before CT scan. Unexpected new elements related to diagnosis were reported in 22.9 % of the cases. A therapeutic change after the CT scan was observed in 54.4 % of the cases. Twenty-two percent of AE occurred during intra-hospital transport for CT scan while 37% of these AEs were considered by the clinicians to alter ICU duration of stay or hospital mortality, including almost 7 % considered life threatening. AE occurred more frequently when IHTs for CT scan were performed in the first 48 h after ICU admission. In this period, AE were significantly increased in the most unwell patients (higher SAPS II at ICU admission) and when the amount of equipment was greater.

To our knowledge, this is the first prospective study focused on CT scan as a diagnostic procedure, exploring several aspects including both diagnostic and therapeutic yields and safety in IHT. To evaluate diagnostic yield, we chose an approach based on the agreement between the physician's diagnostic hypothesis before the CT scan and its confirmation or lack thereof after the CT scan. This original approach seemed to us to be the closest to questions a physician asks himself to evaluate the risk/ benefit ratio of a CT scan for a critically ill patient. However, our study only considered the main diagnostic hypothesis to assess agreement before and after the CT scan because there was no second hypothesis in more than half of the CT scans. In this study, we have shown that a CT scan invalidated a diagnostic hypothesis more often (53.7 %) than it confirmed it. Nevertheless, a CT scan led to a therapeutic change in 54.4 % of the cases. In some cases, the CT scan could have been performed to rule out a life-threatening condition (e.g. pulmonary embolism), and a disagreement between physician's expectation and CT scan result would not reflect the value added by the CT scan. The design of this study does not allow us to see how many unnecessary therapeutic changes have been avoided thanks to CT scan results.

As reported by Indeck [START_REF] Indeck | Risk, cost, and benefit of transporting ICU patients for special studies[END_REF] and Hurst [START_REF] Hurst | Cost and complications during in-hospital transport of critically ill patients: a prospective cohort study[END_REF], we evaluated therapeutic yield by the number of therapeutic changes; moreover, we specified the type of treatment changed: medical treatment (initiation or withholding) or interventional treatment (any surgery, drainage, interventional radiology or endoscopy). Those single-centre studies included B100 trauma and major surgery ICU patients and were not entirely focused on CT scans for diagnostic purposes. Our study gathered a larger population of critically ill medical and surgical patients. Trauma patients were not included to avoid systematic CT scans at admission, and also systematic monitoring imagery. Our inclusion criteria might explain the higher therapeutic change rate observed after the CT scan (54.4 %) compared to the Indeck [START_REF] Indeck | Risk, cost, and benefit of transporting ICU patients for special studies[END_REF] (24 %) and Hurst [START_REF] Hurst | Cost and complications during in-hospital transport of critically ill patients: a prospective cohort study[END_REF] (39 %) studies.

Safety of the entire CT scan procedure included adverse event analysis and the influence of patients' severity rating, transport equipment and timing of IHT after ICU admission. Patients with continuous sedation and/or vasopressors appeared to have a higher rate of complications during IHT compared to those who had none. Our results for sedation are in line with the Damm study, in which sedated patients had an excess risk of demonstrating agitation or haemodynamic problems [START_REF] Damm | Complications during the intrahospital transport in critically ill patients[END_REF]. A difference between the level of sedation required for comfort in an ICU bed and that needed for transport and transfer onto the CT scan table might explain this phenomenon. Moreover, sedation and vasopressors are used with severely ill patients [START_REF] Seymour | Adverse events during rotary-wing transport of mechanically ventilated patients: a retrospective cohort study[END_REF]. The relationship between AE and patient illness severity, quantified by SAPS II at ICU admission, or the amount of pieces of medical equipment, particularly in the first 48 h of ICU admission, is an important result for clinical practice. However, the design of this study did not enable us to know how many times the CT scan was not performed due to the critical condition of the patient. Our study emphasises that the risk/benefit ratio evaluation must be rigorous, especially in the first 48 h after ICU admission, where patients seem to be less stable. In our study, the association of life-threatening AE were not in line with the results of Schwebel et al. [START_REF] Schwebel | Safety of intrahospital transport in ventilated critically ill patients: a multicenter cohort study[END_REF], where IHT was not shown to impact hospital mortality. However, the purpose and the methods of our study were not comparable with the Schwebel et al. [START_REF] Schwebel | Safety of intrahospital transport in ventilated critically ill patients: a multicenter cohort study[END_REF] study.

Many professional societies have developed guidelines to improve safety during the transport of critically ill patients by setting rules for pre-transport planning and coordination, escort, equipment and monitoring procedures [START_REF] Warren | American College of Critical Care Medicine: guidelines for the inter-and intrahospital transport of critically ill patients[END_REF][START_REF] Quenot | Intrahospital transport of critically ill patients (excluding newborns) recommandations of the Socie ´te ´de Re ´animation de Langue Franc ¸aise (SRLF), the Socie ´te Franc ¸aise d'Anesthe ´sie et de Re ´animation (SFAR), and the Socie ´te Franc ¸aise de Me ´decine d'Urgence (SFMU)[END_REF][START_REF] Fanara | Recommandations for the intra-hospital transport of critically ill patients[END_REF][START_REF]American College of Critical Care Medicine, Society of Critical Care Medicine and Transfer Guidelines Task Force (1993) Guidelines for the transfer of critically ill patients[END_REF]. In our study, each participating ICU had a written procedure but no checklist for IHTs. Numerous studies confirmed that the IHT of critically ill patients leads to a significant number of AE. However, it remains difficult to compare these because the definitions of AE vary from study to study. Our classification of AE was inspired by the Fanara [START_REF] Fanara | Recommandations for the intra-hospital transport of critically ill patients[END_REF] review because it seemed the most clinical relevant approach.

The overall prevalence of contrast-induced nephropathy (CIN) in the literature is highly variable and estimated to be between 1 and 30 % [START_REF] Lakhal | Acute Kidney Injury Network definition of contrast-induced nephropathy in the critically ill: incidence and outcome[END_REF][START_REF] Azoulay | Year in review in Intensive Care Medicine 2013: II. Sedation, invasive and noninvasive ventilation, airways, ARDS, ECMO, family satisfaction, end-of-life care, organ donation, informed consent, safety, hematological issues in critically ill patients[END_REF][START_REF] Hoste | Epidemiology of contrast-associated acute kidney injury in ICU patients: a retrospective cohort analysis[END_REF][START_REF] Valette | Incidence, morbidity, and mortality of contrast-induced acute kidney injury in a surgical intensive care unit: a prospective cohort study[END_REF], which is linked to the studied population's baseline characteristics but also to a lack of uniformity in the definition used [START_REF] Nash | Hospital-acquired renal insufficiency[END_REF]. Patients in the ICU frequently have multiple, unavoidable, confounding Acute Kidney Injury (AKI) risk factors (sepsis, shock and nephrotoxic medications) [START_REF] Boumendil | Should elderly patients be admitted to the intensive care unit?[END_REF]. Our study showed that 13 % of patients meet the AKIN criteria for CIN after an ICM injection. The design of our study does not allow us to establish a causal link. In a recent prospective matched cohort study, Ehrmann et al. [START_REF] Ehrmann | Acute kidney injury in the critically ill: is iodinated contrast medium really harmful?[END_REF] showed that, contrary to the Sequential Organ Failure Assessment score at inclusion and the number of other nephrotoxic agents, ICM infusion was not an independent risk factor for AKI.

We were unable to assess the potential effects of factors, such as CT scan procedure timing (off-hours, weekdays, elective compared to emergency procedures). We did not collect information on the experience and seniority of accompanying staff members. The fact that data for AE during IHT were collected by the physician in charge of the patient is also a limit in this study. It is likely that some episodes (e.g. hypotension) were not recorded. An electronic recording would have been more accurate.

In conclusion, the CT scan is a major diagnostic tool in critically ill patients. Indeed, the CT scan invalidates a diagnostic hypothesis and leads to a therapeutic change in more than half of the cases. However, transporting patients out of ICU is a period of increased risk for AE.

Fig. 2

 2 Fig. 2 Influence of amount of equipment on transport perception and adverse event (AE) occurring during intrahospital transport equipment included: mechanical invasive ventilation (MV) = 1 point; MV with severe hypoxemia criteria (PEEP C10 cm H 2 O or FiO 2 C60 %) = 1 extra point; any type of vasopressors = 1 point; continuous sedation = 1 point; drains (chest tube or surgical drainage) = 1 point; and extra corporeal life support = 1 point

Table 1

 1 CT scans and IHT characteristics Anatomical regions explored by CT scan, % (n)Patient's equipment during IHT, % (n)

	Thoraco-abdominal-pelvic	36 (192)	Invasive mechanical ventilation (MV)	70.4 (375)
	Brain	27.4 (146)	MV with PEEP [10 cm H 2 O or FiO 2 [60 %	24 (90)
	Whole body	13.5 (72)	Vasopressors support	32.1 (171)
	Chest	10.1 (54)	Continuous sedation	43.7 (233)
	Abdominal-pelvic	7.3 (39)	Drains (chest tubes or any surgical drainage)	30.4 (161)
	Brain and chest	5.6 (30)	Extra corporeal life support (ECLS)	1.1 (6)

Table 2

 2 Main diagnostic hypotheses formulated by physician and confirmation by CT scan

		Diagnostic	Diagnostic
		hypothesis	confirmation
		before CT	by CT
		scan, % (n)	scan, % (n)
	Infectious cause	42.2 (225)	48.9 (110)
	Intracranial disease	33.0 (176)	46.0 (81)
	Venous thromboembolism	8.8 (47)	27.7 (13)
	Extracranial bleeding	7.7 (41)	39.0 (16)
	Pleural effusion or Lung atelectasis	3.6 (19)	63.2 (12)
	Malignant tumour	0.9 (5)	40.0 (2)
	Other varied causes	3.8 (20)	65.0 (13)

Table 3

 3 Comparison of expected therapeutic change (before CT) and effective therapeutic change (after CT)

	Effective therapeutic change after CT scan % (n)
	Interventional	Medical	No change

Definitions of therapeutic changes are the following: (1) interventional: any change concerning surgery, drainage, interventional radiology or endoscopy; (2) medical: treatment initiation or withholding significant differences were shown for the other types of equipment.

Acknowledgments The authors thank the residents, physicians and nurses, in the three ICU departments for their significant contribution in this study.

Conflicts of interest

The authors declare that they have no conflict of interest.


Rosen Ivanov

Frédéric Alexis Deschamps

F De Geuser

Clustering kinetics during natural ageing of Al-Cu based alloys with (Mg, Li) additions

Keywords: Aluminium alloys, ageing, precipitation hardening, small-angle scattering

published or not. The documents may come     Clustering kinetics during natural ageing of Al-Cu based alloys with (Mg, Li) additions

Introduction

Natural ageing of Aluminium alloys encompasses the changes at room temperature to the microstructure and related properties after they have been quenched from solution treatment temperature. First observed by Wilm in 1906 [START_REF] Duparc | Alfred Wilm and the beginnings of Duralumin[END_REF] and later characterised by Guinier and Preston [START_REF] Guinier | Structure of Age-Hardened Aluminium-Copper Alloys[END_REF][START_REF] Preston | Structure of Age-Hardened Aluminium-Copper Alloys[END_REF], the increase of hardness experienced during natural ageing at room temperature is related to the changes in solute distribution at the atomic scale. Solute clustering describes the initial stage of decomposition of a supersaturated solid solution into one with solute-rich domains retaining the host crystal structure. It results in measurable changes of the materials properties, in particular hardness, but also electrical resistivity, lattice parameter etc. Solute clusters, being of the same crystal structure as the host Al matrix, showing no interface and only mild compositional contrast have posed great difficulties to be unambiguously characterized and render necessary the combined use of several analytical techniques [START_REF] Banhart | Natural Aging in Al-Mg-Si Alloys -A Process of Unexpected Complexity[END_REF]. Most common experimental techniques based on global sample methods such as differential scanning calorimetry (DSC) [START_REF] Charai | Coexistence of clusters, GPB zones, S''-, S'and S-phases in an Al-0.9% Cu-1.4% Mg alloy[END_REF][START_REF] Starink | The origins of room temperature hardening of Al-Cu-Mg alloys[END_REF][START_REF] Starink | Room temperature precipitation in quenched Al-Cu-Mg alloys: a model for the reaction kinetics and yield strength development[END_REF][START_REF] Kim | Effects of Cu Addition on Behavior of Nanoclusters during Multi-Step Aging in Al-Mg-Si Alloys[END_REF][START_REF] Kim | Formation Behavior of Nanoclusters in Al-Mg-Si Alloys with Different Mg and Si Concentration[END_REF][START_REF] Weng | Effect of Ag and Cu additions on natural aging and precipitation hardening behavior in Al-Mg-Si alloys[END_REF],

electrical resistivity [START_REF] Kim | Effects of Cu Addition on Behavior of Nanoclusters during Multi-Step Aging in Al-Mg-Si Alloys[END_REF][START_REF] Kim | Formation Behavior of Nanoclusters in Al-Mg-Si Alloys with Different Mg and Si Concentration[END_REF] and of course hardness [START_REF] Marceau | A study of the composition dependence of the rapid hardening phenomenon in Al-Cu-Mg alloys using diffusion couples[END_REF][START_REF] Pogatscher | Diffusion on Demand to Control Precipitation Aging: Application to Al-Mg-Si Alloys[END_REF][START_REF] Werinos | Design strategy for controlled natural aging in Al-Mg-Si alloys[END_REF][START_REF] Werinos | Hardening of Al-Mg-Si alloys: Effect of trace elements and prolonged natural aging[END_REF] provide evidence for the formation and evolution of clusters. Direct imaging of Cu-Mg "clusters" has been reported by Ralston et al. by highresolution aberration-corrected TEM [START_REF] Ralston | Role of nanostructure in pitting of Al-Cu-Mg alloys[END_REF]; however this method has proven very difficult due to the small quantity and low Z-contrast of the solute species associated in individual clusters with large number density. Techniques based on positron annihilation spectroscopy [START_REF] Banhart | Natural Aging in Al-Mg-Si Alloys -A Process of Unexpected Complexity[END_REF][START_REF] Nagai | Role of vacancy-solute complex in the initial rapid age hardening in an Al-Cu-Mg alloy[END_REF][START_REF] Banhart | Kinetics of natural aging in Al-Mg-Si alloys studied by positron annihilation lifetime spectroscopy[END_REF][START_REF] Klobes | Natural ageing of Al-Cu-Mg revisited from a local perspective[END_REF][START_REF] Zou | Vacancy-Mg complexes and their evolution in early stages of aging of Al-Mg based alloys[END_REF][START_REF] Klobes | Early stage ageing effects and shallow positron traps in Al-Mg-Si alloys[END_REF][START_REF] Liu | Early stages of solute clustering in an Al-Mg-Si alloy[END_REF][START_REF] Liu | Positron lifetime study of the formation of vacancy clusters and dislocations in quenched Al, Al-Mg and Al-Si alloys[END_REF][START_REF] Liu | Effect of Cu and Ge on solute clustering in Al-Mg-Si alloys[END_REF], nuclear magnetic resonance [START_REF] Bastow | Early stage hardening in ALCuMg alloy studied by Cu nuclear magnetic resonnance and positron annihilation[END_REF][START_REF] Deschamps | In-Situ Evaluation of the Microstructure Evolution during Rapid Hardening of an Al-2.5Cu-1.5Mg (wt. %) Alloy[END_REF] or X-ray absorption spectroscopy [START_REF] Klobes | Natural ageing of Al-Cu-Mg revisited from a local perspective[END_REF][START_REF] Klobes | Early stages of decomposition in Al alloys investigated by X-ray absorption[END_REF] provide more information about the local environment of solutes and can shine some light on solute-vacancy relationships. Atom Probe Tomography (APT), giving access to the 3D position and chemical identity of atoms, has been extensively used in conjunction with cluster-finding algorithms or radial distribution functions (RDFs) to provide information on the correlation of solutes and size distributions of clustered domains [START_REF] Ringer | Cluster hardening in an aged Al-Cu-Mg alloy[END_REF][START_REF] Ringer | Origins of hardening in aged Al-Cu-Mg-(Ag) alloys[END_REF][START_REF] Reich | Origin of the initial rapid age hardening in an Al-1.7 at. % Mg-1.1 at.% Cu alloy[END_REF][START_REF] Geuser | 3D atom probe study of solute atoms clustering during natural ageing and pre-ageing of an Al-Mg-Si alloy[END_REF][START_REF] Serizawa | Three-dimensional atom probe characterization of nanoclusters responsible for multistep aging behavior of an Al-Mg-Si alloy[END_REF][START_REF] Torsaeter | The influence of composition and natural aging on clustering during preaging in Al-Mg-Si alloys[END_REF][START_REF] Cao | Clustering behaviour in an Al-Mg-Si-Cu alloy during natural ageing and subsequent under-ageing[END_REF][START_REF] Marceau | Analysis of strengthening in AA6111 during the early stages of aging: Atom probe tomography and yield stress modelling[END_REF][START_REF] Zheng | Solute clustering and solute nanostructures in an Al-3.5Cu-0.4Mg-0.2Ge alloy[END_REF][START_REF] Aruga | Evaluation of Solute Clusters Associated with Bake-Hardening Response in Isothermal Aged Al-Mg-Si Alloys Using a Three-Dimensional Atom Probe[END_REF][START_REF] Pogatscher | Process-controlled suppression of natural aging in an Al-Mg-Si alloy[END_REF][START_REF] Aruga | Formation and reversion of clusters during natural aging and subsequent artificial aging in an Al-Mg-Si alloy[END_REF][START_REF] Fallah | Cluster evolution mechanisms during aging in Al-Mg-Si alloys[END_REF][START_REF] Jia | The Influence of Composition on the Clustering and Precipitation Behavior of Al-Mg-Si-Cu Alloys[END_REF][START_REF] Ying | Effects of pre-strain on Cu-Mg coclustering and mechanical behavior in a naturally aged Al-Cu-Mg alloy[END_REF][START_REF] Gault | A nexus between 3D atomistic data hybrids derived from atom probe microscopy and computational materials science: A new analysis of solute clustering in Al-alloys[END_REF].

Small angle scattering (SAS) techniques, providing a global view of the decomposition of the solid solution, have been until now only sparsely used to study clustering [START_REF] Banhart | Natural Aging in Al-Mg-Si Alloys -A Process of Unexpected Complexity[END_REF][START_REF] Deschamps | In-Situ Evaluation of the Microstructure Evolution during Rapid Hardening of an Al-2.5Cu-1.5Mg (wt. %) Alloy[END_REF][START_REF] Decreus | The influence of Cu/Li ratio on precipitation in Al-Cu-Li-x alloys[END_REF][START_REF] Ivanov | A combined characterization of clusters in naturally aged Al-Cu-(Li, Mg) alloys using small-angle neutron and X-ray scattering and atom probe tomography[END_REF], despite them being used extensively to describe the degree of inhomogeneity of solute during spinodal decomposition, such as in the Fe-Cr system [START_REF] Bley | Neutron small-angle scattering study of unmixing in Fe-Cr alloys[END_REF][START_REF] Ujihara | Kinetic analysis of spinodal decomposition process in Fe-Cr alloys by small angle neutron scattering[END_REF][START_REF] Hornqvist | Early stages of spinodal decomposition in Fe-Cr resolved by in-situ small-angle neutron scattering[END_REF][START_REF] Couturier | Direct comparison of Fe-Cr unmixing characterization by atom probe tomography and small angle scattering[END_REF][START_REF] Xu | Effect of cooling rate after solution treatment on subsequent phase separation during aging of Fe-Cr alloys: A small-angle neutron scattering study[END_REF][START_REF] Zhou | Effect of solution treatment on spinodal decomposition during aging of an Fe-46.5 at.% Cr alloy[END_REF].

Since the diffusion of all major solute elements in Aluminium is substitutional, clustering kinetics depends on the presence of vacancies, their supersaturation resulting from the quench from the solution treatment temperature, and their interaction with the solutes they are conveying as well as with the clusters themselves. These interactions have been particularly studied in Al-Mg-Si alloys [START_REF] Serizawa | Three-dimensional atom probe characterization of nanoclusters responsible for multistep aging behavior of an Al-Mg-Si alloy[END_REF][START_REF] Banhart | Natural Aging in Al-Mg-Si Alloys -A Process of Unexpected Complexity[END_REF][START_REF] Torsaeter | The influence of composition and natural aging on clustering during preaging in Al-Mg-Si alloys[END_REF][START_REF] Kim | Effects of Cu Addition on Behavior of Nanoclusters during Multi-Step Aging in Al-Mg-Si Alloys[END_REF][START_REF] Banhart | Kinetics of natural aging in Al-Mg-Si alloys studied by positron annihilation lifetime spectroscopy[END_REF][START_REF] Lay | Vacancy Behavior and Solute Cluster Growth During Natural Aging of an Al-Mg-Si Alloy[END_REF][START_REF] Martinsen | Reversal of the negative natural aging effect in Al-Mg-Si alloys[END_REF][START_REF] Kim | Formation Behavior of Nanoclusters in Al-Mg-Si Alloys with Different Mg and Si Concentration[END_REF][START_REF] Cao | Clustering behaviour in an Al-Mg-Si-Cu alloy during natural ageing and subsequent under-ageing[END_REF][START_REF] Aruga | Evaluation of Solute Clusters Associated with Bake-Hardening Response in Isothermal Aged Al-Mg-Si Alloys Using a Three-Dimensional Atom Probe[END_REF][START_REF] Pogatscher | Process-controlled suppression of natural aging in an Al-Mg-Si alloy[END_REF][START_REF] Pogatscher | Diffusion on Demand to Control Precipitation Aging: Application to Al-Mg-Si Alloys[END_REF][START_REF] Aruga | Formation and reversion of clusters during natural aging and subsequent artificial aging in an Al-Mg-Si alloy[END_REF][START_REF] Klobes | Early stage ageing effects and shallow positron traps in Al-Mg-Si alloys[END_REF][START_REF] Liu | Early stages of solute clustering in an Al-Mg-Si alloy[END_REF][START_REF] Fallah | Cluster evolution mechanisms during aging in Al-Mg-Si alloys[END_REF][START_REF] Liu | Effect of Cu and Ge on solute clustering in Al-Mg-Si alloys[END_REF][START_REF] Werinos | Design strategy for controlled natural aging in Al-Mg-Si alloys[END_REF][START_REF] Werinos | Hardening of Al-Mg-Si alloys: Effect of trace elements and prolonged natural aging[END_REF][START_REF] Jia | The Influence of Composition on the Clustering and Precipitation Behavior of Al-Mg-Si-Cu Alloys[END_REF][START_REF] Weng | Effect of Ag and Cu additions on natural aging and precipitation hardening behavior in Al-Mg-Si alloys[END_REF] owing for the prominentgenerally negativeeffect of clustering on the subsequent artificial ageing kinetics sought during paint baking cycles for automotive sheet. An extensive picture of clustering in this system has been reached by combining experimental observations, thermodynamic modelling [START_REF] Starink | A model for the thermodynamics of and strengthening due to co-clusters in Al-Mg-Si-based alloys[END_REF], and more recently atomistic modelling [START_REF] Gault | A nexus between 3D atomistic data hybrids derived from atom probe microscopy and computational materials science: A new analysis of solute clustering in Al-alloys[END_REF][START_REF] Francis | Microalloying for the controllable delay of precipitate formation in metal alloys[END_REF]. These results show that clusters are generally present as early as the as-quenched state [START_REF] Liu | Early stages of solute clustering in an Al-Mg-Si alloy[END_REF] and then evolve in number density, size but also chemistry, with several families of clusters involving several types of solutes coexisting in the microstructure. These characteristics depend of course on the alloy chemistry, with noticeable effects having been demonstrated by adding controlled amounts of minor solutes effective at trapping vacancies and thus delaying the natural ageing kinetics [START_REF] Pogatscher | Diffusion on Demand to Control Precipitation Aging: Application to Al-Mg-Si Alloys[END_REF][START_REF] Werinos | Design strategy for controlled natural aging in Al-Mg-Si alloys[END_REF]. The other landmark system for clustering studies is Al-Cu-Mg, in which Mg and Cu form co-clusters that are very effective at increasing the alloy's strength. Only a few seconds at moderate artificial ageing temperatures (150-200°C) are sufficient to obtain up to 70% of the maximum precipitation strengthening potential of such alloys, hence the name "rapid hardening" for this effect of clustering [START_REF] Charai | Coexistence of clusters, GPB zones, S''-, S'and S-phases in an Al-0.9% Cu-1.4% Mg alloy[END_REF][START_REF] Ringer | Cluster hardening in an aged Al-Cu-Mg alloy[END_REF][START_REF] Ringer | Origins of hardening in aged Al-Cu-Mg-(Ag) alloys[END_REF][START_REF] Reich | Origin of the initial rapid age hardening in an Al-1.7 at. % Mg-1.1 at.% Cu alloy[END_REF]. Clustering kinetics in this system has also been evaluated by combinations of APT, DSC, PALS, and modelling [START_REF] Nagai | Role of vacancy-solute complex in the initial rapid age hardening in an Al-Cu-Mg alloy[END_REF][START_REF] Starink | The origins of room temperature hardening of Al-Cu-Mg alloys[END_REF][START_REF] Starink | Room temperature precipitation in quenched Al-Cu-Mg alloys: a model for the reaction kinetics and yield strength development[END_REF][START_REF] Lu | Precipitation behavior of AA2618[END_REF][START_REF] Klobes | Early stages of decomposition in Al alloys investigated by X-ray absorption[END_REF][START_REF] Klobes | The role of quenched-in vacancies for the decomposition of aluminium alloys[END_REF][START_REF] Starink | The thermodynamics of and strengthening due to co-clusters: General theory and application to the case of Al-Cu-Mg alloys[END_REF][START_REF] Zurob | A model for the growth of solute clusters based on vacancy trapping[END_REF][START_REF] Marceau | Solute clustering in Al-Cu-Mg alloys during the early stages of elevated temperature ageing[END_REF][START_REF] Klobes | Natural ageing of Al-Cu-Mg revisited from a local perspective[END_REF][START_REF] Marceau | A study of the composition dependence of the rapid hardening phenomenon in Al-Cu-Mg alloys using diffusion couples[END_REF][START_REF] Zheng | Solute clustering and solute nanostructures in an Al-3.5Cu-0.4Mg-0.2Ge alloy[END_REF][START_REF] Gault | A nexus between 3D atomistic data hybrids derived from atom probe microscopy and computational materials science: A new analysis of solute clustering in Al-alloys[END_REF][START_REF] Ying | Effects of pre-strain on Cu-Mg coclustering and mechanical behavior in a naturally aged Al-Cu-Mg alloy[END_REF]. Despite a weakly attractive interaction between Cu and vacancies and a weak repulsion between Mg and vacancies [START_REF] Wolverton | Solute-vacancy binding in aluminum[END_REF], the addition of Mg to Al-Cu considerably accelerates the natural ageing process [START_REF] Klobes | Early stages of decomposition in Al alloys investigated by X-ray absorption[END_REF][START_REF] Marceau | A study of the composition dependence of the rapid hardening phenomenon in Al-Cu-Mg alloys using diffusion couples[END_REF]. "Mg-vacancy complexes" (more on this expression in the discussion) have been claimed to already form during quenching [START_REF] Nagai | Role of vacancy-solute complex in the initial rapid age hardening in an Al-Cu-Mg alloy[END_REF][START_REF] Zou | Vacancy-Mg complexes and their evolution in early stages of aging of Al-Mg based alloys[END_REF][START_REF] Liu | Positron lifetime study of the formation of vacancy clusters and dislocations in quenched Al, Al-Mg and Al-Si alloys[END_REF]. However, clusters are mainly rich in Cu in the as-quenched state and incorporate Mg gradually during natural ageing [START_REF] Starink | Room temperature precipitation in quenched Al-Cu-Mg alloys: a model for the reaction kinetics and yield strength development[END_REF][START_REF] Lu | Precipitation behavior of AA2618[END_REF]. Meanwhile, vacancies are surrounded by solute atoms and seem to become gradually trapped within clusters during ageing [START_REF] Klobes | Natural ageing of Al-Cu-Mg revisited from a local perspective[END_REF]. However, due to the low concentration of quenched-in vacancies (of the order of 10 -5 according to [START_REF] Klobes | The role of quenched-in vacancies for the decomposition of aluminium alloys[END_REF]), most clusters are rapidly vacancy-free.

A successful model for cluster growth has been developed considering that the limiting process was the detachment rate of vacancies trapped in these clusters [START_REF] Zurob | A model for the growth of solute clusters based on vacancy trapping[END_REF]. The interaction of vacancies with solutes during the clustering process seem to be better described by non-trivial vacancy-clusters interactions rather than the sum of pairwise vacancy-solute bindings [START_REF] Gault | A nexus between 3D atomistic data hybrids derived from atom probe microscopy and computational materials science: A new analysis of solute clustering in Al-alloys[END_REF].

Al-Cu-Li-Mg alloys have been the object of intensive research in the last 10 years for aerospace applications [START_REF] Rioja | The Evolution of Al-Li Base Products for Aerospace and Space Applications[END_REF][START_REF] Prasad | Aluminium-Lithium Alloys[END_REF]. Despite considerable work devoted to describing the precipitation sequence in these alloys as a function of thermo-mechanical history and alloy composition [START_REF] Cassada | The effect of plastic deformation on Al2CuLi (T1) precipitation[END_REF][START_REF] Itoh | Effects of a small addition of magnesium and silver on the precipitation of T1 phase in an Al-4%Cu-1.1%Li-0.2%Zr alloy[END_REF][START_REF] Gilmore | Trace elements effects on precipitation processes and mechanical properties in an Al-Cu-Li alloy[END_REF][START_REF] Huang | Independent and combined roles of trace Mg and Ag additions in properties precipitation process and precipitation kinetics of Al-Cu-Li-(Mg)-(Ag)-Zr-Ti alloys[END_REF][START_REF] Hirosawa | Effects of Mg addition on the kinetics of low-temperature precipitation in Al-Li-Cu-Ag-Zr alloys[END_REF][START_REF] Gable | The role of plastic deformation on the competitive microstructural evolution and mechanical properties of a novel Al-Cu-Li-X alloy[END_REF][START_REF] Murayama | Role of Ag and Mg on precipitation of T1 phase in an Al-Cu-Li-Mg-Ag alloy[END_REF][START_REF] Yoshimura | Transmission electron microscopy in the early stages of precipitates in aged Al-Li-Cu alloys[END_REF][START_REF] Yoshimura | Transmission electron microscopy study of the evolution of precipitates in aged Al-Li-Cu alloys: the θ′ and T1 phases[END_REF][START_REF] Wang | Precipitates and intermetallics phases in precipitation hardening Al-Cu-Mg-(Li) based alloys[END_REF][START_REF] Decreus | The influence of Cu/Li ratio on precipitation in Al-Cu-Li-x alloys[END_REF][START_REF] Araullo-Peters | Microstructural evolution during ageing of Al-Cu-Li-x alloys[END_REF][START_REF] Dorin | Quantification and modelling of the microstructure/strength relationship by tailoring the morphological parameters of the T1 phase in an Al-Cu-Li alloy[END_REF][START_REF] Gumbmann | The effect of minor solute additions on the precipitation path of an AlCuLi alloy[END_REF][START_REF] Rodgers | Quantification of the influence of increased pre-stretching on microstructure-strength relationships in the Al-Cu-Li alloy AA[END_REF][START_REF] Gumbmann | Influence of Mg, Ag and Zn minor solute additions on the precipitation kinetics and strengthening of an Al-Cu-Li alloy[END_REF], the study of natural ageing has been so far quite limited. In the high Li-containing alloys developed initially, most of the low-temperature phenomena have been identified to precipitation of the '-Al 3 Li phase [START_REF] Starink | Microstructure and strenghtening of Al-Li-Cu-Mg alloys and MMCS: I. Analysis and modelling of microstructural changes[END_REF][START_REF] Gao | Microstructure and precipitation in Al-Li-Cu-Mg-(Mn-Zr) alloys[END_REF]. However, in many of the recently developed Al-Cu-Li alloys, lower levels of Li do not result in appreciable amounts of this phase [START_REF] Decreus | The influence of Cu/Li ratio on precipitation in Al-Cu-Li-x alloys[END_REF][START_REF] Deschamps | Influence of Mg and Li content on the microstructure evolution of AlCuLi alloys during long-term ageing[END_REF] and the natural ageing has been shown to involve Cu-rich clusters [START_REF] Lefebvre | Characterization of preprecipitation stages by Atom Probe Tomography and Small-Angle X-ray Scattering in an Al-Li-Cu-Mg-Ag alloy[END_REF][START_REF] Decreus | The influence of Cu/Li ratio on precipitation in Al-Cu-Li-x alloys[END_REF]. Recently, we have set up a correlative methodology for the quantitative evaluation of the quantity of solute atoms involved in clusters and the corresponding Mg/Cu ratio using X-ray and neutron small-angle scattering (SAXS & SANS), supplemented by atom probe tomography [START_REF] Ivanov | A combined characterization of clusters in naturally aged Al-Cu-(Li, Mg) alloys using small-angle neutron and X-ray scattering and atom probe tomography[END_REF]. Using this methodology, it has been possible to demonstrate that a small addition of Mg to Al-Cu-Li profoundly changes the clustering behaviour of Cu atoms [START_REF] Ivanov | A combined characterization of clusters in naturally aged Al-Cu-(Li, Mg) alloys using small-angle neutron and X-ray scattering and atom probe tomography[END_REF]. The study of a compositionally graded Al-Cu-Li-(Mg) alloy with varying Mg concentration has shown that this positive effect of Mg on the clustering rate of Cu monotonically increases with Mg concentration [START_REF] Ivanov | High throughput evaluation of the effect of Mg concentration on natural ageing of Al-Cu-Li-(Mg) alloys[END_REF].

In order to understand the respective roles of Li, Cu and Mg on clustering in this quaternary alloy, it is useful to evaluate separately the role of the different solutes and thus compare the different ternary alloys Al-Cu-Mg, Al-Cu-Li to the quaternary alloy Al-Cu-Li-Mg. Using the recently developed correlative SAXS / SANS methodology on three such alloys, the aim of the present paper is to provide a quantitative characterization of the chemistry (Mg/Cu ratio) and quantity of clusters continuously during natural ageing. These results will be supplemented by a more classical DSC evaluation, hence providing a better understanding of the heat events that have been already observed by previous studies.

Materials and experimental methodology

Three subsets of the Al-Cu system were chosen to study the clustering behaviour during natural ageing.

The alloys tested have nominal compositions shown in Table . The starting material was provided as 27 mm thick plates by Constellium-Voreppe C-TEC, France. The plates were homogenized at 500 °C for 24 h, quenched and subsequently hot rolled to 3 mm at 350 °C. Flat samples from the 3 mm plates were ground and polished for micro-hardness observation using a 200 gf Vickers indenter. They were solution treated at 500 °C for 30 min, water quenched and tested. The measurements obtained within 5 min after quench correspond to the as-quenched condition (AQ). Hardness evolution was monitored during the following 2 weeks. Samples aged for 72 h or longer are referred to as naturally aged (NA).

Differential scanning calorimetry samples were prepared from the rolled plates by cutting 3 mm diameter discs at 0.5 mm thickness by a slow speed saw. The samples were batch solution treated at 500 °C for 30 min, water quenched with the as-quenched (AQ) samples being tested within 2 min.

Additional samples were left at room temperature after quench for 1, 2, 4, 6, 16 and 72 hours to represent steps along the ageing process. DSC experiments were carried out using a TA instruments Q200 DSC equipped with an RCS 90 cooling system allowing experiments to start at -50 °C. The experiments used pure Al crucibles and a 10 °C/min heating rate for all runs. As clustering reactions usually take place at room temperature, they are expected to generate formation and dissolution peaks at temperatures below 300 °C at the rate tested in the DSC. To focus on the low-temperature clustering region and maximize the quality of the baseline correction so as to measure very weak clustering peaks, a three-step DSC procedure was used similarly to that used in [START_REF] Deschamps | Influence of Mg and Li content on the microstructure evolution of AlCuLi alloys during long-term ageing[END_REF]. It consists of 1) heating ramp from -sample (versus an empty crucible). This procedure generates a sample specific baseline (step 3) which does not depend on estimates of the heat capacity of the alloy, the reference used, the crucibles used or the sample vs reference position within the DSC. Subtracting the signal of step 3 from step 1 generates accurate baseline corrected data for the clustering reactions taking place.

Small angle neutron scattering (SANS) experiments were carried out at the D11 instrument at the Institute Laue Langevin (ILL) in Grenoble, France under proposal 1-01-142 [83]. Samples from the 3 mm thick plate were solution treated, quenched and measured during natural ageing up to 12 h. Additional samples aged ex-situ were tested for the naturally aged condition (72h of natural ageing). A wavelength of 5 Å was used, above the Bragg cut-off, ensuring that no double diffraction could bring additional noise. The sample to detector distance was kept constant at 1.2 m capturing scattering vectors from 0.07 to 0.6 Å -1 . All experiment data has been background corrected, normalized to absolute units and azimuthally averaged using the Graphical Reduction and Analysis SANS Program package (GRASP).

Small angle X-ray scattering samples were obtained by grinding and polishing the 3 mm plates down to ~300 µm, solution treating at 500 °C for 30 mins and water quenching. The final thickness reduction to 80 µm was achieved within 15 mins after the quench. These samples were labelled as quenched (AQ) and their evolution was monitored in-situ during 72h up to the naturally aged (NA) condition. X-rays were generated using a Rigaku MicroMax-007 HF rotating anode with Cu K α X-ray source (λ=1.52Å) and scattering data was collected using a DECTRIS Pilatus 300K detector. The photon counting Pilatus detector, with its virtually zero noise, allowed for excellent statistics even at the low counting rates measured in the present study. The collected data were background corrected and normalized to absolute units with a glassy carbon sample as a secondary calibration standard using in-house scripts.

The sample to detector distance was 0.6 m allowing for measurement of scattering vectors ranging between 0.02 and 0.5 Å -1 . For better comparison with neutron scattering, we chose to convert the X-ray intensities to cm -1 rather than the more conventionally used in SAXS (e Å -3 ), which requires a normalization by the scattering cross section of an electron. The combined scattering data from experiments with neutrons and X-rays have been interpreted using the recently proposed methodology described in [START_REF] Ivanov | A combined characterization of clusters in naturally aged Al-Cu-(Li, Mg) alloys using small-angle neutron and X-ray scattering and atom probe tomography[END_REF] which yields results as a correlation length indicative of cluster size, a modulation periodicity ( ) related to the distance between clusters and a mean square number of excess solutes ( ) involved in clusters.

Results

The evolution of solute distribution taking place at room temperature during natural ageing was monitored using micro-hardness, DSC, SAXS and SANS. The majority of changes occurred during the first 24 h of ageing and measurements were found to plateau after 72 h resulting in the NA condition.

The details of this evolution are described in the following sections. an Al-Li-Mg system [START_REF] Deschamps | Experimental and modelling assessment of precipitation kinetics in an Al-Li-Mg alloy[END_REF][START_REF] Gault | Atom probe microscopy investigation of Mg site occupancy within delta ' precipitates in an Al-Mg-Li alloy[END_REF] suggest that the endothermic peak at 100 °C corresponds to disordering of Li short-range order present in the NA condition [START_REF] Deschamps | Influence of Mg and Li content on the microstructure evolution of AlCuLi alloys during long-term ageing[END_REF][START_REF] Okuda | In-situ and simultaneous synchrotron-radiation small-angle and 100 scattering experiments on the low-temperature structure in As-quenched Al-Li alloy during heating[END_REF][START_REF] Okuda | Nature of an endothermic peak of As-quenched Al-11.8 mol%Li alloys[END_REF].

The profiles group up and remain in close proximity during the reactions in the second region, namely the temperature range between 135 and 250 °C. Dissolution of clusters is taking place independently of their formation at room temperature (NA) or during the DSC experiment (AQ). The shape of the endothermic peaks resembles those observed for the Al-Cu-Mg alloy (Figure 2) where Cu-Mg clusters dissolve, albeit at a lower temperature. For temperature above 200 °C, the dissolution reactions approach completion and precipitation starts, mainly of the T 1 phase (Al 2 CuLi) [START_REF] Dorin | Quantitative description of the T1 formation kinetics in an Al-Cu-Li alloy using differential scanning calorimetry, small-angle X-ray scattering and transmission electron microscopy[END_REF] leading to exothermic signal at temperatures above 250 °C.

Small angle scattering

Scattering profiles obtained during the first 10 h after quench and for the naturally aged condition (72h) are shown in Figure 5, which shows together data for X-rays (SAXS) and neutrons (SANS) at the same ageing times. Overall, X-ray scattering results in higher intensity compared to neutrons due to the higher scattering cross-section of X-ray radiation. The X-ray scattering intensity observed is predominantly representative of Cu clustering as this atom yields the highest contrast to the Al matrix (Table 2). Additional and complementary information is derived from neutron scattering where the contrasts of Mg and Cu with respect to Al are comparable. In Li-containing alloys, clustering of Li would result in a high scattering intensity owing to the large contrast between Li and Al. However, Atom Probe Tomography has shown that this solute is not clustered in the states presented [START_REF] Ivanov | A combined characterization of clusters in naturally aged Al-Cu-(Li, Mg) alloys using small-angle neutron and X-ray scattering and atom probe tomography[END_REF] so that we will not consider the contribution of Li to clustering from now on. During the ageing period, the scattering intensity for both X-rays and neutrons increases for scattering vectors, q, in the range 0.1 -0.4 Å -1 corresponding to domains with a characteristic size of the order of (10 -2.5) Å.

In the Al-Cu-Mg alloy, an increase in small-angle scattering intensity is observed in Figure 5a and this behaviour agrees with hardness and DSC results shown above. Development of the clusters leads to a more pronounced intensity change for neutron scattering as compared to X-rays. Since both Mg and Cu contribute to SANS intensity compared to predominantly Cu contribution observable by X-ray scattering, it can be inferred that clustering in the Al-Cu-Mg alloy involves both Cu and Mg atoms.

The scattering profiles for the Al-Cu-Li alloy show only a small degree of evolution during natural ageing for both neutron and X-ray scattering (Figure 5b). Any small degree of scattering for this alloy is due to Cu rich clusters under the assumption that Li atoms remain randomly dispersed. These Curich clusters thus show only a small evolution during natural ageing, in agreement with hardness and DSC results.

Finally, clusters in the Al-Cu-Li-Mg system (Figure 5c) show a drastic evolution despite the only small addition of 0.4 at.% Mg when compared to the Al-Cu-Li alloy. The large scattering intensity appearing in SAXS proves that a large part of this effect is related to Cu clustering. The critical role of Mg for the clustering at room temperature in the Al-Cu-Li-Mg system is evidenced by the dramatic difference between the Al-Cu-Li and Al-Cu-Li-Mg alloys (Figures 5b and5c).

The model describing the scattering intensity due to concentration fluctuations arising from clusters developed by Ivanov et al. [START_REF] Ivanov | A combined characterization of clusters in naturally aged Al-Cu-(Li, Mg) alloys using small-angle neutron and X-ray scattering and atom probe tomography[END_REF] has been fitted to the in-situ data for combined neutron and X-ray scattering experiments. The model successfully captures the evolution of intensity during natural ageing as shown by the solid lines in Figure 5. The simultaneous use of complementary scattering from X-rays and neutrons grants access to the chemical nature of clusters, as well as the quantity of solutes involved in the clusters. This quantity, available independently for both Mg and Cu, is expressed as the mean square number of excess solutes involved in the clusters per unit volume, and thus is a measure of the total quantity of solute atoms involved in the clusters irrespective of their composition. In this sense, it is more representative of the degree of completion of the clustering reaction for a given species that of a volume fraction, which in the case of clustering has no clear meaning, in the absence of a welldefined interface, and a possibly evolving chemical composition of forming objects. To further emphasize the chemical evolution of the clusters, the Mg/Cu ratio in clusters can be then calculated and compared to the global alloy ratio.

We first discuss the behaviour of the Al-Cu-Mg alloy. Initially (AQ condition), a small amount of clustering is observed, predominantly Cu rich (Mg/Cu ratio of less than 0.5). Throughout ageing the excess Cu in clusters remains relatively stable, increasing from 5 to 10 nm -3 , which is consistent with the only moderate increase of SAXS intensity during this ageing period. Conversely, during the first hour of ageing, the excess Mg in clusters increases to match the Cu and surpasses it as shown by the rapid evolution of the Mg/Cu ratio. Initially, clusters contain less Mg compared to the matrix concentration, but when natural ageing progresses, the mean square number of excess Mg increases up to the NA condition reaching 34 ±11 nm -3 and representing a ratio of 1.82 to Cu.

Similarly, the initial clusters present in the Al-Cu-Li-Mg alloy are on average domains with excess Cu (Figure 7a) and almost no Mg. The degree of clustering of Mg begins to increase alongside a further increase of the degree of clustering of Cu for ageing times above 2h. Finally, the naturally aged clusters contain on average an excess of 38.9 ±0.6 nm -3 of Cu and 9.0 ±0.18 nm -3 of Mg resulting in an Mg/Cu ratio of 0.48 that is above the mean ratio of the matrix. In terms of size, the clusters in the Al-Cu-Li-Mg alloy become significantly larger than that of the Al-Cu-Mg alloy

In the case of the Al-Cu-Li alloy, obviously, only the Cu clustering behaviour is measured.

Consistently with the results seen before, the clustering kinetics in this alloy is extremely sluggish, and both the size and quantity of clusters is hardly evolving with time.

Discussion

The results detailed above evidence a series of effects that need now to be rationalized. In terms of strengthening, the ternary Al-Cu-Li alloy shows a very sluggish natural ageing, whereas the ternary Al-Cu-Mg and the quaternary Al-Cu-Li-Mg alloys show a comparable faster strengthening behaviour. In fact, the natural ageing strengthening of the quaternary alloy is larger despite the low Mg content, while an Mg/Cu ratio close to 1 has often be considered necessary to maximize the cluster strengthening effect in Cu and Mg-containing alloys.

The specific feature of our results is to obtain a quantitative evaluation of the clustering kinetics for both Mg and Cu separately. It demonstrates the considerable acceleration of clustering in these alloys brought by Mg addition. Our results evidence in addition that the rates of clustering of Cu and Mg at room temperature are profoundly different. In the two Mg-containing alloys under consideration, the Mg/Cu ratio monotonously increases during ageing. Initially much lower than the alloy composition's ratio, it becomes slightly larger after three days of natural ageing, reaching ~2 in the Al-Cu-Mg alloy and ~0.5 in the Al-Cu-Li-Mg alloy. It is interesting to note that the Mg/Cu cluster ratio reached in these two alloys is quite different from a ratio of ~1 often found in the literature [START_REF] Starink | Room temperature precipitation in quenched Al-Cu-Mg alloys: a model for the reaction kinetics and yield strength development[END_REF][START_REF] Ying | Effects of pre-strain on Cu-Mg coclustering and mechanical behavior in a naturally aged Al-Cu-Mg alloy[END_REF] and sometimes hypothesized as intrinsic to the formation of Cu-Mg co-clusters [START_REF] Starink | The thermodynamics of and strengthening due to co-clusters: General theory and application to the case of Al-Cu-Mg alloys[END_REF].

In fact, while the clusters are initially only moderately richer in Cu than in Mg in the Al-Cu-Mg alloy (Mg/Cu ratio of 0.3-0.4), the situation is very different in the Al-Cu-Li-Mg alloy. In this case, during the first 2 hours of natural ageing, the clusters are virtually Mg-free while Cu rapidly clusters, with kinetics comparable to that of the Al-Cu-Mg alloy but up to a much larger amount. It is only when the Cu clustering is more than halfway completed that the Mg starts to be incorporated within the clusters.

However, most interestingly, this does not mean that the presence of Mg is unimportant for the initial formation of Cu clusters since, in the absence of Mg, clustering barely happens (Al-Cu-Li). In Al-Cu-Mg alloys, the fact that clustering initially proceeds by Cu atoms and involves later formation of Cu-Mg rich clusters has been observed by several authors, by APT [START_REF] Starink | Room temperature precipitation in quenched Al-Cu-Mg alloys: a model for the reaction kinetics and yield strength development[END_REF] and by the evolution of lattice parameter [START_REF] Lu | Precipitation behavior of AA2618[END_REF]. The dramatic effect of Mg alloying on Al-Cu and Al-Cu-Li has been shown by electrical resistivity and hardness [START_REF] Sato | Roles of microalloying elements on the cluster formation in the initial stage of phase decomposition of Al-based alloys[END_REF]. Hirosawa et al. [START_REF] Hirosawa | Effects of Mg addition on the kinetics of low-temperature precipitation in Al-Li-Cu-Ag-Zr alloys[END_REF] showed that the addition of 0.5% Mg to an Al-Cu-Li alloy accelerated the formation of Cu-rich GPI zones. Klobes et al. [START_REF] Klobes | Early stages of decomposition in Al alloys investigated by X-ray absorption[END_REF] showed by X-ray absorption spectroscopy that the rate of Cu decomposition at room temperature was considerably accelerated in the presence of Mg.

The difference in clustering kinetics between the three alloys illustrates the complex interactions between the various solutes, alone or in combination, and the quenched-in vacancies. In this context, the literature often makes use of expression such as "vacancy-solute clusters" or "vacancy-solute complexes". These are possibly misleading in our opinion since 1) there are at least 3 orders of magnitude between any number of solutes and the number of vacancies present at all time and 2) there are at least 5 orders of magnitude between the diffusivity of vacancies and that of solutes. Given these two points, a much better reasoning consists in describing the amount of time spent by the vacancies in the vicinity of certain objects. This is also true for the concept of vacancy trapping which should be understood as some sort of dynamical trapping: each vacancy spends most of the time in the vicinity of the trapping element, but necessarily navigates from one trapping atom to the other. We will use this kind of description in the following.

The easiest case to rationalize is that of the Al-Cu-Li alloy. Well documented in the literature [START_REF] Hirosawa | Effects of Mg addition on the kinetics of low-temperature precipitation in Al-Li-Cu-Ag-Zr alloys[END_REF][START_REF] Hirosawa | Classification of the role of microalloying elements in phase decomposition of Al based alloys[END_REF][START_REF] Wei | Aging behavior of Li containing Al-Zn-Mg-Cu alloys[END_REF], there is a strong binding energy between Li and vacancies, resulting in the trapping of vacancies by Li atoms after quenching and resulting in sluggish clustering kinetics. The interactions between vacancies and solutes have also been well documented in Al-Cu-Mg alloys. In the asquenched state, Nagai et al. [START_REF] Nagai | Role of vacancy-solute complex in the initial rapid age hardening in an Al-Cu-Mg alloy[END_REF] showed that vacancies were preferentially bound to Mg atoms rather than Cu atoms in Al-Cu-Mg, or rather, spent more time close to Mg atoms than to Cu atoms. In a binary Al-Mg alloy, Zou et al. [START_REF] Zou | Vacancy-Mg complexes and their evolution in early stages of aging of Al-Mg based alloys[END_REF] found so-called vacancy-Mg complexes after quenching, that did not evolve with further natural ageing, which we interpret as the fact that the vacancies were mostly around Mg atoms. This has been confirmed by Liu et al. [START_REF] Liu | Positron lifetime study of the formation of vacancy clusters and dislocations in quenched Al, Al-Mg and Al-Si alloys[END_REF] who further observed a decrease in the vacancy jump frequency. This vacancy-Mg attraction may seem contradictory with the reported slightly repulsive interaction between these two entities [START_REF] Wolverton | Solute-vacancy binding in aluminum[END_REF]. However, it has been shown that Mg-Mg atoms could bind together at a distance of ~0.5 nm [START_REF] Martinsen | Reversal of the negative natural aging effect in Al-Mg-Si alloys[END_REF] so that the binding energy of a vacancy with a group of atoms may be different to that with a single atom. Recent calculations [START_REF] Gault | A nexus between 3D atomistic data hybrids derived from atom probe microscopy and computational materials science: A new analysis of solute clustering in Al-alloys[END_REF] actually proposed an attractive binding energy between vacancies and Cu-Mg clusters, which helps to understand the mechanism proposed by Klobes et al. [START_REF] Klobes | Natural ageing of Al-Cu-Mg revisited from a local perspective[END_REF] of a gradual trapping of vacancies within the Cu-Mg clusters after an initial regime where the environment of the vacancies does not change.

While the concept of vacancy-solute binding energy is itself not unambiguous, it does not capture the actual diffusion mechanism which may lead to different situations depending on the actual vacancy jump probabilities around solutes. Because of this, different views can be found in the literature concerning the role of Mg with respect to the concentration of quenched-in vacancies. According to Nagai et al. [START_REF] Nagai | Role of vacancy-solute complex in the initial rapid age hardening in an Al-Cu-Mg alloy[END_REF] the migration of Mg-vacancy complexes to dislocations causes a rapid decrease of the vacancy concentration. According to Marceau et al. [START_REF] Marceau | A study of the composition dependence of the rapid hardening phenomenon in Al-Cu-Mg alloys using diffusion couples[END_REF][START_REF] Marceau | Solute clustering in Al-Cu-Mg alloys during the early stages of elevated temperature ageing[END_REF], the presence of Mg increases the concentration of vacancy-type defects and reduces the loss of vacancies during ageing. While different mechanisms may be at play, it seems clear that vacancies have an average vicinity which is enriched in Mg. This certainly helps the stabilization of quenched-in vacancies around clustering solutes. This picture does not really explain the formation of the initial Cu clustering, however. This question becomes much more acute in the Al-Cu-Li-Mg alloy.

Indeed, two interesting features in the quaternary alloy combine: first, the dramatically increased clustering kinetics with respect to the Al-Cu-Li alloy with only 0.4 at% Mg addition, and secondly the absence of Mg within the clusters in the first two hours of ageing. The first effect can only be understood if the addition of Mg overcomes the binding of Li to vacancies. Actually, the movement of vacancies during natural ageing does not result in long-range diffusion of Li, as evidence by APT in [START_REF] Ivanov | A combined characterization of clusters in naturally aged Al-Cu-(Li, Mg) alloys using small-angle neutron and X-ray scattering and atom probe tomography[END_REF], although some short-range ordering of Li seems to occur, whose reversion results in the endothermic peak at 100°C observed in the DSC scan of the naturally aged Al-Cu-Li-Mg alloy. The effect of Mg on triggering the clustering of Cu has actually been shown to be active even for very small amounts of Mg [START_REF] Ivanov | High throughput evaluation of the effect of Mg concentration on natural ageing of Al-Cu-Li-(Mg) alloys[END_REF] and to vary monotonously with the Mg concentration. Moreover, Honma et al. [START_REF] Honma | Coincidence Doppler broadening and 3DAP study of the pre-precipitation stage of an Al-Li-Cu-Mg-Ag alloy 1016/j.actaniat[END_REF] have proposed that the addition of Li to an Al-Cu-Mg-Ag alloy decreased the quenched-in vacancy concentration. Thus, from the available knowledge, the effect of the Mg addition seems to replace the Li atoms network as vacancy dynamical trapping sites by an Mg atoms network, or even simply to offer proxy trapping positions in-between Li atoms. Since Mg has a tendency to form energetically stable Cu-Mg bonds, clustering proceeds. Nevertheless, the effective diffusion coefficient of Mg, which depends on the actual jump rates, is lower than that of Cu. This scenario is consistent with the findings of Klobes et al. [START_REF] Klobes | Natural ageing of Al-Cu-Mg revisited from a local perspective[END_REF] that vacancies are surrounded both by Cu and Mg atoms already early in the ageing process, despite the clustering involving first mainly Cu atoms. The gradual incorporation of Mg atoms within clusters would then lead to the observed enrichment of the clusters in Mg.

Based on the understanding of the clustering kinetics directly evidenced by the combined use of SAXS and SANS, it is now possible to revisit the interpretation of the DSC curves presented in figures 2 to 4.

Concerning the Al-Cu-Mg alloy, the exothermic peak between 40-130°C shows a clear correlation with the clusters that form during natural ageing. Namely, the kinetics of the decrease of the area of this peak (corresponding to the clustering of solutes that have not yet gathered during natural ageing) matches the kinetics of cluster formation. In the case of the quaternary alloy Al-Cu-Li-Mg, the asquenched state shows an exothermic peak in the same temperature range as compared to the Al-Cu-Mg alloy, suggesting a similar nature of clustering forming in the ternary and quaternary alloys during ramp heating. In the naturally aged condition, the interpretation of the DSC signal of the quaternary alloy is made more complicated by the presence of the endothermic event that we attribute to the formation of short-range ordering of Li (which may also be present to a smaller degree in the naturally aged condition of the Al-Cu-Li alloy). This endothermic event may be already present to some degree at shorter ageing times and thus modify the apparent evolution of the exothermic peak corresponding to the cluster formation. This may explain why the evolution of the exothermic peak seems to occur faster than expected from the cluster formation kinetics measured by small-angle scattering: from DSC, the peak decreases by a factor of 2 in 1 hour, however at that time clustering has hardly started to occur.

However, it interesting to note that the endothermic events corresponding to the dissolution of the clusters formed during natural ageing (between 140 and 270°C approximately) are very similar in the ternary and quaternary alloys, despite a very different Mg/Cu ratio. If we combine this information with the evolution of hardness which is comparable in the two alloys, we can conclude that similar evolutions of cluster hardness and thermodynamics of the system can be obtained with very different cluster chemistry and size.

Conclusion

Clustering kinetics during natural ageing post-quench have been successfully characterised using a combination of differential scanning calorimetry and small angle scattering and complemented with micro-hardness evolution. The results clearly identify Mg as a solute necessary for clustering at room

3. 1 .

 1 HardnessHardness evolution after quench depicts the undergoing changes in solute distribution from nearly random in the AQ condition to clustered in the NA condition in the alloys studied. The hardness increase at room temperature versus time is shown in Figure1. The Al-Cu-Li and Al-Cu-Li-Mg alloys both start at 67±2 HV evidencing the negligible effect of adding 0.4 at. % Mg to the Al-Cu-Li in the AQ state. The Al-Cu-Mg has a higher AQ hardness at 74±2 HV due to the higher Mg contribution to solid solution strengthening. These initial hardness values serve as an indication of the degree of solute solution strengthening by alloying elements as no significant amount of clustering is expected this early after the quench.As natural ageing progresses, alloys containing Mg show a significant increase in hardness compared to the Mg-free alloy. The AQ difference between Al-Cu-Mg and Al-Cu-Li-Mg alloys diminishes for longer ageing times. Hardening begins to saturate after about 48h and for longer ageing times the hardness changes remain within experimental errors around the average NA value. Ageing for 72 h (3 days) after quench has been chosen as a point beyond which all alloys are considered stable and can be termed 'naturally aged'. The NA hardness values are 77±3, 117±3 and 115±3 HV for the Al-Cu-Li, Al-Cu-Mg and Al-Cu-Li-Mg alloys respectively. Exposure to room temperature after quench has on average resulted in a 20, 55 and 82 % hardness increase in these alloys respectively. A vast change in the behaviour of the Al-Cu-Li alloy by the addition of 0.4 at. % Mg is clearly shown and highlights the important role of Mg solute atoms for the natural ageing processes. Furthermore, kinetic and quantitative similarities of the Al-Cu-Mg and Al-Cu-Li-Mg alloys, which contains a significantly different amount of Mg, suggests that only a small quantity of Mg is necessary to achieve cluster strengthening.3.2. Differential scattering calorimetryThe heat flux vs temperature profiles at selected times during natural ageing of the Al-Cu-Mg alloy are shown in Figure2. The profiles can be divided into two distinct regions with the first containing the exothermic peak between 0 and 150 °C and a second with the endothermic region between 150 and 260 °C. Within the first region, Cu-Mg clusters are forming during the DSC run, which gives rise to the exothermic peak. The potential for cluster formation decreases with ageing time at room temperature as more clusters have formed prior to the DSC scan leading to the magnitude and integral of this region to halve within 1h and continue to decrease during the first 6h. The formation of Cu-Mg clusters observed here is in line with previously reported DSC experiments on Al-Cu-Mg alloys[START_REF] Starink | The origins of room temperature hardening of Al-Cu-Mg alloys[END_REF][START_REF] Starink | Room temperature precipitation in quenched Al-Cu-Mg alloys: a model for the reaction kinetics and yield strength development[END_REF]. The second region covers the dissolution of clusters previously formed in the sample (whether at room temperature or during the DSC scan). The area of the second region does not vary significantly with ageing time, meaning that the sum of the solute (Cu, Mg) involved in clusters formed at room temperature (during natural ageing) and those involved in cluster formation during the DSC experiment (in the as-quenched sample) is the same. The dissolution of these clusters results in a consistently observable double minimum endothermic region that is characteristic of the Al-Cu-Mg alloy. Variations in cluster chemistry, cluster size distribution, or even a complex dissolution-growth process may lead to such behaviour. Finally, the dissolution of Cu-Mg clusters liberates solute necessary for the subsequent precipitation reactions of the S phase and causes strong exothermic signal for all ageing times at temperatures above 260 °C[START_REF] Wang | Precipitates and intermetallics phases in precipitation hardening Al-Cu-Mg-(Li) based alloys[END_REF][START_REF] Genevois | Quantitative investigation of precipitation and mechanical behaviour for AA2024 friction stir welds[END_REF].The temporal evolution of the heat flux profile for the Al-Cu-Li alloy is shown in Figure3with the same y-axis (heat flux) range as for Al-Cu-Mg in Figure 2. In this alloy, the profiles remain almost flat with only a small magnitude endothermic region between 50 and 200 °C. No well-defined exothermic reactions are observed during the DSC experiments independently of the ageing time. For longer ageing times at room temperature, e.g. NA condition, the endotherm increases with a broad peak at 125 °C indicative of more dissolution compared to the AQ condition. Therefore, clustering reactions in this alloy are too slow to occur during the DSC scan but can occur during the course of a long natural ageing, yet yielding a much smaller signal as compared to Al-Cu-Mg. Addition of 0.4 at% Mg to the Al-Cu-Li alloy vastly changes the heat flux profiles occurring at various stages of ageing as shown for the Al-Cu-Li-Mg alloy in Figure4. Globally, the curves can be divided into two regions with one for the reactions taking place between 50 and 135°C and a second for the reactions between 135°C and 250°C. Within the first region, an exothermic peak is observed for short ageing times and its magnitude is reduced with ageing up to 4h. This peak is in close proximity to that resulting from the formation of Cu-Mg clusters in the Al-Cu-Mg alloy (Figure2). Ageing for longer than 4h leads to an endothermic peak appearing in the same temperature range. The proximity of the exothermic peak (80 °C) in the AQ condition and the endothermic peak (100 °C) in the NA condition makes it unlikely that the solutes involved in these reactions are the same. The presence of Li in this alloy compared to the Al-Cu-Mg and previously reported the strong influence of Mg on Li ordering in

  temperature in the Al-Cu-(Li, Mg) system. The small quantity of Cu rich clusters formed during quench from solution temperature does not evolve in the Mg-free solid solution. When the Mg/Cu ratio of the alloy is high, Mg rapidly clusters with the initial Cu rich domains resulting in an increase of hardness due to the formation of strong Cu-Mg bonds. The Mg/Cu ratio of these clusters in the naturally aged condition is close to 2. For the Al-Cu-Li-Mg alloy, where the Mg/Cu ratio is low, clustering is dominated by the formation of Cu rich domains. These domains contain Mg but in significantly lower concentrations with the Mg/Cu ratio remaining below 0.5 for the NA condition, a value which is higher than the nominal Mg/Cu ratio. The combination of these results provides strong evidence for Mg acting in a manner to effectively increase the concentration and/or the mobility of vacancies available for diffusion. These results also suggest that the composition of Cu-Mg clusters may vary significantly leading to clusters showing, however, similar signatures in calorimetry and in terms of hardening capability.

Figure 1 :

 1 Figure 1: Natural age hardening curves for Al-Cu-Mg, Al-Cu-Li and Al-Cu-Li-Mg alloys.

Figure 2 :

 2 Figure 2: DSC heat flux profiles for Al-Cu-Mg alloy carried out after various ageing times at room

Figure 3 :

 3 Figure 3: DSC heat flux profiles for Al-Cu-Li alloy carried out after various ageing times at room

Figure 4 :

 4 Figure 4: DSC heat flux profiles for Al-Cu-Li-Mg alloy carried out after various ageing times at room

Figure 5 :

 5 Figure 5: Radially averaged scattering data evolution for a) Al-Cu-Li, b) Al-Cu-Mg and c) Al-Cu-Li-

Figure 6

 6 Figure 6 Evolution of the clusters characteristics during natural ageing for the three alloys: (a) Mean

Table 1 :

 1 Alloy compositions

		Cu	Mg	Li
	SAXS	1.23	-0.08	-0.77
	SANS	1.23	0.55	-1.55

Table 2 :

 2 SAS elemental sensitivity in aluminium alloys as defined by , with and the scattering factors of element i and Al, respectively

Acknowledgements

The authors would like to thank Dr Christophe Sigli for providing the alloys and fruitful discussions. The authors acknowledge the financial support from Constellium C-Tec.

The staff of Institut Laue Langevin (ILL) at beamline D11 is thanked for helping with the SANS experiments (doi:10.5291/ILL-DATA.1-01-142).