Claire Aumeran
email: caumeran@chu-clermontferrand.fr

Benoit Mottet-Auselo

Christiane Forestier

Paul-Alain Nana

Claire Hennequin

Frédéric Robin

Bertrand Souweine

Ousmane Traoré

Alexandre Lautrette

A prospective study on the pathogenesis of catheter-associated bacteriuria in critically ill patients

Keywords: Catheter-associated bacteriuria, Critically ill patients, Pathogenesis

Background: Updating the pathogenesis of catheter-associated bacteriuria (CA-bacteriuria) in the intensive care unit (ICU) is needed to adapt prevention strategies. Our aim was to determine whether the main pathway of CAbacteriuria in ICU patients was endoluminal or exoluminal. In a prospective study, quantitative urine cultures were sampled from catheter sampling sites, collector bags and the catheter outer surface near the meatus from days 1 to 15 after catheterization. The endoluminal pathway was CA-bacteriuria (defined as 10 2 CFU/mL) first in collector bags and then in catheters. The exoluminal pathway was CA-bacteriuria first in catheters, on day 1 in early cases and after day 1 in late cases. Results: Of 64 included patients, 20 had CA-bacteriuria. Means of catheterization days and incidence density were 6.81 days and 55.2/1000 catheter-days. Of 26 microorganisms identified, 12 (46.2%) were Gram positive cocci, 8 (30.8%) Gram negative bacilli and 6 yeasts. Three (11.5%) CA-bacteriuria were endoluminal and 23 (88.5%) exoluminal, of which 10 (38.5%) were early and 13 (50%) late. Molecular comparison confirmed culture findings. A quality audit showed good compliance with guidelines.

Conclusion:

The exoluminal pathway of CA-bacteriuria in ICU patients predominated and surprisingly occurred early despite good implementation of guidelines. This finding should be considered in guidelines for prevention of CA-bacteriuria.

Background

With a prevalence of up to 40%, urinary tract infections (UTI) are the first cause of nosocomial infections [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF][START_REF] Apic A For P In | APIC implementation guide: guide to preventing catheter-associated urinary tract infections[END_REF][3][START_REF]RPC-infections_urinaires_associees_aux_soins[END_REF][START_REF]sante-mai-juin-2017[END_REF]. The presence of a urinary catheter is the main risk factor for nosocomial UTI [START_REF] Apic A For P In | APIC implementation guide: guide to preventing catheter-associated urinary tract infections[END_REF]3]. A diagnosis of catheterassociated bacteriuria (CA-bacteriuria) is established when no distinction is made between catheter-associated asymptomatic bacteriuria and catheter-associated urinary tract infection (CA-UTI) [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF]. CA-bacteriuria is correlated with the duration, mainly 6 days, of catheterization [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF][START_REF] Maki | Engineering out the risk for infection with urinary catheters[END_REF]. The risk of CA-UTI increases in the intensive care unit (ICU), where incidence rates range between 3.6 and 14.71 per 1000 urine catheter days [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF]3,[START_REF]sante-mai-juin-2017[END_REF][START_REF] Dudeck | National healthcare safety network report, data summary for 2013, device-associated module[END_REF][START_REF] Peng | Epidemiology of pathogens and antimicrobial resistanceof catheterassociated urinary tract infections in intensivecare units: a systematic review and meta-analysis[END_REF]. The first step in the pathogenesis of CA-UTI is the endoluminal or exoluminal colonization of the urinary catheter, which is more frequently involved than the blood-borne pathway [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF][START_REF] Maki | Engineering out the risk for infection with urinary catheters[END_REF][START_REF] Tambyah | A prospective study of pathogenesis of catheter-associated urinary tract infections[END_REF]. Some studies have reported that endoluminal CAbacteriuria involves exogenous flora originating from the colonization of the collector bag or a breach of the closed system during manipulations of the urinary catheter [START_REF] Garibaldi | Factors predisposing to bacteriuria during indwelling urethral catheterization[END_REF][START_REF] Hartstein | Nosocomial urinary tract infection: a prospective evaluation of 108 catheterized patients[END_REF][START_REF] Nickel | Catheter-associated bacteriuria. An experimental study[END_REF][START_REF] Rogers | Examination of biofilm formation and risk of infection associated with the use of urinary catheters with leg bags[END_REF]. Exoluminal CA-bacteriuria involves endogenous flora from the urinary meatus. This kind of colonization occurs early during the insertion of the catheter or later as a result of the colonization of the urinary meatus by the digestive flora [START_REF] Hartstein | Nosocomial urinary tract infection: a prospective evaluation of 108 catheterized patients[END_REF][START_REF] Nickel | Catheter-associated bacteriuria. An experimental study[END_REF][START_REF] Rogers | Examination of biofilm formation and risk of infection associated with the use of urinary catheters with leg bags[END_REF][START_REF] Kass | Entry of bacteria into the urinary tracts of patients with inlying catheters[END_REF][START_REF] Brehmer | Route and prophylaxis of ascending bladder infection in male patients with indwelling catheters[END_REF][START_REF] Bultitude | The relationship between the urethral flora and urinary infection in the catheterised male[END_REF][START_REF] Garibaldi | Meatal colonization and catheter-associated bacteriuria[END_REF][START_REF] Schaeffer | Urethral meatal colonization in the pathogenesis of catheter-associated bacteriuria[END_REF]. After adhesion, the microorganisms migrate within a biofilm along the endoluminal and exoluminal sides of the urinary catheter. In 1999, a study reported the predominance of the exoluminal pathway in a non-selected population [START_REF] Tambyah | A prospective study of pathogenesis of catheter-associated urinary tract infections[END_REF]. No study has explored the pathway mechanisms of CA-bacteriuria solely in critically ill patients. The impact of guidelines on the pathogenesis of pathways for CA-bacteriuria is unknown [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF][START_REF] Apic A For P In | APIC implementation guide: guide to preventing catheter-associated urinary tract infections[END_REF][START_REF]RPC-infections_urinaires_associees_aux_soins[END_REF][START_REF] Lo | Strategies to prevent catheterassociated urinary tract infections in acute care hospitals: 2014 update[END_REF][START_REF] Gould | Guideline for prevention of catheter-associated urinary tract infections 2009[END_REF]. Up-to-date knowledge of these pathways is needed to improve the prevention of CA-bacteriuria and hence CA-UTI [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF][START_REF] Apic A For P In | APIC implementation guide: guide to preventing catheter-associated urinary tract infections[END_REF][START_REF]RPC-infections_urinaires_associees_aux_soins[END_REF][START_REF] Lo | Strategies to prevent catheterassociated urinary tract infections in acute care hospitals: 2014 update[END_REF], which is one of the most frequent nosocomial infections in the ICU and is associated with a heavy health burden [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF][START_REF] Apic A For P In | APIC implementation guide: guide to preventing catheter-associated urinary tract infections[END_REF][START_REF] Lo | Strategies to prevent catheterassociated urinary tract infections in acute care hospitals: 2014 update[END_REF][START_REF] Rosser | Urinary tract infections in the critically ill patient with a urinary catheter[END_REF][START_REF] Clec'h C | Does catheter-associated urinary tract infection increase mortality in critically ill patients?[END_REF].

The main aim of this prospective study was to explore the pathways (exoluminal vs endoluminal) of CAbacteriuria in critically ill patients. Secondarily, we investigated the characteristics of patients and microorganisms involved in the infection and performed a quality audit on urinary catheterization.

Results

Of the 225 patients admitted to the ICU (Fig. 1), 64 were included. CA-bacteriuria was identified in 20 patients (31.2%), of whom 15 were monomicrobial and 5 polymicrobial, corresponding to an incidence density of 55.2 per 1000 urinary catheter-days. There was no difference in patient characteristics between those with CAbacteriuria and those without, except for the sex/ratio and for the number of prescriptions of anti-infective therapy before catheterization or during patient followup (Table 1). Most of the urinary catheters were manufactured with 100% silicone (n = 54, 84.4%). The mean duration of catheterization was 6.81 ± 0.58 days, with no difference between patients with or without CAbacteriuria (Table 1). For 39 (60%) patients, the duration of catheterization was less than 6 days. Four patients had CA-UTI, which gave an incidence density of 9.1 per 1000 urinary catheter-days. No bacteremia or fungemia with the same microorganism as CA-bacteriuria was reported (See Supplementary Table 1, Additional File 1).

Of the 26 microorganisms identified, 12 (46.2%) were Gram-positive cocci, with a predominance of E. faecalis (n = 5, 19.2%) and S. epidermidis (n = 4, 15.4%), 8 (30.8%) were Gram-negative bacilli, with a predominance of E. coli (n = 4, 15.4%), and 6 (23.1%) were Candida sp. (Fig. 1). Not all patients required anti-infective therapy before catheter insertion or during follow-up. In the CA-bacteriuria group, only four patients had a catheterassociated urinary tract infection with the microorganism responsible for bacteriuria. They were treated accordingly to the identified microorganism. The other anti-infective therapies were secondary to another infection

The list of microorganisms obtained in the urethral flora samples is shown in the Additional files (See Supplementary Table 1, Additional File 1). There were 3 (11.5%) endoluminal and 23 (88.5%) exoluminal cases of CA-bacteriuria (n = 23, 88.5%), of which 10 (38.5%) were early and 13 (50%) late (Fig. 2a, b andc 1, Additional File 1). No difference was observed when the endoluminal and exoluminal groups of CA-bacteriuria were compared, whether for major risk factors (duration of catheterization, chronic kidney disease, and diabetes mellitus), outcomes (death, acute renal failure, dialysis, mechanical ventilation invasive or not, and use of amines), gender, age or the microorganisms identified. No difference was found either when early and late exoluminal groups of CA-bacteriuria were compared. Detailed data are presented in Supplementary Table 2, Additional file 1. Molecular comparison confirmed culture findings in all but one patient, in whom early exoluminal developed into endoluminal CAbacteriuria (S. epidermidis, patient 33). Since Staphylococcus epidermidis and Candida sp. are not common uropathogens, the results of their molecular comparisons are given in Additional file 2 (See Supplementary Figures 1 to 13, Additional File 2). In 16 cases (69.5%), comparison with microorganisms identified on swabs confirmed early exoluminal (n = 7/10) and late exoluminal CAbacteriuria (n = 9/13).

The quality audit was performed without prior notice by the same intensivist in all observations. The quality audit on urinary catheterization showed that there were no problems in following international catheterization guidelines [START_REF] Apic A For P In | APIC implementation guide: guide to preventing catheter-associated urinary tract infections[END_REF][START_REF]RPC-infections_urinaires_associees_aux_soins[END_REF][START_REF] Lo | Strategies to prevent catheterassociated urinary tract infections in acute care hospitals: 2014 update[END_REF]. All hand hygiene procedures were complied with but 50% were performed with alcoholbased products (Table 2).

Discussion

This study investigated the pathways of CA-bacteriuria. The exoluminal pathway was predominant and accounted for more than one third of cases of early exoluminal CA-bacteriuria. This result was not related to the quality of urinary catheterization.

CA-bacteriuria occurred in one third of patients admitted to the Medical ICU without any effect on catheterization duration in contrast what is expected with CA-UTI. The proportion of CA-bacteriuria cases was consistent with that in other ICU studies [START_REF] Leone | A randomized trial of catheter change and short course of antibiotics for asymptomatic bacteriuria in catheterized ICU patients[END_REF][START_REF] Tissot | Risk factors for catheter-associated bacteriuria in a medical intensive care unit[END_REF]. We observed a greater number of cases of exoluminal CA-bacteriuria (88.5%) and a low rate of endoluminal CA-bacteriuria (11.5%). In our study, the main pathway was exoluminal and occurred at a higher rate than in the study of Tambyah et al., in which 46, 23.2 and 30.8% of CA-bacteriuria cases were exoluminal, endoluminal and indeterminate CA-bacteriuria, respectively [START_REF] Tambyah | A prospective study of pathogenesis of catheter-associated urinary tract infections[END_REF]. These authors reported a 10% rate of disconnections between urinary catheters and collector bags, which is a risk factor for endoluminal CA-bacteriuria. During the 4 months of our study, only two disconnections (3%) in 64 included patients were observed, which could explain the very low proportion of endoluminal CA-bacteriuria cases. These findings suggest that by concentrating attention on preventing disconnection the guidelines lead to a large reduction in the endoluminal pathway [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF][START_REF] Apic A For P In | APIC implementation guide: guide to preventing catheter-associated urinary tract infections[END_REF]. Another explanation could be the increasing use of 100% silicon urinary catheters, which delay the obstruction caused by biofilm encrustation [START_REF] Daifuku | Association of rectal and urethral colonization with urinary tract infection in patients with indwelling catheters[END_REF].

Tambyah et al. observed 12.4% (n = 31) of early exoluminal CA-bacteriuria cases among 250 identified microorganisms [START_REF] Tambyah | A prospective study of pathogenesis of catheter-associated urinary tract infections[END_REF] as against 38.5% in our study. Early exoluminal colonization could be related to a defect in the aseptic procedure during insertion of the catheter. To assess this assumption, we performed a quality audit on catheter insertion in accordance with the most recent guidelines [START_REF] Apic A For P In | APIC implementation guide: guide to preventing catheter-associated urinary tract infections[END_REF][START_REF]RPC-infections_urinaires_associees_aux_soins[END_REF][START_REF] Lo | Strategies to prevent catheterassociated urinary tract infections in acute care hospitals: 2014 update[END_REF]. The only flaw observed was a low observance of hydro-alcoholic hand rubbing (approximately 50%) during the different stages of insertion where alcohol-based products are recommended. This failure was not a major infringement of the guidelines but could have been involved in early exoluminal CAbacteriuria. However, the microorganisms of early exoluminal colonization in our study did not come only from the skin flora. Another cause of early exoluminal CA-bacteriuria could be the presence of microorganisms in the final centimeters of the urethra carried away during catheterization. In our study, 69.5% of the microorganisms of exoluminal CA-bacteriuria were also identified on samples of urinary meatus. This is consistent with other reports which showed that in 75% of cases the microorganisms of exoluminal bacteriuria preexisted in the urethral flora [START_REF] Brehmer | Route and prophylaxis of ascending bladder infection in male patients with indwelling catheters[END_REF][START_REF] Bultitude | The relationship between the urethral flora and urinary infection in the catheterised male[END_REF] and that a positive culture of urinary meatus increased the incidence of CAbacteriuria [START_REF] Garibaldi | Meatal colonization and catheter-associated bacteriuria[END_REF][START_REF] Schaeffer | Urethral meatal colonization in the pathogenesis of catheter-associated bacteriuria[END_REF][START_REF] Tenover | Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: criteria for bacterial strain typing[END_REF] However, meatal care does not result in a reduction in CA-UTI or urethral colonization [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF][START_REF] Gould | Guideline for prevention of catheter-associated urinary tract infections 2009[END_REF]. Before insertion, there is a physical inability to access the inside of the urethra during antisepsis [START_REF] Tambyah | A prospective study of pathogenesis of catheter-associated urinary tract infections[END_REF]. It is likely that meatal care does not completely eliminate the microbial flora present in the last few centimeters of the urethra. In addition, the presence of diarrhea and the catheter maintenance environment could affect late exoluminal CA-bacteriuria.

After insertion, the persistence of CA-bacteriuria could be related to the formation of biofilm at the interface of the catheter and the urethra, to repeated catheter manipulations or to inadequate residual activity of the antiseptic [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF]. Consequently, the strict implementation of guidelines by health workers does not avoid exoluminal CA-bacteriuria.

The first limitation of our study is the low number of patients included. Because of the lack of data available in the literature on this subject, no calculation of population size has yet been made. However, this was compensated by the large number of samples (n = 1008 with a maximum of 27 samples for 15 days), which is indicative of a good follow-up of each patient. We do not exclude the possibility that, owing to a lack of statistical power, rare events could not be highlighted. A second limitation was the viable non-cultivable bacteria that we were unable to isolate. To reduce this bias, it would have been necessary to remove the urinary catheter and culture its end or to carry out a molecular analysis with 16S PCR. However, as we were performing a real-life observational study, we used the usual microbial analysis techniques. However, this is the first report to confirm microbial results by molecular comparison of the same microorganisms isolated. A final limitation was the choice of a threshold of 10 2 CFU/mL in bladder urine to define CAbacteriuria: in French and American guidelines, it is set at 10 3 CFU/ml [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF][START_REF]RPC-infections_urinaires_associees_aux_soins[END_REF]. This could have artificially increased the detection of CA-bacteriuria. However, our aim was earlier detection of bacteriuria. The change in threshold was possible because standardization of the microbiological technique allowed a detection threshold of 10 CFU/m. We do not rule out an impact of antiinfective therapy on the detection threshold. However, there was no difference in mean duration of anti-infective therapy between the two groups. In addition, it is established that in patients with a urinary catheter not receiving antimicrobial therapy, bacteriuria or candiduria ≥10 2 CFU/ml will increase to > 10 5 CFU/mL in 1 to 3 days if the urinary catheter remains in place [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF][START_REF]RPC-infections_urinaires_associees_aux_soins[END_REF].

Conclusions

This prospective observational study assessed the occurrence of CA-bacteriuria in a medical ICU. The exoluminal pathway was predominant, and even when guidelines were fully complied with, 38.5% of cases of CA-bacteriuria were early exoluminal. Two factors could explain these findings: the inability to remove the microorganisms from the final centimeters of the urethra during meatal care, and the design of catheter materials. To explore the first hypothesis, a better knowledge of urethral and perineum microbiota is needed. Measures could then be taken to act on the balance of these microbiota to prevent their adhesion to urinary catheters. To explore the second hypothesis, the mechanisms of CAbacteriuria and biofilm formation on urinary catheters need to be elucidated to guide research into new and safe devices. It would be interesting to study bacterial adhesion to different kinds of urinary catheters according to variations in the environment such as the composition or pH of urine. This could lead to the development of new devices or to medical modification of the composition of urine. The prevention of CAbacteriuria and, even more importantly, of CA-UTI is a challenge for the medical community, which should now develop interdisciplinary innovation projects.

Methods

Population study

We conducted a four-month (from May to September, 2015) observational and prospective clinical study in a 16-bed medical intensive care unit of the University (See figure on previous page.) Fig. 2 Origin of catheter-associated bacteriuria. Black line: Threshold of detection of 10 2 CFU/mL that defines catheter-associated bacteriuria. Black bar: Bladder urine; grey bar: outer surface of the urinary catheter near the urinary meatus; hatched bar: urine from the collector bag. Figures 2a, b andc give an example of the dynamics of the occurrence of CA-bacteriuria of each group (a endoluminal, b early exoluminal, c late exoluminal) which reflects the dynamics in the whole group. CA-bacteriuria was defined as a number of microorganisms higher than or equal to 10 2 CFU/mL in at least one bladder urine sample. The origin of CA-bacteriuria was defined by comparing the dynamics of the occurrence of microorganisms in bladder urine, collector bag urine and urinary catheter swabs. a Endoluminal catheter-associated bacteriuria. Identification of microorganisms, first in collector bag urine and then in bladder urine. Morganella morganii in patient 76, first in collector bag urine on day 2 and then in bladder urine on day 12. The molecular comparison is given in Additional file 2 (See Supplementary Figures 14 and16, Additional File 2). b Early exoluminal catheter-associated bacteriuria. Identification of microorganisms on the first day of catheterization in bladder urine with or without identification in urine from collector bags. Klebsiella pneumoniae in patient 22 on the first day of catheterization in bladder urine. It was also detected from day 1 in the collector bag and on the outer surface of the urinary catheter near the urinary meatus. The molecular comparison is given in Additional file 2 (See Supplementary Figure 17, Additional File 2). c. Late exoluminal catheter-associated bacteriuria. Identification of microorganisms after the first day of catheterization in bladder urine without a preliminary identification in urine from collector bags. Morganella morganii in patient 56 in bladder urine and collector bag urine on day 3. It was detected from day 1 on the outer surface of the urinary catheter near the urinary meatus. The molecular comparison is given in Additional file 2 (See Supplementary Figures 14 and15, Additional File 2)

Hospital of Clermont-Ferrand, France. The study was approved by the regional ethics committee of South-East France 6 (Comité de Protection des Personnes Sud-Est 6, reference # N°2015/CE 59 -IRB00008526). Patients were informed of the nature and purpose of the study as requested in French guidelines. Informed consent is obtained from all participants and in case of participants who are dead now informed consent is obtained from their legal guardian. Inclusion criteria were adult patients with urinary catheter inserted for a duration of more than 48 h. Catheterization was performed only in the ICU. Exclusion criteria were no urinary catheter or catheter inserted for a duration of less than 48 h, identification of a microorganism by cytobacteriological examination of the urine (CBEU) on the day the catheter was inserted (day-0), pregnant or breastfeeding women and subjects protected by law. Patient care, choice and management of the urinary catheter were left to the discretion of the healthcare team. There was continuous monitoring of disconnections during follow-up by the ICU care team. Infections were defined according to American and French guidelines [START_REF] Hooton | Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America[END_REF][START_REF] Apic A For P In | APIC implementation guide: guide to preventing catheter-associated urinary tract infections[END_REF][START_REF]RPC-infections_urinaires_associees_aux_soins[END_REF].

Sampling

Two investigators from the infection control team performed samplings. Patient follow-up did not exceed 15 days depending on the duration of catheterization and hospital stay. Samples were taken daily from the first to the sixth day of catheterization and then on the ninth, twelfth and fifteenth days. Each time, three samples were taken (i) in bladder urine at the urinary catheter sampling site according to national recommendations using a needle or suitable adapter [START_REF]RPC-infections_urinaires_associees_aux_soins[END_REF] (ii) in urine from the collector bag after disinfection of the drain end-piece with chlorhexidine-alcohol 0.5% and (iii) in swabs with transport media (Transystem®, COPAN©, Brescia, Italy) of the outer surface of the urinary catheter near the urinary meatus. All samples were collected in CBEU tubes (BD Vacutainer®, BD Diagnostics©, Le Pont de Claix, France).

Microbiological analysis

Each sample was streaked on two agar plates for Gramnegative bacilli (Drigalski agar, bioMerieux©, Craponne, France) and for Gram-positive bacteria and yeasts (Columbia CAP Agar, Oxoid©, Basingstoke, United Kingdom). Plating was standardized (easySpiral Dilute®, Interscience©, Saint Nom la Brétèche, France) and 100 μL were inoculated on agar to obtain a threshold detection of 10 colony-forming units (CFU)/ml. Each agar plate was incubated at 37 °C for 48 h and the bacterial count was automatized (Scan® 500, Interscience©, Saint Nom la Brétèche, France). Results were expressed quantitatively for urine samples and semi-quantitatively for swab samples because they were drained in 1000 μL of saline solution before being streaked. When the CFU count from the bladder urine sample was higher than or equal to 10 2 CFU/mL, all strains isolated from the patient were identified by MALDI TOF mass spectrometry (Matrix-Assisted Laser Desorption/Ionisation time-offlight, VITEK® MS, bioMerieux©, Craponne, France). For each patient, clonal relatedness was determined either Establishing the first localization of catheter-associated bacteriuria (CA-bacteriuria)

The first localization of CA-bacteriuria was defined by observing the dynamics of the occurrence of microorganisms in the bladder urine and collector bags. CAbacteriuria was defined as a number of microorganisms higher than or equal to 10 2 CFU/mL in at least one bladder urine sample collected at the urinary catheter collection site. As previously reported [START_REF] Tambyah | A prospective study of pathogenesis of catheter-associated urinary tract infections[END_REF], the CA-bacteriuria pathway was identified by comparing the dynamics of the occurrence of microorganisms on the three samples (bladder urine, collector bag urine, urinary catheter swabs). Endoluminal CA-bacteriuria was defined by the identification of the same microorganism first in collector bag urine and then in bladder urine. Early exoluminal CA-bacteriuria was defined by the identification of the same microorganism on the first day of catheterization in bladder urine with or without identification in urine from the collector bag. Late exoluminal CA-bacteriuria was defined by the identification of the same microorganism after the first day of catheterization in bladder urine without preliminary identification in urine from the collector bag. A molecular comparison of the strains was then performed that confirmed the culture findings. In some cases, molecular comparison with microorganisms identified on swabs helped to confirm exoluminal CA-bacteriuria.

Quality audit of urinary catheter insertion

We carried out a quality audit on urinary catheter insertion according to our hospital protocol, which is based on the international guidelines [START_REF] Apic A For P In | APIC implementation guide: guide to preventing catheter-associated urinary tract infections[END_REF][START_REF]RPC-infections_urinaires_associees_aux_soins[END_REF][START_REF] Lo | Strategies to prevent catheterassociated urinary tract infections in acute care hospitals: 2014 update[END_REF]. One intensivist investigator from the medical ICU, who was trained by the infection control team, observed the insertion of 10 consecutive urinary catheters. The audit grid followed the insertion protocol and included the knowledge of protocol, the number of people performing the insertion, the kind of hand hygiene and the personal protective equipment used, the kind of meatal cleansing and antisepsis of the urinary meatus, the respect of asepsis, positioning of the collector bag and traceability of catheter insertion in the medical file.

Statistical analyses

Patients with and without CA-bacteriuria were compared with Student test for quantitative data, and a Fisher or CHI2 test for qualitative data. The occurrence of each microorganism was analyzed as an independent case of CA-bacteriuria. Categorical data were expressed as numbers and percentages, and quantitative parameters as mean ± standard-deviation. P values of < 0.05 were considered to indicate statistical significance. Analyses were performed with SAS® software (SAS Institute Inc.). SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc. in the USA and other countries. ® indicates USA registration.

Fig. 1

 1 Fig. 1 Flow chart of study. CA-bacteriuria: catheter-associated bacteriuria, ICU: Intensive Care Unit, CBEU: cytobacteriological examination of the urine

Fig. 2 (

 2 Fig. 2 (See legend on next page.)

Table 1

 1 Comparison of included patients with and without catheter-associated bacteriuria (CA-bacteriuria)

	Variables	Patients
		CA-bacteriuria	No CA-bacteriuria	p. value
		(n = 20; 31.2%)	(n = 44; 68.8%)
	Demographics
	Age (years) a	71 ± 12.9	63.7 ± 15.5	0.06
	Male/Female (number)	8/12	37/7	0.001
	Medical past history
	Chronic kidney disease (%)	4 (20%)	5 (11.4%)	0.44
	Diabetes mellitus (%)	3 (15%)	4 (9.1%)	0.66
	Primary disease
	Acute renal failure (%)	2 (10%)	1 (2.3%)	0.23
	Cardiac arrest (%)	1 (5%)	3 (6.8%)	1.00
	Coma (%)	4 (20%)	7 (15.9%)	0.73
	Postoperative care (%)	1 (5%)	3 (6.8%)	1.00
	Respiratory failure (%)	2 (10%)	1 (2.3%)	0.23
	Sepsis (%)	5 (25%)	17 (38.6%)	0.39
	Shock (%)	4 (20%)	11 (25%)	0.75
	Traumatism (%)	1 (5%)	1 (2.3%)	0.53
	ICU Data
	Length of stay (days) a	11.3 ± 10.1	11.3 ± 8.8	0.99
	Admission weight (Kg) a	82.9 ± 25.7	76.4 ± 24.7	0.34
	BMI (kg/m 2 ) a	30.5 ± 9.5	30.6 ± 30.2	0.98
	SAPS II score a	50.3 ± 29.2	50.3 ± 21.8	0.69
	Anti-infective therapy b
	Prior to urinary catheterization (%)	6 (30%)	34 (77.3%)	0.0006
	During patient follow-up (%)	10 (50%)	35 (79.5%)	0.04
	Mean duration (days) ab	6.45 ± 1.72	7.68 ± 1.05	0.55
	Complications
	Death (%)	1 (5%)	5 (11.4%)	0.65
	Mechanical ventilation (%)	8 (40%)	22 (50%)	0.59
	Non-invasive ventilation (%)	10 (50%)	27 (61.4%)	0.42
	Vasoactive amine (%)	9 (45%)	16 (36.4%)	0.58
	Acute renal failure (%)	5 (25%)	9 (20.5%)	0.74
	Dialysis (%)	3 (15%)	6 (13.6%)	1.00
	Urinary catheterization
	100% silicon catheter (%)	16 (80%)	38 (86.3%)	0.71
	Silicon-coated-latex catheter (%)	4 (20%)	6 (13.7%)	0.71
	Mean duration of catheterization (days) a	6.45 ± 0.94	6.98 ± 0.73	0.89
	BMI Body Mass Index, SAPS II simplified acute physiology score II
	Statistical significance: P values of < 0.05
	a Results expressed as mean ± standard deviation
	b

  Klebsiella pneumoniae CA-bacteriuria followed by acute prostatitis treated with cefotaxime. The three other patients were classified as cases of late exoluminal CAbacteriuria. Patient 26 was infected by Proteus mirabilis and treated with cefotaxime, cefepime and then meropenem. Patient 44 was infected by Escherichia coli and treated with cefotaxime. Patient 75 was infected by Escherichia coli and treated with nitrofurantoin (See Supplementary Table

	;
	see Supplementary Table 1, Additional File 1; see
	Supplementary Figures 14 to 17, Additional file 2). Four
	patients had CA-UTI. Patient 22 had early exoluminal

Table 2

 2 Quality audit of the insertion of a urinary catheter Staphylococcus epidermidis and Enterococcus faecalis, and BssHII for Candida albicans and Candida glabrata. The run conditions were 6 V/cm, 22 h, 120°a ngle, linear ramp, initial switch 2.2 s, final switch 54.2 s. DNA banding patterns were interpreted according to Tenover et al. [29]. Isolates were considered to be closely related if the PFGE patterns differed by three or fewer bands. ERIC2-PCR was performed according to Dumarche et al. for Escherichia coli, Klebsiella pneumoniae, Morganella morganii, and Proteus mirabilis. No molecular comparison was performed for Corynebacterium aurimucousum and Streptococcus agalactiae because these strains are rarely involved in urinary tract infections.

	Questions	% of answers in
		accordance with
		recommendations
	Knowledge of protocol	100% (10/10)
	Two people performing urinary catheterization	80% (8/10)
	Genital cleaning	100% (10/10)
	Sterile single-dose plain soap	70% (7/10)
	Non-sterile plain soap	10% (1/10)
	Chlorhexidine scrub	20% (2/10)
	Hand hygiene before genital cleaning	100% (10/10)
	Alcohol-based hand rubbing	50% (5/10)
	Plain soap handwashing	20% (2/10)
	Antiseptic soap handwashing	30% (3/10)
	Use of vinyl gloves	100% (10/10)
	Hand hygiene after genital cleaning	80% (8/10)
	Alcohol-based hand rubbing	50% (4/8)
	Plain soap handwashing	25% (2/8)
	Antiseptic soap handwashing	25% (2/8)
	Installer: mask, hygiene cap, disposable apron	100% (10/10)
	Antisepsis of urinary meatus with sterile gloves	100% (10/10)
	Dakin solution	80% (8/10)
	Chlorexhidine 0.05% (sterile single dose)	20% (2/10)
	Hand hygiene after sterile glove removal	100% (10/10)
	Alcohol-based hand rubbing	50% (5/10)
	Plain soap handwashing	20% (2/10)
	Antiseptic soap handwashing	20% (2/10)
	Sterile urinary catheterization	100% (10/10)
	Hand hygiene after catheterization	90% (9/10)
	Alcohol-based hand rubbing	56% (5/9)
	Plain soap handwashing	22% (2/9)
	Antiseptic soap handwashing	22% (2/9)
	Securing the collector bag in a sloping position	100% (10/10)
	Traceability = date of catheterization
	On collector bag	100% (10/10)
	In patient file	90% (9/10)

observations were made by one investigator of 10 consecutive catheterizations. The audit grid was established in accordance with national recommendations[START_REF]RPC-infections_urinaires_associees_aux_soins[END_REF]

Acknowledgements

We are indebted to Mr. Jeffrey Watts for assistance in the preparation of the manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Availability of data materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

CA-UTI: Catheter-associated urinary tract infection; CA-Bacteriuria: Catheterassociated bacteriuria; ICU: Intensive care unit

Supplementary Information

The online version contains supplementary material available at https://doi. org/10.1186/s12866-021-02147-9.

Additional file 1: Supplementary

Declarations

Ethics approval and consent to participate

The study was approved by the regional ethics committee of South-East France 6 (Comité de Protection des Personnes Sud-Est 6, reference # N°2015/ CE 59 -IRB00008526). All methods were performed in accordance with the relevant guidelines and regulations. Patients were informed of the study as requested in the French guidelines. Informed consent is obtained from all participants and in case of participants who are dead now informed consent is obtained from their legal guardian.

Consent for publication Not applicable

Competing interests

The authors have no financial conflicts of interest related to this study.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


PhD Sheng Jiang
email: shengji@kth.se

PhD Roman Khymyn

PhD Sunjae Chung

Tuan Quang Le

PhD Liza Herrera Diez

PhD Afshin Houshang

PhD Mohammad Zahedinejad

Dafiné Ravelosona

Professor Johan Åkerman

| Quang

Tuan Le Phd

Dafiné Ravelosona Professor

Strong control of spin torque nano-oscillator linewidth using He + irradiation

We demonstrate a new approach for improving the spectral linewidth of a spin torque nano-oscillator (STNO). Using He + ion irradiation, we tune the perpendicular magnetic anisotropy (PMA) of the STNO free layer such that its easy axis is gradually varied from strongly out-of-plane to moderate in-plane. As the PMA impacts the non-linearity N of the STNO, we can in this way control the threshold current, the current tunability of the frequency, and, in particular, the STNO linewidth, which dramatically improves by two orders of magnitude. Our results are in good agreement with the theory for nonlinear auto-oscillators, confirm theoretical predictions of the role of the nonlinearity, and demonstrate a straightforward path towards improving the microwave properties of STNOs.

K E Y W O R D S

spin-torque nano-oscillators, He + irradiation, perpendicular magnetic anisotropy 1

| INTRODUCTION

Spin-torque nano-oscillators (STNOs) are among the most promising candidates for nanoscale broadband microwave generators [1,2,3,4,5,6] and detectors. [7,8,9] STNOs can generate broadband microwave frequencies ranging from hundreds of MHz to the sub-THz, [10,11,12,13] controlled by both magnetic fields and dc currents. [5,14] Moreover, the device size can be reduced to a few tens of nanometers, which is of great opportunity for industrial applications.

They can also host a range of novel magnetodynamical spin wave modes, such as propagating spin waves of different orders, [15,16] and magnetodynamical solitons, such as spin wave bullets [15] and droplets. [3] However, the applicability of these devices has suffered from their low power emission and large linewidth. Nonlinear auto-oscillator theory [17,18,19,20] explains the large linewidth as a consequence of the strong nonlinearity N, i.e. the dependence of the microwave frequency on its precession amplitude. N can be controlled not only by the magnitude and direction of the magnetic field, [14,21,22,23,24,25] but also by the magnetic properties of the free layer of the STNO, such as the magnetic anisotropy and the effective magnetization. [20] For instance, in an easy-plane free layer, N changes gradually from positive to negative values as the direction of magnetic field rotates from out-of-plane to in-plane. [17,20] Several experimental studies have corroborated [14,15,17,22,26,27,28] this theoretical prediction, as the linewidth can be minimized when N approaches to zero at the critical angle of magnetic field. This can show a way how to improve the linewidth by selectively reducing N. Whereas all previous studies, which aimed at minimizing the N, have focused only on varying the direction and magnitude of magnetic field on single device, and this minimal N can be achieved at a narrow range of conditions, limited generating frequency, and which will require a complicate design for applications as microwave generators. In our work, we therefore study systematically how N is affected by the strength of perpendicular magnetic anisotropy (PMA) H k in a set of nanocontact (NC) STNOs with a [Co/Pd]/Cu/[Co/Ni] spin valve structure. To engineer the PMA, we utilize He + irradiation to modify the interface/surface of [Co/Ni] multilayer where the PMA is originated from and sensitive to. [29,30,31,32] We show how N can be continuously tuned as H k is controlled by He + irradiation fluence in otherwise identical devices. Most importantly, the linewidth is dramatically improved at moderate H k values, where N → 0. Finally, we show excellent agreement of our experimental results with nonlinear auto-oscillator theory. [20]

| RESULTS AND DISCUSSION

It is well known that irradiation with Ar + , He + , and/or Ga + can be utilized to tune the magnetic properties of thin films by modifying the microstructure of the magnetic material. [29,33] Here, we use He + irradiation to engineer the PMA of the [Co/Ni] multilayer free layer in all-perpendicular STNOs, since the PMA of magnetic multilayers is highly sensitive to its surface or interface characteristic. [31,34,35] He + irradiation was hence implemented as a separate step in our device fabrication recipe (see details in the Experimental Section). The devices were irradiated with the fluence F varied from 6 to 20×10 14 He + /cm 2 . [36] Figure 1a shows a schematic of the irradiation process during the device fabrication. First, the magnetoresistance (MR) was measured in a perpendicular magnetic field (see the inset of Figure 1b). The MR is slightly degraded but remains better than 1% even for the highest fluence (Figure 1b). This confirms that the SV structure remains of a good quality. Second, spin-torque ferromagnetic resonance (ST-FMR) [37,38,39,40,41] measurements were performed to determine the effective magnetization, µ 0 M eff = µ 0 M sµ 0 H k [H k being the perpendicular magnetic anisotropy (PMA)] of [Co/Ni] free layers. Figure 1c inset shows a representative spectrum of ST-FMR at f = 34 GHz at F =6×10 14 He + /cm 2 . [36] The signals exhibit one main peak and one side peak. The main peak is identified as the ferromagnetic resonance (FMR) peak, and the additional side peak O . O ' --------' -0------' ---5. . _______. __1_, __0___. ______. _1 5------' ---2-' --0----' -----2----' -5____,____,3 0

Fluence (x10 14 He+/cm 2 ) (d) 1.0 ~-•---1 --- I ---1 -- 1 --- I ---- ....-.... 0.5 - I- '-"' ~ NiFe: µ0Mett = 0.98 T - ~(J) 0.0 -• • • • • • • • • • • • • • • -~• • • • • • • • • • • .. f / .
-0.

f = γµ 0 2π H int H int + M eff • cos 2 θ int , (1)
where H int and θ int are the internal field and angle; their values are determined by solving for the magnetostatic equilibrium conditions:

H • cos θ ext = H int • cos θ int H • sin θ ext = (H int + M eff ) • sin θ int , (2)
where θ ext = 10 • is the applied field angle. The saturation magnetization µ 0 M s = 1.1 T of [Co/Ni] was found to be independent of He + irradiation, as previously measured by alternating gradient magnetometry. [36] Note that here NiFe (Permalloy) free layer has been used as a reference of in-plane magnetic anisotropy (IMA) with stronger M eff . By fitting frequency vs. the resonance field with Equation ( 1) and ( 2), which are shown as solid lines in Figure 1c, the values of µ 0 M eff for all samples are obtained and summarized in Figure 1d.

In Figure 2, we compare the calculated FMR frequency, f FMR , using the measured M eff , with the microwave signals generated from the STNO devices. The inset in Figure 2 shows a typical power spectral density (PSD) of the microwave signals for a fluence of F = 10 × 10 14 He + /cm 2 . All PSD spectra are well fitted with a Lorentz function, and the extracted frequency f versus magnetic field is presented in Figure 2 with different symbols for each different fluence. All data show a quasi-linear dependence on the magnetic field, and the generated microwave frequency f extends to lower values as M eff (H k ) increases (decreases). This behavior is consistent with the calculated value of the FMR frequency f FMR , plotted as dashed lines in Figure 2. The overall trends of f FMR are in good agreement with the auto-oscillation f . The difference between the calculated f FMR and the measured auto-oscillation f is a direct measure of the nonlinearity of the magnetization precession, [43,24,15,5] which is discussed in detail below. We note that there are double peaks at around 0.9 T fields for F = 6 × 10 14 He + /cm 2 . This double peak phenomenon is infrequent and happens randomly between devices. It is likely an apparent effect of mode hopping between two closely spaced auto-oscillation modes. The sputtered [Co/Ni] films are polycrystalline and it is possible that grain boundaries underneath the nano-contact can impact the auto-oscillation modes from device to device and lead to slightly different local modes.

We now turn to the current-induced frequency tunability. out-of-plane for [Co/Ni] to in-plane for NiFe, and further details will be discussed later.

We carried out detailed measurements at different magnetic fields to understand further the behavior of df /dI dc .

Figure 4a shows one example of extracted f versus I dc at different fields, ranging from 0.37 to 1.12 T with a 0.05 T step, for F = 6 × 10 14 He + /cm 2 . All data show clear linear dependencies on I dc . Here we would like to define one numerical relation about the tunability, df /dζ = I th (df /dI dc ), to compare our experimental results directly with theoretical calculation, where ζ = I dc /I th is the dimensionless supercriticality parameter [20] and I th is the threshold current. I th were extracted from plots of inverse power 1/P versus I dc as described in the Supplemental Materials. After obtained all I th and df /dI dc for different M eff , df /dζ are represented as solid dots in Figure 4b. All df /dζ for different M eff show similar behaviors that is inverse proportional to magnetic field. It is noteworthy that the overall df /dζ decreases as M eff (H k ) increases (decreases). It reaches around zero when the µ 0 M eff ≈ 0 for F = 20 × 10 14 He + /cm 2 . The sign of df /dζ for NiFe is even negative.

To understand the behavior of tunability versus M eff (H k ) from He + -irradiated STNOs, we considered the nonlinear auto-oscillator theory of A. Slavin and V. Tiberkevich, [44,43,19,20] which was derived from universal auto-oscillation systems and has proved to be consistent with the Landau-Lifshitz-Gilbert-Slonczewski (LLGS) equation. [20] This theory allows us to describe the experimental observation analytically. The auto-oscillation frequency f generated from an STNO is expressed as:

f (I dc ) = f FMR + N 2π ζ -1 ζ + Q , ( 3
)
F I G U R E 4 (a)
Extracted auto-oscillation frequency f vs. I dc at different magnetic fields for F = 6×10 14 He + /cm 2 . Some minor frequency jumps at µ 0 H = 0.87 T are shown as rectangular boxes, possibly due to film inhomogeneities generating different dynamical behaviors. (b) df /dζ [i.e. I th (df /dI dc )] vs. magnetic field, where I th is extracted from the intercept of the inverse power of the auto-oscillation signals and the df /dI dc are the slopes of the linear fits of frequency as I dc > I th (see the Appendix). The solid lines are the theoretical calculation from Equation ( 4)-( 6).

where N is the nonlinearity factor, ζ-1 ζ+Q = P is the normalized power of the stationary precession, and Q is the nonlinear damping coefficient. From Equation (3), the frequency shift is mainly decided by the nonlinearity N. Taking the derivation of Equation (3), df /dζ is derived as:

df dζ = I th df dI dc = N 2π 1 + Q (ζ + Q ) 2 . ( 4
)
The nonlinear frequency shift coefficient N for STNOs dominates the frequency tunability, and may be positive, zero, or negative, depending on magnetic field direction and magnetic anisotropy of free layer in STNOs.

To explain the experimental observations using this analytical theory, we derive N with our experimental conditions. The nonlinearity is expressed as [43]

N = - ω H ω M (ω H + ω M /4) ω 0 (ω H + ω M /2) , (5)
             ω = γH ω M = 4πγM eff ω 0 = γ ω H (ω H + ω M ). (6)
We note that Equation ( 5) and ( 6) are valid for the magnetization of the free layer being aligned to the magnetic field direction. Utilizing Equation ( 5) and ( 6), we calculate df /dζ (∝ N), where ζ and Q are used as fitting parameters for all data in Figure 4b, and we find reasonable good agreements with 1.5 for ζ and 3.0 for Q, respectively. All calculated results are shown as the solid lines alongside the experimental results in Figure 4b. It should be noted that the theoretical calculation coincides with experimental results in the overall trend, although there are discrepancies between experiment and theory. One reason for these discrepancies is likely that the theory does not take into account the current-induced Joule heating and Oersted fields that are present in the experiments. In addition, the calculated nonlinearity N can also explain the frequency difference between the calculated f FMR and the generated microwave frequency f in Figure 1. Due to the negative value of N (or df /dζ) for NiFe, f is expected to be lower than f FMR , as predicted in Equation ( 3) and consistent with our experimental observations in Figure 2. This auto-oscillation mode is often characterized as a localized bullet. [14,15,43] In contrast, N is positive for easy out-of-plane [Co/Ni], so f > f FMR in Figure 2. [14,43,45] In this case, its mode favors to be a propagating spin-wave. [14,28,46] All of these experimental observations confirm the theoretical predictions very well.

Furthermore, according to nonlinear auto-oscillator theory, the linewidth ∆f of the generated microwave signals can be expressed as [20]

∆f = Γ + k B T E (P ) 1 + N Γ eff 2 , (7)
where k B is the Boltzmann constant and T is the temperature. Γ + and E (P ) are the damping function and timeaveraged oscillation energy as a function of the power P , respectively. Γ eff is the effective damping. In Equation( 7), the linewidth ∆f exhibits a quadratic dependence on the nonlinearity N. To compare with our experimental results, we extracted the linewidth from the data in Figure 3a-e, as shown in Figure 5. The linewidth was indeed dramatically improved by about two orders of magnitude as N decreases (as M eff increases), it reaches to a lowest value for µ 0 M eff = 0.03 T, where N → 0. ∆f again increases for the NiFe free layer when N becomes moderately negative.

There are also contributions due to the variation of other parameters, like Γ + , Γ eff , and E (P ). The values Γ + and Γ eff are proportional to the damping constant α, [47] however, it only changes by about a factor of 2 at F = 20 × 10 14 He + /cm 2 as compare to the non-irradiated one. [36] The oscillation energy E (P ) for the circular precession can be assumed as [20,47] where θ is the precessional angle, which can be derived from the experimental output power P out ∼ GMR sin θ sin β . [26] Here β is the relative angle of the magnetization between the free and fixed layer. GMR is the ratio of giant magnetoresistance. We found that E (P ), calculated from the values in Ref. Jiang2018a, only shows ∼ 10% reduction by He + irradiation. In fact, we are able to fit the experimental data shown in Figure 4b with a single value of the nonlinear damping Q and supercriticality ζ for the all irradiation fluences. That particularly means that the power P = (ζ -1)/(ζ + Q ) also remains the same, so does E (P ). We therefore argue that decreasing of N dominates the linewidth reduction, while the variation of other parameters in Equation ( 7) has a minor contribution.

E (P ) ∝ sin θ,
The excellent agreement between our experimental results and theory confirms that the linewidth can be minimized intentionally by controlling the nonlinearity in general, and tuning it to zero in particular. When the PMA compensates the demagnetization field, the nonlinearity identically equals zero regardless of the external conditions.

We can therefore minimize the linewidth by choosing free layer materials with µ 0 M eff → 0. We hence would emphasize that our study can offers a universal path to solving one of the key issues in utilizing STNOs as microwave generators. As for the generated microwave power-another key drawback of this type of microwave generators-we did not observe an improvement in this study, mainly due to the slightly degradation in MR values. [36] We expect that the power can be dramatically improved using magnetic tunnel junction-based STNOs, whose MR can be over two orders of magnitude greater than that of spin valve-based STNOs. [2,16]

| CONCLUSION

In conclusion, we have presented a systematic study of the variation of nonlinearity against PMA in STNOs. By using He + irradiation to continuously tune the PMA of the [Co/Ni] free layer, the nonlinearity N (along with the frequency tunability df /dI dc ) shows a continuous decreasing trend as H k (M eff ) decreases (increases). As a consequence of this decreasing nonlinearity, we have achieved an approximately hundredfold improvement in the linewidth. Our experimental observations are in excellent agreement with nonlinear auto-oscillator theory. This systematic study not only verifies the theoretical prediction, but also offers a route to improving the linewidth-selecting a free layer's material whose M eff → 0, which is of great importance for commercializing microwave generators. varied from 6 to 20×10 14 He + /cm 2 . [36] This is done by a commercial irradiation facility with highly uniform ion beam in millimeter-scale. Fabrication was completed with lift-off lithography and deposition of a Cu (500 nm)/Au (100 nm) top electrode in a single run with all irradiated pieces. Our protocol hence ensures that all other properties, except the He + fluence, are identical from device to device.

Spin-torque Ferromagnetic Resonance ST-FMR involves using a microwave generator (capable of up to 40 GHz) to inject a fixed frequency through a bias-tee to a STNO, which is connected with a commercial picoprobe. The rf power is set to -2 dBm to avoid nonlinear magnetodynamics. The rf signal is modulated at a frequency of 313 Hz for lock-in detection. [39] The resulted mixing dc voltage [48] is measured by a lock-in amplifier. The magnetic field is swept from 0 to 2 T at a small (10 • ) out of plane angle as this produced cleaner resonances than in in-plane fields.

D.C. and Microwave characterization

We used our custom-built probe station for static and microwave characterization. A direct current I dc was injected into the devices using a Keithley 6221 current source, and the dc voltage was detected using a Keithley 2182 nanovoltmeter. The magnetic field was applied in the plane of the film. The generated microwave signals from the STNO device were decoupled from the dc voltage via a bias-tee, amplified using a low-noise amplifier, and then recorded with a spectrum analyzer. [49,50]

1 F ( 10 14

 110 He+/cm2 )

  Fluence (10 14 He+/cm 2 ) F I G U R E 1 (a) A schematic of He + irradiation process and stack information. (b) Magnetoresistance (MR) as a function of irradiation fluence, obtained by sweeping perpendicular fields in the inset, where the numbers indicate the fluence F with a unit of 10 14 He + /cm 2 . (c) Extracted main resonant fields at various frequencies: the solid lines are fits using the Kittel equation [Equation (1) and (2)]. The inset shows a representative ST-FMR spectrum at f = 34 GHz for F = 6 × 10 14 He + /cm 2 . (d) The obtained effective magnetization µ 0 M eff versus the irradiation fluence, and the dashed line shows the value of the NiFe free layer.at lower field may result from spin-wave resonances, as studied in detail in Ref. MasoumehPRB2016. We then fit the spectra using two peaks with both symmetric and antisymmetric contributions as shown by the red line in the inset of Figure1c. The main FMR fields at different frequencies are utilized and presented in Figure1c. The FMR field is fitted by the universal Kittel equation[42,23]

F

  q u e n c y ( G H z ) M a g n e t i c F i e l d ( T ) = 1 0 × 1 0 1 4 H e + / c m 2 F r e q u e n c y ( G H z ) ؍ 0 H ( T ) F I G U R E 2 Auto-oscillation frequency versus in-plane magnetic field for various irradiated STNOs with R NC = 35 nm. The dashed lines are the calculated FMR frequencies f FMR , based on the values of µ 0 M eff obtained from ST-FMR measurements. Inset: A typical power spectral density (PSD) of an STNO with F = 10×10 14 He + /cm 2 at I dc = -14 mA.

8 F؍ 0 2 F

 802 Figure 3a-e shows the generated microwave frequency f versus dc current I dc at a fixed magnetic field, µ 0 H = 0.72 T; f linearly depends on the I dc at different values of M eff . The current-induced frequency tunability df /dI dc can be extracted from the slopes of linear fits which plot as each dashed line in Figure 3a-e. df /dI dc for M eff are then summarized in Figure 3f. We found that i) df /dI dc decreases from 0.50 GHz/mA for nonirradiated [Co/Ni] to -0.13 GHz/mA for NiFe as M eff increases (or H k decreases), ii) the sign of df /dI dc changes from positive (for [Co/Ni]) to negative (for NiFe), consistent with the easy axis transition from r e q u e n c y ( G H z ) F r e q u e n c y ( G H z ) F r e q u e n c y ( G H z ) C u r r e n t ( m A ) ( c ) F = 1 0 ×1 0 1 4 H e + / c m 2 | | | | | | | | | | | | | | | ( d ) F = 2 0 ×1 0 1 4 H e + / c m 2 | | | | | ؍ 0 M e f f = -0 . 1 4 T ؍ 0 M e f f = 0 . M e f f = 0 . 9 8 T d f / d I d c ( G H z / m A ) ؍ 0 M e f f ( T ) ( a ) F = 0 | | | | | | | | | | | | | | | | | | | | | | | | | ( b ) F = 6 ×1 0 1 4 H e + / c m I G U R E 3 (a)-(e) PSD versus I dc in STNOs with different irradiated fluences at µ 0 H = 0.72 T. The red dotted line represents the linear fits of the auto-oscillation frequency. (f) slope df /dI dc versus µ 0 M eff extracted from the fits of (a)-(e).

؍ 0

 0 M e f f = -0 . 6 8 T ؍ 0 M e f f = -0 . 4 4 T ؍ 0 M e f f = -0 . 1 4 T ؍ 0 M e f f = 0 . 0 3 T ؍ 0 M e f f = 0 . 9 8 T F I G U R E 5 Linewidth ∆f versus I dc with different effective magnetization µ 0 M eff at µ 0 H = 0.72 T. The linewidth were extracted from the data in Figure 3a-e.

4 |

 4 EXPERIMENTAL SECTION Device Fabrication and He + Irradiation The STNO devices were fabricated from all-perpendicular (all-PMA) [Co/Pd/ Cu/[Co/Ni][36, 45] and orthogonal [Co/Pd]/Cu/NiFe spin valves (SVs). The full stack consists of a Ta (5)/Cu (15)/Ta (5)/Pd (3) seed layer, an all-PMA [Co (0.5)/Pd (1.0)]×5/Cu (7)/[Co (0.3)/Ni (0.9)]×4/Co (0.3) or orthogonal [Co (0.5)/Pd (1.0)]×5/Cu (7)/Ni 80 Fe 20 (4.5) SV with a Cu(3)/Pd(3) capping layer (here NiFe is served as a reference with ignorable PMA), sputtered onto a thermally oxidized 100 mm Si wafer (numbers in parentheses are layer thicknesses in nanometers). The deposited stacks were first patterned into 8 µm × 20 µm mesas using photolithography and ion-milling etching, followed by chemical vapor deposition (CVD) of an insulating 40-nm-thick SiO 2 film. Electron beam lithography and reactive ion etching were used to open nanocontacts (with nominal radius of R NC 35 nm) through the SiO 2 in the center of each mesa. The processed wafer was then cut into different pieces for He + irradiation with the fluence F

Acknowledgements

This work was supported by the China Scholarship Council (CSC), the Swedish Foundation for Strategic Research (SSF), the Swedish Research Council (VR), and the Knut and Alice Wallenberg Foundation (KAW). Additional support for the work was provided by the European Research Council (ERC) under the European Community's Seventh Framework Programme (FP/2007-2013) /ERC Grant 307144 "MUSTANG".

Conflict of interest

The authors declare that they have no competing interests. references


A Di Syskaki

Y Pietro

R Pachat

D Ourdani

J W Van Der Jagt

M.-A Syskaki

A Di Pietro

Y Roussigné

S Ono

M S Gabor

M Chérif

G Durin

J Langer

M Belmeguenai

D Ravelosona

L Herrera Diez

Multiple Magnetoionic Regimes in

I. INTRODUCTION

Controlling magnetic properties with electric (E) fields is of great importance for spintronics applications due to its potential for lowering power consumption in novel memory prototypes. It has been shown that E-field induced charge accumulation can lead to important changes in magnetic anisotropy [START_REF] Weisheit | Electric Field-Induced Modification of Magnetism in Thin-Film Ferromagnets[END_REF][START_REF] Daalderop | Magnetocrystalline anisotropy and orbital moments in transition-metal compounds[END_REF][START_REF] Nakamura | Giant Modification of the Magnetocrystalline Anisotropy in Transition-Metal Monolayers by an External Electric Field[END_REF][START_REF] Duan | Surface Magnetoelectric Effect in Ferromagnetic Metal Films[END_REF], which can be used to reliably control domain wall (DW) pinning and velocities [START_REF] Bernand-Mantel | Electric-field control of domain wall nucleation and pinning in a metallic ferromagnet[END_REF][START_REF] Liu | Electric field controlled domain wall dynamics and magnetic easy axis switching in liquid gated CoFeB/MgO films[END_REF], and assist the magnetization switching in magnetic tunnel junctions [START_REF] Wang | Electric-field-assisted switching in magnetic tunnel junctions[END_REF] in ferromagnetic (FM) metallic films. More complex mechanisms like switching between ferromagnetic and skyrmionic states [START_REF] Hsu | Electric-field-driven switching of individual magnetic skyrmions[END_REF][START_REF] Schott | The Skyrmion Switch: Turning Magnetic Skyrmion Bubbles on and off with an Electric Field[END_REF] have been also demonstrated, where the E-field control of the Dzyaloshinskii-Moriya Interaction (DMI) [START_REF] Srivastava | Large-Voltage Tuning of Dzyaloshinski-iMoriya Interactions: A Route toward Dynamic Control of Skyrmion Chirality[END_REF][START_REF] Koyama | Electric field control of magnetic domain wall motion via modulation of the Dzyaloshinskii-Moriya interaction[END_REF] is also at play. In addition to the effects of charge accumulation, magneto-ionics can also provide nonvolatility and a more extended effect over the entire magnetic layer, unlike charge accumulation, limited by electrostatic screening [START_REF] Zhang | Spin-Dependent Surface Screening in Ferromagnets and Magnetic Tunnel Junctions[END_REF]. Large magneto-ionic effects in magnetic anisotropy can be achieved, including a spin reorientation transition, which applied to DW motion can be used to create nonvolatile and very efficient domain wall traps [START_REF] Bauer | Voltage-controlled domain wall traps in ferromagnetic nanowires[END_REF][START_REF] Bauer | Magnetoionic control of interfacial magnetism[END_REF]. In addition, magneto-ionic control of spin accumulation [START_REF] Mishra | Electric-field control of spin accumulation direction for spin-orbit torques[END_REF] and DMI [START_REF] Herrera Diez | Nonvolatile Ionic Modification of the Dzyaloshinskii-Moriya Interaction[END_REF] have been demonstrated as well as DW chirality switching in a controlled oxygen atmosphere [START_REF] Chen | Large Dzyaloshinskii-Moriya interaction induced by chemisorbed oxygen on a ferromagnet surface[END_REF], which is of capital importance for implementing Efield assisted spin-orbit torques in devices. In these ionic * liza.herrera-diez@c2n.upsaclay.fr materials, the migration of oxygen [START_REF] Bauer | Magnetoionic control of interfacial magnetism[END_REF][START_REF] Gilbert | Structural and magnetic depth profiles of magneto-ionic heterostructures beyond the interface limit[END_REF] or hydrogen species [START_REF] Tan | Magneto-ionic control of magnetism using a solid-state proton pump[END_REF] is at the heart of the ionic effects observed, which have recently been shown to offer operation speeds close to 1 ms [START_REF] Lee | Fast Magneto-Ionic Switching of Interface Using Yttria-Stabilized Zirconia Gate Oxide[END_REF]. The interest in nonvolatility for spintronics applications goes hand in hand with magneto-ionic reversibility. Recently, studies have focused on the magneto-ionic reversibility variations between oxides [START_REF] Fassatoui | Reversible and irreversible voltage manipulations of interfacial magnetic anisotropy in Pt/Co/oxide multilayers[END_REF], pointing out the importance of the differences in the mechanisms governing ionic conduction. A deep understanding of the mechanisms of reversibility in magneto-ionics is therefore needed to design high performing magneto-electric devices. In this study, we unveil a higher degree of complexity in HfO 2 based devices, where two distinct magnetoionic regimes have been identified in a single structure.

In addition, we also shine light on the magneto-ionic effects on the effective damping parameter α eff , largely overlooked in the literature and of great importance for fast magnetization dynamics. We show that α eff can be significantly reduced by inducing ionic motion and that its lowest value (0.012) coincides with the appearance of PMA. The magnetic materials used in this study are amorphous Ta(5 nm)/Co 20 Fe 60 B 20 (1 nm)/HfO 2 (3 nm) films grown by magnetron sputtering, all samples investigated here were cut from the same wafer. The ionic liquid (IL) [EMI][TFSI] (1-Ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide) is added to the surface of the film to incorporate the IL gate, which can provide high E-fields that have been shown to induce ionic motion in a variety of materials [START_REF] Leighton | Electrolyte-based ionic control of functional oxides[END_REF][START_REF] Jeong | Electrolyte-based ionic control of functional oxides[END_REF][START_REF] Shi | A correlated nickelate synaptic transistor[END_REF]. The thickness of the IL is macroscopic, in the range of several hundreds of µm. However, the effective IL thickness is estimated taking into account only the distance over which an electric double layer is formed at the side of each one of the electrodes, which is 1 nm [START_REF] Ono | High-mobility, low-power, and fast-switching organic field-effect transistors with ionic liquids[END_REF]. A counter electrode, a glass substrate coated with a 100 nm thick indium tin oxide (ITO) layer is subsequently placed on top of the IL. The size of the E-field biased area is of about 0.25 cm 2 . Samples were stored in air and at room temperature before conducting the gating experiments if not indicated otherwise. The hysteresis loops have been measured by anomalous Hall effect using a bias current of 400 µA. All magnetic states presented here are nonvolatile, all measurements were conducted after switching off the gate voltage. A graphic representation of the device geometry is presented in Fig. 1. In the initial state, before exposure to the gate voltage, the magnetic layers are underoxidized, exhibiting in-plane magnetic anisotropy (IPA). Under the action of a negative gate voltage applied to the top ITO electrode a first regime (I) is identified, in which IPA transitions into PMA, followed by a second regime (II) where further oxidation drives PMA into IPA. This entire anisotropy evolution is presented in Fig. 2 with the corresponding cumulative biasing times for each case, these values correspond to the accumulated time of all previous operations. The gate voltage G V =-2 V was applied for a total, accumulated time of t=1380 s. It is well known that thin magnetic films can exhibit a window of oxidation levels at the interface with an oxide which promotes PMA, while under/over oxidation will result in IPA [START_REF] Manchon | Analysis of oxygen induced anisotropy crossover in Pt/Co/MOx trilayers[END_REF]. Oxygen species are also known to migrate from the HfO 2 toward the CoFeB layer under gate voltages, as reported for other HfO 2 based devices [START_REF] Herrera Diez | Nonvolatile Ionic Modification of the Dzyaloshinskii-Moriya Interaction[END_REF][START_REF] Nagata | Oxygen migration at Pt/HfO2/Pt interface under bias operation[END_REF], therefore oxygen migration is thought to be at the heart of the effects observed here. In the following, we will describe in detail the two magneto-ionic regimes and the impact of ionic diffusion on the effective damping parameter α eff . FIG. 2. A progressive oxidation is induced upon exposure to a gate voltage GV =-2 V. Different exposure times t drive the system from IPA (a, initial state) through regime I (b) into PMA (c) and back to IPA through regime II (d).

II. MAGNETO-IONIC REGIMES I AND II

Fig. 3 (a) shows the time dependence of the out-ofplane remanence percentage, where 100% corresponds to the Hall voltage at zero applied magnetic field in the PMA state, for the entire anisotropy rang going from the initial underoxidized IPA state through regime I (positive slope), PMA (the point of highest remanence), and regime II (negative slope) to finish in an overoxidized IPA state. As-grown samples have been investigated under three different constant gate voltages of G V =-2.3 V (circles), G V =-2 V (squares), and G V =-1.7 V (triangles). The speed of the entire process critically increases for higher gate voltages, responding to a stronger driving force for ionic motion. For all applied gate voltages, the magneto-ionic process in regime I is significantly faster than in regime II. This difference in the time evolution as a function of gate voltage between regime I and II could be linked to a difference in the chemical environment, and thus of anchoring, of the oxygen species interacting with the CoFeB layer in regimes I and II. In regime I, the energy barrier associated with adding oxygen species to the underoxidized CoFeB interface may be lower than in regime II, where oxygen species have to be added to an already optimally oxidized CoFeB interface. Measurements were also conducted using underoxidized samples that were annealed before applying a gate voltage of -2 V, these measurements are presented in Fig. (open squares) for one hour to reduce moisture without inducing the crystallization of the CoFeB. Under G V =-2 V, the speed of the ionic process in both regimes I and II was critically reduced, while still showing the same difference previously discussed between regimes I and II. This has been linked to a contribution to the mobile oxygen species coming from air humidity, a feature observed in ionic systems based on hydrogen mobility [START_REF] Tan | Magneto-ionic control of magnetism using a solid-state proton pump[END_REF]. A sample annealed at 350 • C (half open squares) for one hour was also investigated under G V =-2 V. These annealing conditions are known to induce the formation of crystallized grains in CoFeB/MgO stacks, where the MgO layer acts as a crystallization template [START_REF] Yuasa | Characterization of growth and crystallization processes in CoFeBMgOCoFeB magnetic tunnel junction structure by reflective high-energy electron diffraction[END_REF][START_REF] Wang | Insitu characterization of rapid crystallization of amorphous CoFeB electrodes in CoFeB/MgO/CoFeB junctions during thermal annealing[END_REF], and the migration of B towards the Ta substrate [START_REF] Sinha | Influence of boron diffusion on the perpendicular magnetic anisotropy in ta/cofeb/mgo ultrathin films[END_REF]. In CoFeB/HfO 2 , a similar behaviour could be tentatively proposed, where B diffusion [START_REF] Vermeulen | Perpendicular magnetic anisotropy of cofeb/ta bilayers on ald hfo2[END_REF] and the formation of crystalline grains would have an impact in ionic mobility. Fig. 3 shows that annealing has an impact in ionic dynamics in this system, regime I is slower than in the as-grown sample while regime II is significantly slower with respect to all other samples investigated. As mentioned earlier, the chemical environment of the mobile oxygen species at their anchoring points in the CoFeB layer is likely to be non equivalent in regimes I and II. An already slower regime II further reducing its velocity in crystallized samples may be an indication that ions in this regime do not only occupy binding sites at the already oxygen rich interface but that they could also penetrate into the layer. In this context, the crystalline structure of the CoFeB grains could hinder the diffusion of ions inside the layer with respect to the amorphous case, significantly reducing the speed and efficiency of the incorporation of oxygen species. However, a detailed study of the impact of annealing on the crystalline structure of Ta/CoFeB/HfO 2 is needed to fully understand the changes observed in the magneto-ionic behaviour. Regimes I and II do not only show two distinct speeds of the magneto-ionic process but they also show different reversibility behaviors. The reversibility of the effects of a gate voltage of -2 V has been tested with positive gate voltages going up to +4 V in regimes I and II of asgrown samples. Higher voltages have not been applied due to the electrochemical limitations of the ionic liquid [START_REF] Seidemann | Iontronics -Field effect study of different devices, using techniques of ionic liquid gating[END_REF]. The effects of the application of +4 V for 10 minutes and up to one hour to a magnetic state close to PMA in regime I are shown in Fig. 4 (a), where only minor changes are induced in the magnetic state. The same effect is found for other intermediate states in regime I and also for the fully perpendicular state, positive gate voltages up to +4 V and long exposures can not induce a recovery of the initial under oxidized state. Regime II shows an entirely different behaviour; a fully reversible transition between IPA and PMA can be observed. The ten cycles show a switching of the remanence between nearly 0 % (IPA) and 100 % (PMA) under gate voltages of -2 V and +4V, respectively. It is interesting to notice that in the first cycle, the PMA → IPA transition is induced by the application of -2 V for 1200 s, while for all subsequent cycles a shorter time of 240 s is required for this transition to occur. For the IPA → PMA transition an exposure time of 600 s has been found to be sufficient for all cycles. This shows that the magneto-ionic process most likely undergoes a first 'activation' phase in which the first diffusion of ions involves an additional energy barrier. This could be related to the energy cost of a first detachment of the ions from their original anchoring points as well as to the formation of ionic conduction channels in the CoFeB layer, after which the ions can be moved reversibly by using significantly lower exposure times.

Regime I is therefore showing a relatively faster dynamics than in regime II under G V =-2 V and a highly suppressed reversibility at G V =+4 V, while in regime II, a slower dynamics and full reversibility are observed. This may be linked to a high degree of stability of the final position of the ions within regime I, which would create a high energy barrier for the inverse process, suppressing reversibility under a gate voltage of +4 V. In regime II, although the energy barrier remains asymmetric between the PMA → IPA and PMA←IPA transitions, a gate voltage of +4 V is sufficient to revert the effects of a gate voltage of -2 V. This could be linked to a weaker anchoring of the mobile oxygen species in regime II.

III. EFFECTIVE DAMPING PARAMETER

In this section, we will discuss the impact of magnetoionics on the effective damping parameter α eff . A series of samples, exposed to gate voltages -2 V and -1.5 V, has been investigated by Brillouin light scattering (BLS) in the Damon-Eshbach geometry after removal of the IL gate. The in-plane magnetic field dependence of the average frequency of the Stokes and anti-Stokes spin-wave frequencies was measured at a wavenumber k =8.08 µm -1 . Fig. 5(a) shows this dependence for the as-grown sample (black circles) and for samples exposed to G V =-2 V for 45 s (underoxidized, green circles), 360 s (PMA, red circles) and 2700 s (overoxidized, cyan circles). A theoretical modelling of this dependence has been performed according to [START_REF] Belmeguenai | Interfacial Dzyaloshinskii-Moriya interaction in perpendicularly magnetized Pt/Co/AlO x ultrathin films measured by Brillouin light spectroscopy[END_REF] resulting in the fitting lines shown in Fig. 5(a). From this fitting, the values of the effective magnetisation M eff = s -H k have been obtained, where M s and H k are the saturation magnetisation and the anisotropy field, respectively. Fig. 5(b) shows the corresponding plots of the BLS frequency full linewidth (∆F ) as a function of the magnetic field applied in the plane of the sample and the corresponding fitting lines to: ∆F = 2α eff (γ/2π)H + ∆F 0 , where α eff can be extracted from the slope. The dependence of α eff on exposure time to a gate voltage of -2 V (black squares) and -1.5 V (yellow squares) is presented in Fig. 5(c), where the inset shows also the dependence on µ 0 M eff . In regime I, the value of α eff rapidly decreases from 0.029 for the as-grown sample to 0.012 for the PMA state. As shown earlier, the change from G V =-2 V to G V =-1.5 V critically decreases the speed of the process. In regime II, a relatively small increase in α eff to 0.014 is observed, however, it does not show to have a marked dependence on the exposure time. This difference between regimes I and II is also expressed in the α eff vs. µ 0 M eff depen-FIG. 5. (a) BLS average frequency and (b) linewidth as a function of magnetic field for an as-grown (black circles) sample, and for samples exposed to GV =-2 V for 45 s (green circles), 350 s (red circles) and 2700 s (cyan circles), and the corresponding fitting lines. (c) α eff dependence on exposure time to GV =-2 V (black squares) and GV =-1.5 V (yellow squares) and on µ0M eff (inset). Lines are a guide to the eye.

dence, where a monotonic decrease is seen in regime I, in contrast with the much less pronounced increase seen for regime II in a similar µ 0 M eff range. It is important to mention that the values of α eff obtained from the slopes of the data points in Fig. 5(b) contain not only the intrinsic contribution from the Gilbert damping parameter but also an extrinsic contribution. This extrinsic contribution can be associated with a variety of sources including spin pumping [START_REF] Nakayama | Geometry dependence on inverse spin Hall effect induced by spin pumping in Ni81Fe19/Pt films[END_REF][START_REF] Belmeguenai | Ferromagneticresonance-induced spin pumping in Co20Fe60B20 /Pt systems: damping investigation[END_REF][START_REF] Belmeguenai | Exchange stiffness and damping constants in diluted CoxFeyB1-x-y thin films[END_REF], due to the proximity with a heavy metal with high spin-orbit coupling, two-magnon scattering [START_REF] Kuanr | Extrinsic contribution to Gilbert damping in sputtered NiFe films by ferromagnetic resonance[END_REF] or the existence of sample inhomogeneities such as a distribution of anisotropy values across the sample [START_REF] Capua | Determination of intrinsic damping of perpendicularly magnetized ultrathin films from time-resolved precessional magnetization measurements[END_REF][START_REF] Diez | Enhancement of the Dzyaloshinskii-Moriya interaction and domain wall velocity through interface intermixing in Ta/CoFeB/MgO[END_REF]. The extrinsic contribution can add a relatively small factor to the value of the Gilbert damping or in more extreme cases it can dominate the ∆F vs H dependence resulting in the loss of linearity [START_REF] Capua | Determination of intrinsic damping of perpendicularly magnetized ultrathin films from time-resolved precessional magnetization measurements[END_REF][START_REF] Diez | Enhancement of the Dzyaloshinskii-Moriya interaction and domain wall velocity through interface intermixing in Ta/CoFeB/MgO[END_REF]. The damping parameter in CoFeB has been shown to depend on the oxidation level at the interface. In CoFeB/Gd/MgO stacks, the thin Gd layer serving as an oxygen sink has been shown to modulate the level of oxidation of an overoxidized CoFeB. In this system, α eff shows a non-monotonic dependence on the thickness of the Gd layer where a minimum is reached for 0.6 nm [START_REF] Yang | Effect of oxygen migration on magnetic anisotropy and damping constant in perpendicular Ta/CoFeB/Gd/MgO/Ta multilayers[END_REF]. However, this has been linked mostly to changes in the degree of homogeneity and quality of the interface. As mentioned, the proximity and quality of the interface with a high spin orbit coupling material has been shown to induce a spin-pumping contribution to the effective damping which shows as an inverse proportionality between α eff and the thickness of the magnetic film [START_REF] Ikeda | A perpendicular-anisotropy CoFeBMgO magnetic tunnel junction[END_REF][START_REF] Benguettat-El Mokhtari | Interface phenomena in ferromagnet/TaOx-based systems: Damping, perpendicular magnetic anisotropy, and Dzyaloshinskii-Moriya interaction[END_REF]. This additional damping contribution has been quantified for Ta by comparing symmetric MgO/CoFeB/MgO and Ta/CoFeB/Ta stacks to asymmetric Ta/CoFeB/MgO, where the Ta contribution dominates over the MgO contribution [START_REF] Iihama | Gilbert damping constants of Ta/CoFeB/MgO(Ta) thin films measured by optical detection of precessional magnetization dynamics[END_REF]. This has also been shown in the case of Hf/CoFeB/MgO stacks, which show for a CoFeB thickness of 1.08 nm, α eff values that are higher than in MgO/CoFeB/MgO stacks by about a factor of five [START_REF] Lourembam | Thickness-Dependent Perpendicular Magnetic Anisotropy and Gilbert Damping in Hf / Co20Fe60B20/MgO Heterostructures[END_REF]. Taking into account these considerations, it can be concluded that in the present case the underoxidized samples could have a significantly larger contact surface with Hf in HfO 2 than in the optimally oxidised case. A progression in regime I toward PMA could therefore decrease the contact surface with Hf and significantly reduce the associated spin pumping contribution to α eff . Interestingly, the changes in α eff are minor in regime II, which supports the idea mentioned earlier that in this regime oxygen species may migrate mostly into the layer rather than binding at the already optimally oxidized interface reached after regime I. This is considered as the main contribution to the observed variations in α eff , however, a reordering of the interface structure throughout regime I is also a likely scenario. A sharper interface may be reached at the end of regime I, also leading to the highest PMA state, which could also play a role in the observed reduction of α eff .

IV. DISCUSSION

The proposed magneto-ionic mechanisms involved in regimes I and II are depicted in Fig. 6. For G V < 0, mobile oxygen species inside HfO 2 , represented as green dots, migrate toward the CoFeB layer and after G V is switched off (b), they remain bound to the CoFeB, achieving an optimum surface coverage and completing the IPA → PMA transition at the end of regime I. If G V < 0 continues to be applied, the magneto-ionic mechanism will move into regime II. After the voltage is switched off (c), the incorporated oxygen species will contribute to the PMA → IPA transition. As the starting point of regime II is an optimally oxidized CoFeB surface, oxygen species incorporated in regime II will be less likely to bind at the same binding sites available in regime I and can potentially penetrate further into the layer (light green dots). Under high enough positive gate voltages, mobile oxygen species are expected to migrate back to the top electrode (d). However, for the same applied G V > 0, reversibility is highly suppressed for oxygen species incorporated in regime I ((b) and (e)), while full reversibility is achieved in regime II ((c) and (f)). This discrepancy in the degree of reversibility of regimes I and II is attributed to the differences in the binding sites, and the associated anchoring strength, of the oxygen species incorporated in each regime. The difference in chemical environment for these two types of binding sites is proposed as the origin of magneto-ionic regimes I and II. A preferential occupation of a limited number of binding sites at the CoFeB/HfO 2 interface in regime I could also explain the observed larger impact of ionic migration on the value of α eff with respect to regime II. As mentioned, the effects observed may be due to a decoupling of the CoFeB surface from the Hf atoms in HfO 2 , mostly linked to ion incorporation at the surface of an underoxidized CoFeB rather than to ionic migration into the layer in regime II. This is valid in a scenario where ionic migration into the layer is limited to the vicinity of the CoFeB/HfO 2 interface and does not extend up to the Ta/CoFeB interface as seen in other systems where higher gate voltages are applied [START_REF] Herrera Diez | Nonvolatile Ionic Modification of the Dzyaloshinskii-Moriya Interaction[END_REF]. It could be anticipated that ionic migration up to the Ta/CoFeB interface could induce a significant decoupling from the Ta layer, an effect observed in Pt/Co reflected as a reduction of the DMI [START_REF] Herrera Diez | Nonvolatile Ionic Modification of the Dzyaloshinskii-Moriya Interaction[END_REF], resulting in a further reduction of α eff . Another important indication supporting the proposed mechanism is found in the measurements done on crystallized samples. In this case, the time evolution of magnetic anisotropy under a negative gate voltage is strikingly reduced in regime II compared to regime I. This could be due to an increased difficulty of ionic diffusion into a crystallized CoFeB layer in regime II, compared to ionic incorporation at the surface in regime I. Surface and bulk components to the magneto-ionic effect have already been introduced in the literature, in particular, in Pd/Co/GdO x and Pt/Co/HfO 2 films, where ion migration deep down into the magnetic layer and beyond can cause partial or total irreversibility [START_REF] Herrera Diez | Nonvolatile Ionic Modification of the Dzyaloshinskii-Moriya Interaction[END_REF][START_REF] Gilbert | Structural and magnetic depth profiles of magneto-ionic heterostructures beyond the interface limit[END_REF]. As mentioned, in the present case the bulk component is thought to be limited only to the vicinity of the CoFeB/HfO 2 interface. The observed suppressed reversibility seen in regime I happens at low oxygen content, ruling out the anchoring of the oxygen species deep into the layer as a potential source of irreversibility. This is also well supported by the subsequent observation of regime II, exhibiting full reversibility, in the overoxidized state. In this context, studies in the literature addressing the incorporation of oxygen species from the gas phase into crystalline Co and Fe systems provide an interesting perspective. In Co, the profile of the oxygen intake as a function of oxygen pressure has a distinct change in slope that is related to a two stage oxidation process. The first step involves the formation of CoO up to a defined surface coverage threshold, after which a higher oxygen and high temperature exposure leads to the formation of Co 3 O 4 [START_REF] Bridge | Oxygen chemisorption, surface oxidation, and the oxidation of carbon monoxide on cobalt (0001)[END_REF]. In Fe crystals, a similar behaviour has been observed at room temperature. The oxygen sticking coefficient as a function of surface coverage is seen to decrease drastically up to a coverage of 0.5, where an inflection point occurs followed by a less pronounced decrease. The initial phase of rapid decrease has been linked to the filling of preferential empty binding sites, while additional oxygen incorporation leads to the inflection point identified as the onset of oxide growth. The oxygen incorporation is proposed to entail a progression from initially adsorbed oxygen species to the nucleation and expansion of a two dimensional layer of FeO at the sticking coefficient inflection point, where it remains fairly constant until the completion of the FeO layer formation. Further oxygen incorporation happens in the presence of FeO, which is responsible for the observation of a reduction in the sticking coefficient after the inflection point. This last process ultimately leads to the formation of Fe 2 O 3 / Fe 3 0 4 together with the appearance of a three dimensional oxide structure [START_REF] Brundle | Oxygen adsorption and thin oxide formation at iron surfaces: An XPS/UPS study[END_REF][START_REF] Simmons | A LEED-AES study of the initial stages of oxidation of Fe (001)[END_REF]. In amorphous systems, the distinction between the well defined oxide phases present in crystalline systems could be less evident, however, a distinction between purely surface incorporation and a subsequent oxygen intake more extended into the magnetic layer could be evidenced. The films used in this study are Fe rich, with a composition of Co 20 Fe 60 B 20 , where variations of the Fe content at the interface with an oxide have been shown to drive large PMA variations [START_REF] Herrera Diez | Controlling magnetic domain wall motion in the creep regime in He + -irradiated CoFeB/MgO films with perpendicular anisotropy[END_REF]. It is therefore worth considering a scenario where the formation of different Fe oxide types is at the origin of regimes I and II. Regime I is likely to reflect the initial oxygen adsorption and formation of FeO, which involves a change in valence from Fe 0 to Fe 2+ . A significantly high energy barrier is therefore introduced for the inverse process which would largely suppress reversibility under a low energy stimulus. On the other hand, the full completion of a two dimensional FeO layer could well lead to an optimum and homogeneous oxidation at the interface, allowing for the highest PMA values observable in this system. As mentioned, further oxygen incorporation in the presence of FeO becomes less favourable, which is in line with the observed slower dynamics seen in regime II. The Fe 2 O 3 / Fe 3 O 4 oxide phase involves a mixture of Fe 2+ and Fe 3+ states, therefore it can be proposed that the path toward a Fe 2+ → Fe 3+ transition involves the progressive addition of oxygen species to the chemical environment of the Fe 2+ centres. This phase is thought to describe regime II, where a relatively low energy barrier is involved in the inverse process due to the conservation of the Fe 2+ valence state. An ultimate change to Fe 3+ would also be expected to introduce a large energy barrier for the inverse process and hinder reversibility, as seen in regime I. This is well in line with the observed behaviour under G V = -3 V (120 s exposure time), where the system enters an irreversible IPA overoxidized state.

V. CONCLUSION

In conclusion, we have shown the existence of two distinct nonvolatile magneto-ionic regimes in Ta/CoFeB/HfO 2 stacks where oxygen species migrate under negative/positive gate voltages toward/away from the CoFeB layer. This voltage driven ionic motion induces first an IPA → PMA transition in regime I, corresponding to a transition from an underoxidized to an optimally oxidized state. In regime II, a PMA → IPA transition occurs and it is correlated to a transition from an optimally oxidized to an overoxidized state. Regime I shows a much faster dynamics and highly suppressed reversibility for positive gate voltages with respect to regime II. In addition, it also shows a marked decrease of the effective damping parameter from 0.029 to 0.012 compared to the relatively small increase to 0.014 observed in regime II. The existence of regimes I and II is proposed to be the result of a difference in the binding strength of the migrated oxygen species, that can be correlated with different binding sites on the surface and inside the CoFeB layer, respectively. The results presented here reveal the complexity of magneto-ionics and the importance of a deep understanding of the ionic mechanisms involved in order to design robust and reliable devices for spintronics applications. This system could be easily transferred to a solid state device where the two regimes could be probed at higher gate voltages in order to re-evaluate reversibility and explore fast operation times. This will allow to choose an IPA to PMA transition, either in regime I or II, that best fits the requirements for practical applications and to design strategies to favour operation in one of the two magneto-ionic regimes.

FIG. 1 .

 1 FIG. 1. Graphic representation of the magneto-ionic stack covered with the ionic liquid [EMI] + [TFSI] -gate. The gate voltage induces the motion of oxygen species in HfO2.

  Fig.3 (a)shows the time dependence of the out-ofplane remanence percentage, where 100% corresponds to the Hall voltage at zero applied magnetic field in the PMA state, for the entire anisotropy rang going from the initial underoxidized IPA state through regime I (positive slope), PMA (the point of highest remanence), and regime II (negative slope) to finish in an overoxidized IPA state. As-grown samples have been investigated under three different constant gate voltages of G V =-2.3 V (circles), G V =-2 V (squares), and G V =-1.7 V (triangles). The speed of the entire process critically increases for higher gate voltages, responding to a stronger driving force for ionic motion. For all applied gate voltages, the magneto-ionic process in regime I is significantly faster than in regime II. This difference in the time evolution as a function of gate voltage between regime I and II could be linked to a difference in the chemical environment, and thus of anchoring, of the oxygen species interacting with the CoFeB layer in regimes I and II. In regime I, the energy barrier associated with adding oxygen species to the underoxidized CoFeB interface may be lower than in regime II, where oxygen species have to be added to an already optimally oxidized CoFeB interface. Measurements were also conducted using underoxidized samples that were annealed before applying a gate voltage of -2 V, these measurements are presented in Fig.3 (b). An underoxidized sample was annealed at 180 • C

FIG. 4 .

 4 FIG. 4. (a) Suppressed reversibility of the IPA → PMA transition under GV =+4 V in regime I. (b) Hysteresis loops for the reversible PMA → IPA cycles 1 (solid line) and 10 (dotted line) in regime II. (c) Remanence as a function of the reversibility cycle number in regime II.

Fig. 4 (

 4 b) shows the Hall voltage hysteresis loops corresponding to reversibility cycles number 1 and 10, while Fig.4(c) shows the remanence variation of the entire series.

t = 0 MFIG. 6 .

 06 FIG.6. Proposed magneto-ionic mechanisms for regimes I and II. (a) For GV < 0 oxygen species migrate toward the CoFeB layer achieving an optimum surface coverage and PMA at the end of regime I (b). If GV < 0 continues to be applied, oxygen species will continue to be incorporated into the CoFeB layer in regime II (c) resulting in IPA. Under GV > 0 mobile oxygen species can migrate back to the top electrode (d). For the same applied GV , there is no reversibility in regime I ((b) and (e)), while full reversibility is achieved in regime II ((c) and (f)).

ACKNOWLEDGMENTS

We gratefully acknowledge financial support from the European Union H2020 Program (MSCA ITN grant No. 860060), from the French National Research Agency (project ELECSPIN), and the program PHC Sakura. This work was in part supported by JSPS KAKENHI Grant Number 20H05304.