Keywords:

Purpose: Artificial urinary sphincter is the reference treatment for stress urinary incontinence in men, but it remains rarely used in women. This study aimed to compare long-term device survival between women and men, after the first implantation of an AMS 800 TM artificial urinary sphincter (Boston Scientific, USA) for the treatment of a non-neurogenic stress urinary incontinence.

Materials and methods: This retrospective cohort study included all patients with nonneurogenic stress urinary incontinence who underwent surgery in a large-volume university hospital between 2000 and 2013. The primary outcome was the overall survival of the device, defined as the absence of any repeated surgery (revision or explantation) during follow-up.

Men and women were matched 3:1 according to age and year of implantation. Differences were analyzed using a Cox model accounting for matching and applying time intervals because hazards were not proportional over time. Sensitivity analyzes were performed, excluding firstly population with history of radiotherapy and secondly population with more than one previous surgery for urinary incontinence.

Results: A total of 107 women were matched to 316 men. Median follow-up was 6.0 years (Q1-Q3 1.8 -9.4): 7.0 years (Q1-Q3 3.1 -10.3) for women and 5.1 years (Q1-Q3 1.3 -9.1) for men. During the follow-up, 56 patients had an explantation of the device: 44 men (13.9%) and 12 women (11.2%) and 113 had a revision: 85 men (26.9%) and 28 women (26.1%). Men have a significantly higher risk of explantation or revision than women between 6 months and 8 years after implantation (HR 2.12 (1.29-3.48)). Before 6 months and after 8 years, there were not significant differences. Both sensitivity analyses found consistent results.

Conclusions: This study suggests that device survival seems better in women after the first 6 months.

Introduction

The first artificial urinary sphincters (AUS) were implanted in 1973 by F. Scott [START_REF] Scott | Treatment of urinary incontinence by implantable prosthetic sphincter[END_REF]. Ten years later, after design modification and improvement, current AUS have been introduced [START_REF] Fishman | Experience with the Artificial Urinary Sphincter Model AS800 in 148 Patients[END_REF].

Nowadays, the AMS 800 TM AUS (Boston Scientific, Marlborough, Massachusetts, MA, USA) is the mostly used device to treat severe stress urinary incontinence (SUI) in men [START_REF] Moening | AMS800 TM[END_REF][START_REF] Herschorn | Surgical treatment of stress incontinence in men[END_REF][START_REF] Suh | Long-term outcomes of primary implantation and revisions of artificial urinary sphincter in men with stress urinary incontinence[END_REF].

Worldwide, AUS is the gold standard treatment for post prostatectomy incontinence [START_REF] Sandhu | Incontinence after Prostate Treatment: AUA/SUFU Guideline[END_REF][START_REF] Van Der Aa | The Artificial Urinary Sphincter After a Quarter of a Century: A Critical Systematic Review of Its Use in Male Non-neurogenic Incontinence[END_REF]. In Europe, it is also used in women to treat intrinsic sphincter deficiency due to reduced urethral/bladder outlet resistance [START_REF]Instructions For Use[END_REF]. European guidelines recommend AUS in women when UI is not corrected by clinical support maneuvers or previous support surgery [START_REF]Guidelines on Urinary Incontinence[END_REF][START_REF] Kowalik | Surgery for female SUI: The ICI algorithm[END_REF].

In both men and women, studies and reviews show an objective reduction of leaking with a significant improvement of quality of life at the mid and long term, despite occurrence of possible complications [START_REF] Buckley | The effect of urinary incontinence on health utility and health-related quality of life in men following prostate surgery: Urinary Incontinence and QoL After Prostate Surgery[END_REF][START_REF] Tutolo | Efficacy and safety of artificial urinary sphincter (AUS): Results of a large multi-institutional cohort of patients with mid-term follow-up[END_REF][START_REF] Peyronnet | AMS-800 Artificial urinary sphincter in female patients with stress urinary incontinence: A systematic review[END_REF][START_REF] Reus | Performance and Safety of the Artificial Urinary Sphincter (AMS 800) for Non-neurogenic Women with Urinary Incontinence Secondary to Intrinsic Sphincter Deficiency: A Systematic Review[END_REF][START_REF] Costa | Long-Term Results of Artificial Urinary Sphincter for Women with Type III Stress Urinary Incontinence[END_REF]. The main complications reported are infections, urethral erosions, and dysfunction of the device. In men, long-term survival studies report revision rates for mechanical failure from 2 to 14%, explantation rates for infection or erosion from 3 to 28% and reintervention rates for any reason from 15 to 45% [START_REF] Van Der Aa | The Artificial Urinary Sphincter After a Quarter of a Century: A Critical Systematic Review of Its Use in Male Non-neurogenic Incontinence[END_REF]. For women, the largest systematic review reports revisions rates from 6 to 44% and explantation rates from 2 to 27% [START_REF] Reus | Performance and Safety of the Artificial Urinary Sphincter (AMS 800) for Non-neurogenic Women with Urinary Incontinence Secondary to Intrinsic Sphincter Deficiency: A Systematic Review[END_REF]. Thus, according to the literature, complication rates seem in the same range in men and women, even if studies directly comparing AUS performance in men and women are limited [START_REF] Petero | Comparison of the Long-Term Outcomes Between Incontinent Men and Women Treated With Artificial Urinary Sphincter[END_REF].

The use of AUS for both incontinent men and women in our large-volume center provides the opportunity to compare AUS performance between both sexes.

The aim of our study is to compare AMS 800 TM long-term survival after a first implantation for non-neurogenic stress UI in men and women.

Materials and Methods

1) Study design and population

This study is a retrospective single-center study, led on a cohort of consecutive patients with a first implantation of an AMS 800™ artificial urinary sphincter (Boston Scientific, Marlborough, Massachusetts, MA, USA) between January 2000 and December 2013 for the treatment of SUI. Patients less than 18 years old at the time of implantation and AUS placement for urinary incontinence secondary to neurogenic bladder were excluded.

2) Description of the procedure

The implantation process of the AUS was standardized as recommended by the operating room manual edited by the manufacturer (3). Only experimented surgeons (more than 10 procedures) underwent the procedure.

For men, the cuff was placed around the bulbous urethra using the perineal approach.

For women, the cuff was placed around the bladder neck thanks to a suprapubic incision.

The device system was left deactivated for four to six weeks following implantation.

3) Data collection

The following data were collected from the medical file of each patient:

-Clinical characteristics: sex and age of the patient at implantation, etiology of urinary incontinence, history of previous incontinence surgery and radiotherapy.

-Intervention characteristics: date of intervention, size of the cuff and pressure regulation balloon.

-Outcomes: revision or explantation including the date. Outcomes data were extracted from follow-up visits in the medical file and from our internal AUS registry. We also contact our patients via phone or mail to update patient and device outcomes when needed.

4) Outcome

Our primary outcome is the overall survival of the device, defined by the absence of any repeated surgery (revision or explantation) during the follow-up after surgery. Explantation was performed for erosion or infection, but also sometimes for other causes as patient convenience. Revisions were performed for recurrence of urinary incontinence or a mechanical failure of the device (due to urethral atrophy, pump malpositioning or device dysfunction) and included complete and partial revisions of the device (i.e. revision of only one part of the device).

The secondary outcomes were survival of the device without explantation or revision considered separately.

The last follow-up was determined by the last date we were able to have news of the patient.

It was either an office visit or a phone call.

5) Statistical analysis

Our objective was to compare long-term device survival between men and women after a first implantation of AMS800 TM . We matched 1:3 women to men on age (+/-5 years) and year of implantation (+/-3 years). General and intervention characteristics were described by frequencies and percentages for qualitative variables and by mean +/-SD or median (Q1-Q3)

as appropriate for quantitative variables. The Kaplan-Meier method was used to describe device survival, from the first implantation to subsequent revision for any reason, device explantation or end of follow-up (date of last visit). Patients without event were censored at the date of the last follow-up. Differences between men and women were analyzed using a Cox model accounting for matching. Because hazards were not proportional over time, we used an analysis by intervals considering three time intervals: short term (ie, within 6 months), medium term (after 6 months to 8 years) and long term (after 8 years). These intervals were fixed at the beginning of statistical analysis by plotting standardized Schoenfeld residuals and were not modified thereafter. Sensitivity analyzes were performed to verify the stability of the results excluding patients with radiotherapy (as it is more frequent in men) and patients with 2 or more previous urinary surgical procedures (as it is more frequent in women). P values < 0.05 were considered to be statistically significant. All analyses were performed using R software (version 3.6.2) (17) [START_REF] Core | R: A language and environment for statistical computing[END_REF].

6) Ethics

The study was registered at the Commission Nationale de l'Informatique et des Libertés (CNIL)

under the number 20201112133406 and approved by the French urology association ethics committee under number CERU_2021/11. Patients were informed of the potential use of their data for research purpose and of the possibility to refuse the use of their personal data.

Results

1) Study population

There were 1076 consecutive patients with an AUS surgery in our urology department; 514 were excluded: 53 for neurogenic bladder and 461 for repeat AUS surgery. Thereby, 562

patients were eligible for this study: 420 men and 142 women (Appendix). Among them, 316 men have been matched with 107 women for a total of 423 patients (Figure 1).

2) Description of the procedure and patient clinical characteristics

In the matched cohort, mean age at implantation was 67.2 years old (SD 7.37) for men and 66.2 years old for women (Standard deviation SD 8.37). Main indications for AUS implantation were post-prostatectomy incontinence (n= 271, 85.8%) in men, and intrinsic sphincter deficiency incontinence (n= 88, 82.2%) in women. Eighty-seven (27.5%) men had a history of radiotherapy, whereas no women had. Ninety-four women (87.5%) had a previous history of incontinence related-surgery, with 48 women (44.8%) having 2 or more previous surgeries, compared to 44 men (13.9%) (Table 1).

The median cuff size for men was 4.5 cm (Q1-Q3 4.0-4.5), 279 men (88%) had a cuff of 4 or 4.5 cm. The median cuff size for women was 7.0 cm (Q1-Q3 6.5-7.5), 75 women (71%) had a cuff between 7 and 8 cm. For women, only 61-70cmH20 pressure regulation balloon (PRB) was used. For men, PRB used were 61-70 cmH20 in 66% (208/316) and 51-60 cmH2O in 23%

(74/316), with missing data in 11% (34/316).

There was no operative mortality. Three women and two men were re-operated before activation for an explantation because of erosion. A man had an early revision. All other devices were activated 4 to 6 weeks after surgery.

3) Outcomes

Median follow up was 6.0 years (Q1-Q3 1.8 -9.4): 7.0 years (Q1-Q3 3.1 -10.3) for women and 5.1 years (Q1-Q3 1.3 -9.1) for men. During the follow-up, 56 patients had an explantation of the device: 44 men (13.9%) and 12 women (11.2%) and 113 had a revision: 85 men (26.9%) and 28 women (26.1%) (Table 2). There was no difference in terms of explantation or revision between women with zero or one previous IU surgery (n=22 events, 37.2%), compared to women with two or more IU surgeries (n =18 events, 37.5%). At the end of the follow up, 57% of men and 60% of women had neither explantation nor revision.

Men have a significantly higher risk of explantation or revision of the device than women between 6 months and 8 years (HR 2.12 (1.29-3.48), p=0. 00274). There was no statistically difference within the 6 first months (HR 1.51 (0.49-4.65), p=0.47) and after 8 years (HR 0.78 (0.43-1.40), p=0.39) (Figure 2). Both sensitivity analyses, without patients with radiotherapy and without patients operated for more than one surgery, found consistent results.

Concerning explantations, there were 4 explantations in women (3.7%) compared to 8 in men (2.5%) during the first six months, with no significant higher risk in term of survival (HR 0.70 (0.21-2.41), p=0.58). Between 6 months and 8 years, there was a higher risk of explantation in men (HR 4.52 (1.35-15.09), p=0.0142). There was no significant difference after 8 years (HR 0.37 (0.09-1.48), p=0.16).

Concerning revisions, women have a significantly lower risk of revision than men in the short term with no revision during the first six months versus 13 revisions in men (HR 1,47 x 10 7 (7,61 x 10 6 -2,83 x 10 7 ), p <0.001). There was no significant difference between six months and 8 years (HR 1,43 (0,83-2,48), p=0,20) and after 8 years (HR 0,98 (0,49-1,97), p=0,95).

Discussion

This study was intended to compare long-term artificial urinary sphincter survival between men and women implanted with a first AUS for a non-neurogenic SUI. We found a significantly lower rate of explantation or revision at the mid term (6 months -8 years) for women while there was no significant difference during the short and long-term follow-up between men and women. Both sensitivity analyses, without patients with radiotherapy and without patients operated for more than one surgery, found consistent results. To our knowledge, this is the largest cohort focusing on device survival with a long-term follow-up to date.

In contrast to what is usually thought, AUS device seems to have a better long-term survival in women than in men, which is consistent with the study by Petero and al. published in 2006 (16). However, our study has some limits. One important limit shared with other studies comparing AUS survival between men and women is that the two populations are not comparable because of different surgical procedures and different medical histories. We matched men and women on age and year of implantation to make these populations more comparable and also conducted sensitivity analyzes based on the main differences between the two populations related to risk factors of complications in AUS surgery. Another limit in our study is the lack of information about anastomosis strictures history. As all the urologists in the department did not systematically require a specific cystoscopy, it was not possible to report it objectively. We also miss data about general comorbidities and quality of life. Indeed, this was a retrospective study and data on immediate satisfaction after implantation or quality of life during the follow-up were not available for many patients.

AUS long-term complications rate reported in the literature seems in the same range in men and women. Van der Aa and al. ( 7) reported, a revision rate for mechanical failure from 2 to 14% and for urethral atrophy from 2 to 30%. Also, he reported an explantation rate for infection or erosion from 3 to 28% and a reintervention rate for any reason from 15 to 45% in men. For women, Reus and al. [START_REF] Reus | Performance and Safety of the Artificial Urinary Sphincter (AMS 800) for Non-neurogenic Women with Urinary Incontinence Secondary to Intrinsic Sphincter Deficiency: A Systematic Review[END_REF] found revisions rates from 6 to 44% and explantation rates from 2 to 27%.

The good AUS survival in women can be explained by several factors. First, the cuff is larger in women because implanted around bladder neck whereas the device is implanted around bulbous urethra in men. Moreover, the intra-abdominal bladder neck position of the cuff in women allows a transmission of abdominal pressure on the cuff. That position seems to be associated with a better efficiency of the device and thereby less revision for recurrence of urinary incontinence [START_REF] Richard | Recommandations pour le traitement de l'incontinence urinaire féminine non neurologique par le sphincter artificiel urinaire[END_REF]. Finally, contrary to women's condition, bulbous urethra in men is more thin and vulnerable to trauma (sitting position) compared to the bladder neck that is thicker and intraabdominally protected. These technical factors may explain that there is less erosion and failure in women than in men.

The main reason for the low level of AUS implantation in women in the United States was related to a presumed high rate of explantation and erosion, compared to the easier surgery of pubovaginal slings. Indeed, it seems that there is more explantation in women than in men in the first six months, even if there is no significant difference. But, consistently with the study by Petero and al.( 16), long-term survival device seems globally better in women, especially in the mid-term. In our cohort, the bladder neck dissection challenge reported after past urinary incontinence surgery did not seem to be associated with an increased rate of complications compared to non-operated women. Moreover, contrarily to slings, there is a possibility to remove AUS and to implant a new one in case of failure or patient dissatisfaction. Also, the risk of erosion largely reported in men is low in women thanks to a larger cuff and a thicker urethra. All these elements suggest that the indication of AUS in women may be extended.

Finally, as reported by Chartier-Kastler and al., robot assisted laparoscopic surgery will decrease the technical difficulties encountered with the open dissection for deep pelvic surgery [START_REF] Chartier-Kastler | Robot-assisted laparoscopic artificial urinary sphincter insertion in women with stress urinary incontinence: a pilot single-centre study: Robotic artificial urinary sphincter implantation in female stress urinary incontinence[END_REF]. We believe that AUS may be a good option even in women with previous multiple pelvic dissections including failed sling procedure.

Conclusion

Our study gives a comprehensive assessment of long-term differences between men and women AUS results It suggests that long-term survival device is better in women at mid-term, despite a slightly higher rate of explantation (not statistically significant) in women in the first 6 months. Both sexes should benefit of this inflatable and active prosthesis for treatment of SUI. Medico-administrative databases may help to provide long-term data in a more exhaustive population of patients.

Tables and Figures

Figure 1 :Figure 2 :Figure 3 :Figure 4 :

 1234 Figure 1: Flow diagram showing enrollment and matching of men and women in a study comparing long-term device survival after a first implantation of AMS800 TM for stress urinary incontinence. (Adapted from CONSORT)

Table 1 :

 1 Characteristics of men and women after matching 3:1

			Men (n=316)	Women (n=107)
	Characteristics of the matched population	With explantation or revision	With no explantation or revision	With explantation or revision	With no explantation or revision
			N= 129	N= 187	N= 40	N=67
	Age (Mean +/-SD)		66.59 +/-6.72 67.56 +/-7.77	64.8 +/-9	67.11+/-7.91
	Indication	Post prostatectomy	106 (82.1)	165 (88.2)	0	0
	(n, %)	Gynecologic intrinsic sphincter deficiency	0	0	30 (75.0)	58 (86.6)
		Post TURP	20 (20.0)	19 (10.2)	0	0
		Post pelvic surgery
		(without	2 (1.55)	0	3 (7.5)	2 (2.99)
		prostatectomy)
		Post traumatic	1 (0.78)	2 (1.07)	7 (17.5)	7 (10.5)
		Post radiotherapy	0	1 (0.53)	0	0
		Radiotherapy	35 (27.1)	52 (27.8)	0	0
		No UI surgery	116 (90.0)	156 (83.4)	7 (17.5)	6 (9.0)
		1 UI surgery	11 (8.5)	25 (13.4)	15 (37.5)	31 (46.3)
	Medical history	2 or more UI surgery	2 (1.55)	6 (3.2)	18 (45.0)	30 (44.8)
		Slings	2 (1.6)	2 (1.1)	27 (67.5)	44 (65.7)
		Adjustable
		compressive therapy	11 (8.5)	21 (11.2)	4 (6.0)	5 (12.5)
		(ACT)
	Implantation	Less than 4cm	2 (1.6)	2 (1.07)	-	-
		4 cm	44 (34.1)	76 (40.6)	-	-
		4.5 cm	66 (51.2)	93 (49.7)	-	-
		Up than 4.5	13 (10.1)	12 (6.4)	-	-
		NA	4 (3.1)	4 (2.1)	-	-
	Size of cuff	Less than 6.5 cm	-	-	5 (12.5)	8 (11.9)
	(n,%)	6.5 cm	-	-	8 (20.0)	8 (11.9)
		7 cm	-	-	13 (32.5)	23 (34.3)
		7.5 cm	-	-	5 (12.5)	13 (19.4)
		8 cm	-	-	9 (22.5)	12 (17.9)
		Up than 8 cm	-	-	0	3 (4.5)

Table 2 .

 2 Survival of the device without revision or explantation in primary and sensitivity analyses according to the Kaplan-Meier method Kaplan-Meier curve for survival of the artificial urinary sphincter without revision or explantation Figure4: Kaplan-Meier curve for survival of the artificial urinary sphincter without revision.

	Men	Women

Table 1 :

 1 Characteristics of men and women after matching 3:1

Table 2 .

 2 Survival of the device without revision or explantation in primary and sensitivity analyses according to the Kaplan-Meier method Appendix: Characteristics of patients in the initial population before matching 3:1

Long-term device survival after a first implantation of AMS800 TM for stress urinary incontinence: Comparison between men and women


Scheifer Carole
email: carole.scheifer@aphp.fr

Elena Luckina

Lebrun-Vignes Bénédicte

Diop Abdoul-Aziz

Damais- Thabut Dominique

Damien Roos Weil

Dechartres Agnès

Lebray Pascal

Départment Carole Scheifer

Mixed Phenotype Acute Leukaemia (MPAL) 1 Acute Myeloid Leukaemia following Direct Acting Antiviral drugs in HCV-infected patients: a 10 years' retrospective single-center study

HCV), hematological malignancies (HM), anti-HCV Direct Acting Antivirals (DAA), Acute Myeloid Leukaemia (AML), Non-Hodgkin Lymphoma (NHL), Mixed Phenotype Acute Leukaemia (MPAL) 2

had Non-Hodgkin Lymphoma, 5 (24%) had an Acute Myeloid Leukaemia (AML) including two with a mixed phenotype, 2 each had Hodgkin Lymphoma, Multiple Myeloma or a myeloproliferative disorder and one each had a chronic Lymphocytic Leukaemia or AL Amyloidosis. In the Group DAA-, HM were NHL in 20(50%) patients, Myeloproliferative neoplasms in 7 (17%) , Multiple Myeloma in 5, Hodgkin Lymphoma in 3, Myelodysplastic syndrome and AML in 2 (5%) each and Acute Lymphoblastic Leukaemia in one. No significant difference between the groups DAA + andwas found according to age, sex, HCV genotype, viral load, co-infection or type and exposition of previous HCV treatments. AML, liver transplantation and cirrhosis were significantly more frequent in the DAA+ group (p = 0.020, 0.045 and 0.032, respectively).

Conclusion

AML seemed more frequent after using DAA treatments, notably in severe HCV patients including cirrhotic and/or liver transplanted patients. A multicentric observational study is ongoing to confirm and explore the results. The interferon-free direct antiviral agents (DAA), first used in 2011, have been a major milestone in the HCV infection treatment due to their efficacy including on severe cirrhosis or liver transplantation and their few side effects [START_REF] Perz | The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide[END_REF]. Since 2016, the World Health Organization recommends DAA as a first-line treatment without interferon for every chronic HCV infection [START_REF]Guidelines for the Screening Care and Treatment of Persons with Chronic Hepatitis C Infection: Updated Version[END_REF]. DAA related viral eradication may result in a decreased risk of HCV related B-cell lymphoma and possible regression of HCV related Non-Hodgkin Lymphoma (NHL) [START_REF] Spengler | Direct antiviral agents (DAAs) -A new age in the treatment of hepatitis C virus infection[END_REF][START_REF] Masarone | Hepatitis C virus infection and non-hepatocellular malignancies in the DAA era: A systematic review and meta-analysis[END_REF].

KEYWORDS

However, several studies have suggested an increased early occurrence or recurrence of hepatocellular carcinoma after DAA use, raising concerns about safety and oncogenicity [START_REF] Reig | Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy[END_REF][START_REF] Kuo | The influence of direct-acting antivirals in hepatitis C virus related hepatocellular carcinoma after curative treatment[END_REF]. Nonetheless, these new insights have not been confirmed by other studies including metaanalyses [START_REF] Waziry | Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and metaregression[END_REF]. Even though HCV infection and liver transplantation are known risk factors for hematological malignancies (HM), predominantly of the B-cell type [START_REF] Perz | The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide[END_REF][START_REF] Giordano | Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus[END_REF][START_REF] Nieters | Hepatitis C and risk of lymphoma: results of the European multicenter case-control study EPILYMPH[END_REF], some recent case studies suggest a possible increase in hematological disorders secondarily to DAA administration [START_REF] Naeim | Chapter 13 -Acute Leukaemias of Ambiguous Lineage[END_REF][START_REF] Samonakis | Aggressive recurrence of Non-Hodgkin's Lymphoma after successful clearance of hepatitis C virus with direct acting antivirals[END_REF][START_REF] Lin | Development of highly aggressive mantle cell lymphoma after sofosbuvir treatment of hepatitis C[END_REF][START_REF] Andrade | Primary Liver Diffuse Large B-Cell Lymphoma following Complete Response for Hepatitis C Infection after Direct Antiviral Therapy[END_REF][START_REF] De Santiago | HCV-positive lymphoma after sustained virological response with direct-acting antiviral agents: The game is not over after HCV eradication[END_REF], which is consistent with our own experience. This retrospective study aimed to identify and describe all cases of hematological malignancies (HM) in patients with chronic HCV infection in hematology or hepatology units in our hospital and to compare characteristics of patients according to the prescription of oral anti-HCV Direct 93 Acting Antivirals (DAA) treatment or not.

MATERIALS AND METHODS

STUDY DESIGN AND SETTING

This is a single-center retrospective observational study.

IDENTIFICATION OF RELEVANT PATIENTS

Every adult patient with a HM and a chronic hepatitis C infection managed between 01/01/2010 and 28/03/2019 in the hematology and/or hepatology departments of the Pitié-Salpêtrière hospital, in Paris, France was eligible. HM were defined according to WHO classifications. Chronic HCV infection was defined as an infection lasting for at least 6 months according to the hospital chart with at least one available HCV viral load. Patients were identified through the list of in-and outpatients managed in the hematology or in the hepatology departments. Non-inclusion criteria were HCV acute infection, benign hematological disorder and HM preceding HCV. In patients with a first HM, a minimal period of remission of 1 year before DAA administration was necessary to get included. Patients with a diagnosis of HM < 3 months following DAA initiation were also excluded. This arbitrarily limits the risk of including a patient with relapsing or subclinical HM at the initiation of DAA.

The retrospective analysis of anonymized data is allowed by French law and all the patients during their medical care were informed of their right to refuse that their data may be used for research purpose. Our study was locally registered according to the General Data Protection Regulation. All cases with a HM after a treatment using DAA were declared to the local pharmacovigilance centre. We evaluated whether eligible patients had received DAA and if so, we recorded the date of dispensation from the database provided by the Pitié-Salpêtrière pharmacy department.

Eligible patients were classified in 2 groups according to the sequence between DAA treatment and HM: Group DAA+ included patients who initiated their first DAA at least 3 months before HM diagnosis. Group DAA-included patients with no DAA before HM.

DATA EXTRACTION

The following detailed information was retrospectively collected from the medical charts of each patient:

-Socio-demographic data including sex and age -Characteristics of the HCV infection: genotype, viral load at time of MH diagnosis, HIV or HBV co-infection, severity of liver disease according to the combination of noninvasive tests (Fibroscan ® and/or Fibrotest ® ) or to a liver biopsy, hepatocellular carcinoma diagnosis.

-Date of liver transplantation if applicable -Past HCV treatments including interferon, pegylated interferon or ribavirin use, with date and duration for each and DAA treatments with the type of combo drugs (NS5B, NS5A and NS3A inhibitors).

-Risk factors for malignant hemopathy: hematological disease at risk, past exposure to chemoor radiotherapy, AIDS, solid organ transplantation or other immunosuppression.

-Hematological malignancy: type, date of diagnosis, time between the first administration of DAA and occurrence of the HM, duration of follow up after HM diagnosis, treatment including bone marrow transplantation, outcome (survival or death).

STATISTICAL ANALYSES

We compared baseline characteristics, types of HM and outcomes in consecutive HCV patients with a HM diagnosis according to previous DAA therapy or not. As the hepatology unit proposed many anti-HCV DAA protocols since 2011 and the patients could have been treated with two or more DAA lines, we decided not to make a comparison by periods to limit the risk of an analytic bias.

STATISTICAL METHODS

All statistical analyses were done using RStudio Version 1.0.153. (R Core Team (2020). Patient characteristics were described as numbers and percentages for categorical data and as medians with interquartile range (IQR) for quantitative variables. Quantitative variables were compared using the Wilcoxon-Mann-Whitney test; qualitative variables were compared by the Chi2 test or the Fisher's exact test as appropriate. Survival times since diagnosis of HM were compared between groups DAA+ and DAA-using a Kaplan Meier curve and Cox test. A p-value < 0.05 was considered statistically significant. Cut-off date for data collection was 23/12/2020.

RESULTS

SELECTION PROCESS

From the 15,842 patients managed in the hematology department and the 3,499 patients managed in the hepatology department between 01/01/2010 to 28/03/2019, we identified 164 potentially eligible patients. From these, 103 patients were excluded mainly for a benign hematological disorder (n = 49), or the absence of chronic HCV infection (n = 22) (Figure 1 and Supplemental data 1). Finally, 61 patients had a history of HM and chronic VHC infection and were included in this study. All but four were followed in the hematology department of our hospital.

Twenty-one patients had a history of DAA use before HM diagnosis and were included in the DAA+ group. The DAA-group comprised 40 patients, having a history of chronic HCV infection without any DAA prior to HM diagnosis with 18 patients that never received any DAA and 22 having received DAA following HM diagnosis. Detailed information can be found in Table 1.

PATIENT CHARACTERISTICS

Among the 61 HCV positive patients identified with HM, 29% were female with a median age at diagnosis of HM of 58 years [ IQR 17]. HCV genotype 1 represented 60% of the cohort.

Nine patients had an HIV infection, 2 an HBV co-infection. There was no significant difference between DAA + and DAA-groups, including age, sex, HCV genotype or viral load, coinfection, ALT levels, F Metavir stage at baseline, except for history of cirrhosis and liver transplantation which were significantly more frequent in the DAA+ group (52% vs. 30%, p = 0.032 and 38% vs. 12.5%, p = 0.045, respectively).

ANTI-HCV TREATMENTS

Type of previous anti-HCV treatments is detailed in Table 1

RISK FACTORS FOR HEMATOLOGICAL MALIGNANCIES

In the DAA+ group, only 2 of the 21 cases were associated with a delayed recurrence of a NHL at 4 years and a multiple myeloma at eight years. Among the 19 patients with first onset HM, ten patients (47%) had at least one risk factor for developing HM including:

-Long term immunosuppressive treatments for renal (n = 1, tacrolimus) or liver transplantation (n = 6), for a mean duration of 6 years before HM.

-HIV infection in 2 patients who developed Hodgkin Lymphoma, with a CD4 count of 168 and 1121/m3 respectively.

-Predisposing hematologic condition prior to DAA (cf. Table 1

Part B) (n=5)
Comparing patients with and without DAA, as described in the Table 1, Part A, proportion of previous hemopathy at risk (benign or malignant) or past chemo or radiotherapy were not different between groups. Concerning patients on chronic immunosuppressive treatments, although proportions of transplanted patients were similar between groups, we found that liver transplanted patients were more frequently found in the DAA group of patients. To note, no congenital risk factor was described in both groups.

OUTCOME

As DAA were authorized only in 2012, follow up was shorter in the DAA+ group with a median post HM-follow up time of 21.1 vs. 42.6 months (p = 0.024). At the cut-off date (23/12/2020), in the DAA+ group, one patient did not require specific treatment, one was lost to follow up, four achieved remission, six had stabilized their HM under treatment including 2 stem-cell transplantations (allogenic, n=1 and autologous, n=1) and nine died. Four of the five AML cases in the DAA+ group died. Nonetheless, outcomes as blood marrow transplantation requirement and mortality according to the Kaplan-Meier curves (Figure 2) did not significantly differ between group DAA+ or -but it should be noted that the follow-up time was shorter in the DAA+ group.

DISCUSSION

We described a total of 61 cases of HM in patients with a chronic HCV infection including 21 HM cases developing after the use of DAA. Our study highlights the following points for the patients using DAA: (1) types of HM seemed to differ when comparing patients with or without previous DAA, with a significant higher proportion of AML cases among patients following DAA therapy.

(2) Of the 5 AML in the DAA+ group, three including two rare cases of Mixed-phenotype Acute Leukaemia had no recognized risk factors.

(3) Three quarter of HM cases in the DAA treated patients occurred within two years after the use of DAA.

To the best of our knowledge, no AML cases after DAA treatment have been reported yet. The difference in frequency between the 2 groups of patients concerning the history of cirrhosis or liver transplantation may represent a confusion bias, yet these characteristics have to date never been associated with a higher risk of AML in the literature. Interestingly two of the five cases of AML in the group DAA+ were of mixed-phenotype meaning that they present morphologic and/or immunophenotypic characteristics of both myeloid and lymphoid lineages. These MPAL usually represent only 4 to 8% of all acute Leukaemias and present an aggressive clinical course, low complete remission and high recurrence rate [START_REF] Naeim | Chapter 13 -Acute Leukaemias of Ambiguous Lineage[END_REF]. Both cases developed in liver transplanted patients, although MPAL is not currently associated with solid organ transplants nor immunosuppressive therapy. Therefore, our findings are quite astonishing and need to be investigated by further studies. Furthermore, it may be of interest to know, that one DAA + liver-transplanted case, with a NHL following DAA therapy treated by anthracyclines developed secondarily an AML not registered in our study as developed after the cut-off date.

Previously described cases of HM following sustained viral response with DAA treatment remain spare but start to seek for awareness: To the best of our knowledge, no AML cases and only six cases of either early occurrence or relapse of NHL have so far been described (14-18).

They occur in a time interval between 1 -19 months after DAA treatment. None of these patients had a liver transplantation.

Aside from liver transplantation, chronic hepatitis C infection is also known to be associated with an increased risk of developing HM predominantly of B-cell type but not AML, whatever the level of liver fibrosis [START_REF] Perz | The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide[END_REF][START_REF] Giordano | Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus[END_REF][START_REF] Nieters | Hepatitis C and risk of lymphoma: results of the European multicenter case-control study EPILYMPH[END_REF][START_REF] Alkrekshi | Risk of Non-Hodgkin's Lymphoma in HCV Patients in the United States Between 2013 and 2020: A Population-Based Study[END_REF]. The underlying pathogenesis is most likely the chronic and continuous antigen stimulation leading to a permanent B-cell response with subsequent genetic mutation and finally clonal and malignant B-cell proliferations [START_REF] Marcucci | Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities[END_REF]. Another possible explanation could be permanent B-cell damage induced either by HCV-derived viral protein production inside B-cells or the transient intracellular infection [START_REF] Sakai | Development of diffuse large B-cell lymphoma after sofosbuvir-ledipasvir treatment for chronic hepatitis C: A case report and literature review[END_REF]. Viral eradication results in hematological response in NHL in about two thirds of the cases suggesting a possible causal connection between the HCV infection and the occurrence of lymphoma [START_REF] Arcaini | Interferon-free antiviral treatment in B-cell lymphoproliferative disorders associated with hepatitis C virus infection[END_REF]. Discordant results were recently highlighted according to the influence of DAA on hematological risk compared to the general population. A retrospective cohort study found a prevalence of NHL after HCV DAA that was still 30-fold higher, [START_REF] Khoury | Extrahepatic Malignancies After Treatment with Direct Antiviral Agents for Chronic HCV Infection[END_REF]. Another study points out that HCV viral eradication with DAA may not be associated with a reduction in NHL risk in HCV population. compared to the global population [START_REF] El-Serag | The effects of sustained virological response to direct-acting anti-viral therapy on the risk of extrahepatic manifestations of hepatitis C infection[END_REF]. Another one shows the disappearance of any higher risk for all hematological cancer following DAA therapy [START_REF] Lam | Cancer in people with and without hepatitis C virus infection: comparison of risk before and after introduction of direct-acting antivirals[END_REF]. We also found B-cell type lymphoma in cured HCV infections with DAA but at a weaker incidence than in patients without DAA, which is consistent with a potential protective effect of viral eradication at an early stage of the chronic infection, limiting the chronic inflammation and the risk of developing lymphoma.

No formal hypothesis emerged yet for the cases of HM cases described. The persistence of CD4 regulatory T cells, inhibiting CD8+ T-cells may be associated with a higher risk of developing HM [START_REF] Langhans | Increased peripheral CD4+regulatory T cells persist after successful direct-acting antiviral treatment of chronic hepatitis C[END_REF]. Recently a study pointed a high level of vascular endothelium growth factor (VEGF) after DAA treatment, which may accelerate tumor growth [START_REF] Villani | DAAs Rapidly Reduce Inflammation but Increase Serum VEGF Level: A Rationale for Tumor Risk during Anti-HCV Treatment[END_REF]. Unfortunately, no VEGF assay was performed in our cohort to corroborate this hypothesis.

Our study has several strengths. Hospital distribution of DAA allows capturing all patients having received DAA since its authorization. We were able to analyse both hepatology and haematology medical records for each patient, assure a long follow up duration and considered multiple several confusion factors. We have been careful not to omit patients who have benefited from treatment outside our hospital. But our study has limitations. First, information collection was retrospective and therefore missing data or incorrect data may be an issue but no variable exceeded 10% missing data. The number of included patients remains extremely small which could result in a possible lack of power. No multivariate analysis was performed because of the limited sample size and influence of a specific DAA could not be specifically evaluated. According to univariate analysis, potential confounding factors may exist in our study as patients in the DAA+ group had shorter follow-up time, more severe fibrosis/cirrhosis and/or liver transplantation. However, all these factors are not known to be associated with AML. Finally, we compared two groups of patients from different time sequences as DAA treatment was progressively used in different schemes starting end of 2011. Therefore, our results need to be taken with precaution and future larger studies are needed.

CONCLUSION:

In this comparative, retrospective and single-center study, we found, among HM in consecutive HCV patients, an unexpected proportion of AML in patients treated with DAA treatment compared to patients without DAA. AML cases included two rare mixed-phenotype forms.

Further studies including an ongoing multicentric observational study to confirm and explore the results.

INTRODUCTION

  Chronic hepatitis C virus infection (HCV) remains a global public health concern affecting an estimated 71.1 million (62.5-79.4) individuals worldwide with mortality four times higher compared to general population (1-3).

  . Groups were not significantly different in type and exposition of first line anti-HCV treatments with interferon and/or ribavirin. Five of 21 patients in the DAA+ group received at least 2 DAA treatment lines with the first line combining DAA with ribavirin (n = 2) or ribavirin + interferon (n = 3). NS5B, NS5A and NS3A inhibitors were part of the last all oral DAA combo treatments in 90, 76 and 29% respectively (Supplemental data 2). Median exposition time to DAA was 3 months [IQR 3]. Median time between initiation of DAA and HM diagnosis was 16.5 months [IQR 20.5] with all HM diagnosed within 6 years after DAA exposure including 3/4 in the first 2 years following DAA initiation. TYPE OF HEMATOLOGICAL MALIGNANCIES Of the 21 patients in the DAA + group, 8 (38%) had a NHL, including 4 EBV induced Post Transplantation Lymphoproliferative Disease, vs. 20 NHL (50%) in the DAA-group (p = 0.42). Surprisingly, 5 (24%) patients in the DAA+ group had acute myeloid Leukaemia (AML) vs. only 2 (5%) in the DAA-group, with a significant difference (p = 0.02). While both DAApatients with AML had previous HM known as risk factor, 3 of 5 DAA+ patients with AML had no specific risk factor including 2 with a Mixed-phenotype Acute Leukaemia (MPAL), a rare and poor-prognosis Leukaemia. Finally, 4 of the 5 DAA+ AML patients developed their HM in the first 3 years following successful DAA combo therapy. All five received a NS5B inhibitor (sofosbuvir). One of the 2 patients with mixed-phenotype acute Leukaemia had the highest number of DAA treatment lines (3) and the largest total duration of sofosbuvir (9 months).

Figure 1 :

 1 Figure 1: Flow Chart Diagram explaining the constitution of our groups

Figure 2 :

 2 Figure 2: Kaplan-Meyer Survival curve after onset of MH between the group DAA + (red) and

Supplemental data 1 :

 1 Detail of Non-inclusion criteriaBenign hematological disorder or no accurate hematologic diagnosis (n=49) Anemia of various etiologies (n=6): deficiency (n=2), unknown (n=2), inflammatory (n=1), multifactorial (n=1) Benign cytopenia (n=6): Moderate thrombocytopenia (n=2), lymphopenia (n=1), neutropenia (n=1), cytopenia linked to a viral infection (n=2) Hemolytic anemia with various etiologies (n=4): mechanic (n=1), autoimmune (n=1), unknown (n=2) MGUS (n=5) Porphyria (n=1) Drug related cytopenia (n=3) Benign ethnic neutropenia (n=3) Hemoglobinopathies: thalassemia (n=3), sickle-cell anemia (n=3), other (n=1) Hemochromatosis or hyperferritinemia (n=3) Benign adenopathy (n=4) Secondary polycythemia (n=5) Bleeding disorder (n=1) Multifactorial pancytopenia (n=1) Absence of chronic HCV infection at time of MH diagnosis (n=22) Identical names (n=16) Negative HCV serology and viral load with birth dates in DAA list (n=2) Chart record error (n=1) Acute HCV infection (n=2) Seroconversion after hemopathy (n=1) Hemopathy related to HCV or HCV treatment (n=14) HCV induced cytopenia (n=4) Thrombocytopenia due to hepatopathy (n=4) Pancytopenia due to Peginterféron alfa-2a (n=1) Interferon linked Hematologic toxicity (n=2) Ribavirin linked hemolytic anemia (n=1) Bone marrow failure linked to protease inhibitor (n=2) Cured malignant MH (n=13) Including bone marrow transplanted patients Other (n=5) Absence of patient (n=1) Preventive Follow up (bone marrow transplant were the donor developed later chronic lymphoid Leukaemia, n=1) Inpatient care for family history of multiple hematologic malignancies (n=1) HIV follow up (n=2)

Table 1 : Overall characteristics and per group Part A

 1

	Total	Group DAA -	Group DAA+	p-value
	(n=61)	(n = 40)	(n = 21)

* Continuous variables are represented with their median and IQR in brackets. Binary variables are represented by their count and percentage in brackets. Fisher's test or Wilcoxontest used. DAA = Direct Acting Agents, HM= hematological malignancy. d= days, y= years, m=month, * Cox test, † includes Non-hodgkin lymphoma, Hodgkin lymphoma, Chronic lymphocytic Leukaemia, ALL, † † includes Multiple myeloma, AL amyloidosis, † † † includes Myeloproliferative neoplasms, Myelodysplastic syndrome and AML

ACKNOWLEDGEMENTS

None

FUNDING SOURCES

No funding sources were perceived

IMPLICATIONS

CS and PL conceived the study. EL, DAA and DRW helped with the acquisition of data AD helped with the study design All authors helped for the critical revision for important intellectual content and have approved the final article.

Abbreviations (in order of appearance): hepatitis C virus (HCV), hematological malignancies (HM), anti-HCV Direct Acting Antivirals (DAA), Acute Myeloid Leukaemia (AML), Non-Hodgkin Lymphoma (NHL), Mixed Phenotype Acute Leukaemia (MPAL)


domain: phys spi chim

text:
Guoyin Shen

Jesse S Smith

Curtis Kenney-Benson

Stefan Klotz

Calibration of ruby (Cr

come

Introduction

Since the invention of ruby (Cr 3+ :Al 2 O 3 ) luminescence shift for pressure measurement [START_REF] Forman | Pressure Measurement Made by the Utilization of Ruby Sharp-Line Luminescence[END_REF] a halfcentury ago, ruby sensor as a pressure gauge has been widely used for pressure determination in experiments using diamond anvil cell (DAC) and other optically transparent pressure devices [START_REF] Piermarini | Calibration of the pressure dependence of the R1 ruby fluorescence line to 195 kbar[END_REF][START_REF] Mao | Specific volume measurements of Cu, Mo, Pd, and Ag and calibration of the ruby R1 fluorescence pressure gauge from 0.06 to 1 Mbar[END_REF][START_REF] Mao | Calibration of the ruby pressure gauge to 800 kbar under quasihydrostatic conditions[END_REF]. At pressures below ∼20 GPa, the shift of the R1 luminescence line may be approximated as linear [START_REF] Piermarini | Calibration of the pressure dependence of the R1 ruby fluorescence line to 195 kbar[END_REF]. At higher pressures, the R1-line shift displays significantly nonlinear behavior, which has been the main concern in developing an accurate extended ruby gauge. Among published ruby gauges [START_REF] Kunc | Diamond under pressure: Ab-initio calculations of the equation of state and optical phonon frequency revisited AU -Kunc[END_REF][START_REF] Chijioke | The ruby pressure standard to 150GPa[END_REF][START_REF] Holzapfel | Progress in the realization of a practical pressure scale for the range 1-300 GPa[END_REF][START_REF] Dorogokupets | Equations of state of MgO, Au, Pt, NaCl-B1, and NaCl-B2: Internally consistent high-temperature pressure scales[END_REF][START_REF] Dewaele | Compression curves of transition metals in the Mbar range: Experiments and projector augmented-wave calculations[END_REF][START_REF] Jacobsen | Compression of single-crystal magnesium oxide to 118 GPa and a ruby pressure gauge for helium pressure media[END_REF][START_REF] Syassen | Ruby under pressure[END_REF][START_REF] Takemura | Isothermal equation of state for gold with a He-pressure medium[END_REF][START_REF] Holzapfel | Equations of state for Cu, Ag, and Au and problems with shock wave reduced isotherms[END_REF][START_REF] Sokolova | Self-consistent pressure scales based on the equations of state for ruby, diamond, MgO, B2-NaCl, as well as Au, Pt, and other metals to 4 Mbar and 3000[END_REF][START_REF] Kraus | Dynamic compression of copper to over 450 GPa: A highpressure standard[END_REF][START_REF] Dewaele | Equations of State of Simple Solids (Including Pb, NaCl and LiF) Compressed in Helium or Neon in the Mbar Range[END_REF][START_REF] Shen | Toward an international practical pressure scale: A proposal for an IPPS ruby gauge (IPPS-Ruby2020)[END_REF] in the last 15 years, they are in reasonable mutual agreement within 2.5% in a pressure range up to 150 GPa. Recently, a ruby gauge (called Ruby2020) [START_REF] Shen | Toward an international practical pressure scale: A proposal for an IPPS ruby gauge (IPPS-Ruby2020)[END_REF] has been proposed by an AIRAPT task group using a second-order polynomial form: P (in GPa) = A/ 0 (1+ B/ 0 ), [START_REF] Forman | Pressure Measurement Made by the Utilization of Ruby Sharp-Line Luminescence[END_REF] with the initial slope A of 1870±10 GPa and the parameter B of 5.63±0.03, where is the ruby R1-line shift in nm, and λ 0 is the wavelength of the R1-line near 694.25 nm at ambient condition.

Calibration at low pressures (<10 GPa) is dominantly affected by the initial slope in Eq (1), A =

. Even though a precision in pressure using a ruby gauge can be 0.01 GPa [START_REF] Syassen | Ruby under pressure[END_REF][START_REF] Grasset | Calibration of the R ruby fluorescence lines in the pressure range 0-1 GPa and the temperature range 250-300K[END_REF], its initial slope is not well constrained. The published A-values were either fixed [START_REF] Mao | Specific volume measurements of Cu, Mo, Pd, and Ag and calibration of the ruby R1 fluorescence pressure gauge from 0.06 to 1 Mbar[END_REF][START_REF] Mao | Calibration of the ruby pressure gauge to 800 kbar under quasihydrostatic conditions[END_REF][START_REF] Jacobsen | Compression of single-crystal magnesium oxide to 118 GPa and a ruby pressure gauge for helium pressure media[END_REF][START_REF] Dewaele | Equations of state of six metals above 94 GPa[END_REF] based on the linear coefficient averaged over a pressure range of 0-20 GPa [START_REF] Piermarini | Calibration of the pressure dependence of the R1 ruby fluorescence line to 195 kbar[END_REF], which tends to over-estimate the initial slope because of nonlinearity, or back-extrapolated using a large pressure range [5-7, 14, 15, 17, 20], which may involve unknown uncertainties.

In principle, reference points with their pressures calibrated by primary piston gauges can be used not only for tightly constraining the initial slope of ruby gauge but also for bridging the ruby gauge with the more fundamental primary gauges. Using six reference points, Forman et al [START_REF] Forman | Pressure Measurement Made by the Utilization of Ruby Sharp-Line Luminescence[END_REF] determined the ruby's R1-line shift with a linear coefficient of 0.372±0.014 nm/GPa with a relative uncertainty of ±3.8%. Based on the melting of pure H 2 O, Grasset [START_REF] Grasset | Calibration of the R ruby fluorescence lines in the pressure range 0-1 GPa and the temperature range 250-300K[END_REF] calibrated the ruby's R1-line shift in a pressure range of 0-1 GPa, resulting in a linear coefficient of 0.371±0.006 nm/GPa with a relative uncertainty of ±1.6%. Here, we report the calibration of the ruby luminescence line shift from the well-calibrated melting line of mercury which has a high precision of less than ±0.2 MPa [START_REF] Molinar | The Mercury Melting Line Up to 1200 MPa[END_REF][START_REF] Molinar | Pressure Measurements with the Mercury Melting Line Referred to ITS-90[END_REF]. The first AIRAPT task group on the International Practical Pressure Scale (IPPS) recommended the mercury melting line [START_REF] Molinar | The Mercury Melting Line Up to 1200 MPa[END_REF] be used as a pressure standard up to 1.2 GPa. Later the melting line was modified in 1991 [START_REF] Molinar | Pressure Measurements with the Mercury Melting Line Referred to ITS-90[END_REF] with reference to the then new International Temperature Scale of 1990 (ITS-90) [START_REF] Mcglashan | The international temperature scale of 1990 (ITS-90)[END_REF].

Luminescence of Sm 2+ in host crystals (SrFCl, BaFCl) is widely used for pressure determination at low pressures (<10 GPa), largely because the pressure coefficient is almost three times larger than that of the ruby doublet [START_REF] Lorenz | Characterization of the new luminescence pressure sensor SrFCl:Sm2+[END_REF][START_REF] Shen | Progress in pressure measurements with luminescence sensors[END_REF]. Sm 2+ :SrFCl or Sm 2+ :BaFCl is also used as a replacement for ruby sensors in sapphire anvil cells, since sapphire often contains trace amount of Cr 3+ , interfering with ruby luminescence signals. In addition, the luminescence spectrum of Sm 2+ :SrFCl or Sm 2+ :BaFCl shows a singlet line, well separated from the other lines, with a narrow linewidth. Due to the large pressure coefficient and the narrow linewidth, the precision of pressure measurement significantly improves, by more than three times with respect to the ruby gauge. In this paper, we also report the calibration of Sm 2+ :SrFCl luminescence line shift from the melting line of mercury.

Experimental procedures

We used a diamond anvil cell (DAC) with anvils of a culet size of 450 m in diameter. In all runs, we used rhenium gaskets and pre-indented each with the DAC to a thickness of 60-80 m. A 275 m hole was drilled at the center of the indentation, and subsequently loaded with a couple of ruby spheres or Sm 2+ :SrFCl chips (about ~3-10 m in size) and the mercury sample, well separated from the rhenium gasket, in the hole. The mercury sample is from Sigma-Aldrich (electronic grade, 99.9999% trace metals basis, product number 294594). The ruby spheres (3600 ppm-Cr 3+ :Al 2 O 3 , from BETSA) are annealed to relax internal strain [START_REF] Chervin | Ruby-spheres as pressure gauge for optically transparent high pressure cells[END_REF]. The Sm 2+ :SrFCl sample contains nominally 0.1 at% Sm 2+ and comes from the same batch as the material studied in refs. [START_REF] Lorenz | Characterization of the new luminescence pressure sensor SrFCl:Sm2+[END_REF] and [START_REF] Shen | Progress in pressure measurements with luminescence sensors[END_REF]. A description of the synthesis conditions can be found in ref. [START_REF] Shen | Effect of pressure on energy levels of Sm 2+ in BaFCl and SrFCl[END_REF]. We mechanically crushed a Sm 2+ :SrFCl crystal into small chips. These chips were used without annealing. The sample chamber was then loaded with neon gas as pressure transmitting medium (Fig. 1). In the pressure range of this study (<2 GPa), neon remains liquid, providing a hydrostatic environment. For precise controls of compression and decompression, we used a doublesided membrane technique [START_REF] Sinogeikin | Online remote control systems for static and dynamic compression and decompression using diamond anvil cells[END_REF]. The membrane pressure, which drives the DAC, was digitally changed by a controller (GE/Druck Model: Pace 5000). The compression or decompression of the DAC was applied by controlling membrane pressure over time with a step of 70-345 Pa/s (0.01-0.05 psi/s).

We also used an empty cell loaded with a ruby sphere from the same batch and a Sm 2+ :SrFCl chip, i.e., loaded in a drilled gasket hole without any pressure on the DAC. The luminescence signals from the empty cell ruby and Sm 2+ :SrFCl crystals were used as references at ambient pressure. Immediately before and after each experimental run, the ambient pressure points were measured multiple times with their average number taken as the initial wavelength  0 .

The luminescence measurements were performed using an Acton SpectroPro-300i spectrograph with a grating of 1800 grooves/mm, coupled with a PIXIS:400BR Digital CCD Camera System. A laser (Spectra Physics model Excelsior-532-300) of wavelength 532 nm was used for exciting luminescence sensors with a fixed laser power (<3 mW) at the sample position. The small laser power minimized the effect of local heating [START_REF] Chervin | Ruby-spheres as pressure gauge for optically transparent high pressure cells[END_REF]. Typical luminescence spectra from the ruby spheres and the Sm 2+ :SrFCl chips in the DAC are shown in Fig. S1 and Fig. S2, respectively. With a collection time of 0.25 s, the luminescence signals from both ruby and Sm 2+ :SrFCl crystal are strong and can be well fitted to determine the peak positions with small uncertainties (<10 -5 nm) from the fitting statistics. In the fitting procedures, we used the Moffat function, defined as: I = a 0 /(u+1) a3 , where I is the intensity, u = [(xa 1 )/a 2 ] 2 , x is the wavelength, and a 1 , a 2 , and a 3 are fitting parameters. Uncertainties in peak position from peak-fitting are negligible (<1.0x10 -5 nm) compared to those from other sources, such as repeatability and data scatters.

In a typical run, we first compressed the DAC via the membrane controller at a given step until the sample pressure reached ~1.5 GPa. We then decompressed the DAC at a similar rate to a pressure of ~0.9 GPa. In both compression and decompression paths, we continuously measured luminescence signals every 0.25 seconds, while the mercury sample crossed its melting point [START_REF] Molinar | Pressure Measurements with the Mercury Melting Line Referred to ITS-90[END_REF]. In a pressure interval of 0.6 GPa, our compression (or decompression) rates allowed us to record 600-6000 luminescence spectra, providing fine recordings of the pressure conditions in the sample chamber.

The DAC temperature was monitored by a K-type thermocouple attached to the cell. We applied a correction of -0.1 o C to the thermocouple readings, based on the temperature measurement of the thermocouple in the icy water, which displayed 0.1 o C. The average temperatures during the ruby runs and Sm 2+ :SrFCl runs were measured to be 23.75±0.05 o C and 23.0±0.05 o C, respectively. According to the melting line of mercury [START_REF] Molinar | Pressure Measurements with the Mercury Melting Line Referred to ITS-90[END_REF], P (MPa) = 19.32845d + 0.0018333d 2 + 0.000059791d 3 [START_REF] Piermarini | Calibration of the pressure dependence of the R1 ruby fluorescence line to 195 kbar[END_REF] where d = 273.15+t-234.3156, and t is temperature in o C, the melting pressures at those temperatures are 1231.5±1.0 MPa for the ruby runs and 1216.3±1.0 MPa for the Sm 2+ :SrFCl runs in this study. The uncertainty of ±1.0 MPa is largely from the uncertainties in temperature (±0.05 o C). Note that the melting pressures here are both slightly above the upper pressure limit of 1200 MPa in the reported melting line of mercury [START_REF] Molinar | Pressure Measurements with the Mercury Melting Line Referred to ITS-90[END_REF]. As discussed by Molinar et al [START_REF] Molinar | The Mercury Melting Line Up to 1200 MPa[END_REF][START_REF] Molinar | Pressure Measurements with the Mercury Melting Line Referred to ITS-90[END_REF], the third-order polynomial form (Eq. 2) precisely represents their experimental data covering a pressure range of 965 MPa (227.4 -1192.5 MPa), with a very small residual standard deviation () of 0.06 MPa. If we assume a 3 value (0.18 MPa) as the uncertainty in the extrapolation of the melting curve (Eq. 2) by 32 MPa to pressures up to 1232 MPa, the total uncertainties are still close to ±1.0 MPa, which is predominantly from the uncertainties in temperature (±0.05 o C).

Results and discussion

Fig. 2a shows the measured shifts of the ruby's R1-line (= p - 0 , here  p is the measured wavelength at high pressure and  0 is the reference at ambient pressure), as we slowly compressed and decompressed the DAC. The rate of compression or decompression in each run was fixed by setting a step of either 70 Pa/s or 345 Pa/s using a membrane controller. Under compression paths, the mercury sample undergoes a liquid to solid transition (freezing). We observe an overall increase in  with time under compression. Notably, when the shift reaches a certain level (~0.475 nm), there is a sudden drop in by ~0.012 nm. Because the sample chamber's volume is nearly constant in the pressure range of this study, this large drop is likely associated with a sudden shrinkage of the mercury sample upon freezing, and a consequent expansion of the remaining materials in the sample chamber (Ne and ruby). Although the drop in  provides a clear indication of the freezing of mercury, the corresponding pressure may be slightly above the melting pressure of mercury, because liquid mercury can often be super-pressurized [START_REF] Molinar | The Mercury Melting Line Up to 1200 MPa[END_REF] under compression, a phenomenon similar to supercooled liquid below melting temperature.

Under decompression, the solid mercury at high pressure undergoes melting via a path of decompression. As shown in Fig. 2a, we observe an obvious plateau in each decompression run of all our experiments. The plateaus are likely caused by the mercury's volume expansion upon melting. Similar to latent heat under heating a solid to melting, the observed plateaus here reflect a latent component on melting, which may be referred as "latent compression". Apparently, the melting process is slower than the freezing. At the time scale in our experiments (seconds), superheating (or over-decompression) of liquid mercury is unlikely. Therefore, we assign the plateaus to the onset of the mercury melting. Because of the well calibrated melting curve of mercury [START_REF] Molinar | The Mercury Melting Line Up to 1200 MPa[END_REF][START_REF] Molinar | Pressure Measurements with the Mercury Melting Line Referred to ITS-90[END_REF], the plateaus thus provide a precise calibration for the  at the mercury melting pressure (Table 1). In Fig. 2b, similar plateaus are observed for the ruby's R2-line, with the numerical data also listed in Table 1.

In the runs of Sm 2+ :SrFCl, we do not observe clear pressure drops under compression. The plateaus under decompression are not as clear as those in the experiments on ruby (Fig. 3), which is likely related to the relatively small volumes of the mercury sample in the Sm 2+ :SrFCl experiments. Nonetheless, the turning points from the mercury melting are still clearly visible, as illustrated in the derivative plots in Fig. 3. Using the data points in the vicinity of the turning points, we can define the shift of the Sm 2+ :SrFCl luminescence line 5 D 0 → 7 F 0 corresponding to the mercury melting (Table 1). As far as we know, no calibration studies have been reported on the Sm 2+ :SrFCl luminescence line shift based on pressure reference points from primary piston gauges. The line shifts of Sm 2+ :SrFCl chips were measured together with ruby sensors [START_REF] Lorenz | Characterization of the new luminescence pressure sensor SrFCl:Sm2+[END_REF][START_REF] Shen | Progress in pressure measurements with luminescence sensors[END_REF] up to a pressure over 10 GPa, from which the pressure dependence of the line positions was defined. The obtained linear coefficient in this study (Table 2) is calibrated against a reference point of the mercury melting at room temperature [START_REF] Molinar | The Mercury Melting Line Up to 1200 MPa[END_REF][START_REF] Molinar | Pressure Measurements with the Mercury Melting Line Referred to ITS-90[END_REF] in a narrow pressure range of 0-1.2 GPa.

The shifts of luminescence lines against pressure in ruby and Sm 2+ :SrFCl display clear nonlinear behavior above ~20 GPa and ~5 GPa, respectively. Among various forms to account for the nonlinear term [START_REF] Syassen | Ruby under pressure[END_REF], a polynomial form to the second order (Eq. 1) is widely used. According to Eq. 1, the nonlinear term at the mercury's melting pressure can be estimated to be 0.0046 GPa for the ruby's R1 line, based on the parameters in Ruby2020 [START_REF] Shen | Toward an international practical pressure scale: A proposal for an IPPS ruby gauge (IPPS-Ruby2020)[END_REF]. The nonlinear term is small, ~0.4% at 1.2 GPa. Then, after correcting the nonlinear term, we can determine the initial slope A in Eq (1) to be 1858±10 GPa. The A value here is smaller than, but still comparable to, that of 1870±10 in Ruby2020 [START_REF] Shen | Toward an international practical pressure scale: A proposal for an IPPS ruby gauge (IPPS-Ruby2020)[END_REF] within uncertainties. Similarly, for the Sm 2+ :SrFCl line, the nonlinear term at the mercury's melting pressure is estimated to be 0.0121 GPa (or ~1% at 1.2 GPa), based on the data in Fig. S3. Thus, the initial slope A in Eq (1) for the Sm 2+ :SrFCl luminescence line is determined to be 620.6±1.1 GPa. This study

Lorenz et al 1994 [START_REF] Lorenz | Characterization of the new luminescence pressure sensor SrFCl:Sm2+[END_REF] Shen et al 1991 [START_REF] Shen | Progress in pressure measurements with luminescence sensors[END_REF]

Forman et al 1972 [ 1 ]

 1 Sm 2+ :SrFCl 620.6±1.1** **The parameter B of -5.0 is used, based on data in Fig.

Table 1 : Shifts of luminescence lines corresponding to the melting of mercury at room temperature

 1

	Ruby data	Cell1	Cell1	Cell1	Cell2	Cell2	Mean of all
		Run 1	Run 2	Run 3	Run 4	Run 5	runs (nm)
	Number of data points on the	60	71	75	16	16
	plateaus
	Rate of membrane pressure	70	70	70	345	345
	(in Pascal per second)
	Ruby R1 shift:
	Mean value (nm) Standard deviation (nm)	0.4559 6.7x10 -4	0.4597 6.4x10 -4	0.4580 6.3x10 -4	0.4595 5.8x10 -4	0.4586 7.2x10 -4	0.4584±0.0015
	Ruby R2 shift:
	Mean value (nm) Standard deviation (nm)	0.4650 7.8x10 -4	0.4675 7.5x10 -4	0.4661 6.0x10 -4	0.4690 5.8x10 -4	0.4680 9.0x10 -4	0.4671±0.0016

Table 2 : The determined linear coefficients and initial slopes in Eq (1)

 2 GPa using data of melting of CCl 4 , H 2 O, n-C 7 H 16 , C 2 H 5 Br, and of solid-solid transitions in CCl 4 (III-IV) and H 2 O(VI-VII)

	Emission	Initial slope A (GPa) back-	Linear coefficient	Comment
	line	Eq (1) extrapolated according to	/P (nm/GPa)
	Ruby-R1	1858±10*	0.3722±0.002	This study
	Cr 3+ :Al 2 O 3
		*The parameter B of 5.63 in	0.371±0.006	Grasset 2001 [29]: melting of H 2 O to
		Eq (1) is from Ruby2020 [17]		0.8GPa
	0.372±0.014 Forman et al 1972 [1]: up to 2.2 Ruby-R2 0.3796±0.002 This study
	Cr 3+ :Al 2 O 3		0.377±0.009	Grasset 2001 [29]
			0.406±0.015

Acknowledgement

This work is supported by the Department of Energy (DOE)-NNSA's Office of Experimental Sciences. We thank D. Y. Chung and P. Rossi for providing the mercury sample and transferring it to HPCAT facilities. We thank S. N. Tkachev for the gas-loading of neon, and V. B. Prakapenka for sharing the IntelliCal calibration lamp. Use of the COMPRES-GSECARS gas loading system is supported by COMPRES under NSF EAR -1606856 and by GSECARS under NSF grant EAR-1634415 and DOE grant DE-FG02-94ER14466. The Sm 2+ :SrFCl samples came from W. B. Holzapfel (Univ. Paderborn, Germany) via M. Bonello (Paris). S.K. is grateful to S. Ninet (IMPMC) for help in the cell preparation for the fluorescence measurements (Fig. S3).

Therefore, in a narrow pressure range up to 1.2 GPa, we can determine the linear coefficients, /P, from the measured shifts of these luminescence sensors (Table 2). The uncertainty in pressure (P) is small, about ±1 MPa from the uncertainties in temperature (±0.05 o C). The uncertainty in  consists of two major components: those from  p and  0 . From the five runs in the ruby experiments (Table 1), the uncertainty in  p is estimated to be ~±0.0016 nm (Table 1). Note that the precision in  p in each run is <±0.0001 nm (Table 1). The larger uncertainty from multiple runs is mainly caused by the repeatability of the spectrometer. A similar level of uncertainty is also obtained from the multiple measurements of ruby spheres in the empty cell before and after the experimental runs, which is ±0.0018 nm. Combining these two components, we obtain a total uncertainty in  of ~±0.0024 nm in the experiments on ruby. The linear coefficients for ruby's R1 and R2 lines are then determined to be 0.3722±0.002 nm/GPa and 0.3796±0.002 nm/GPa, respectively (Table 2).

Because of only two runs in the Sm 2+ :SrFCl experiments, it is difficult to directly estimate the uncertainty in  p . However, due to the narrow linewidth of the luminescence line in Sm 2+ :SrFCl, the uncertainty in  is unlikely to exceed that in ruby's experiments. This is reflected from the multiple measurements of the Sm 2+ :SrFCl chip in the empty cell before and after experimental runs, which gives an uncertainty in  p of ±0.0016 nm. Considering that the uncertainty in  is largely limited by the repeatability of the spectrometer, here we use a similar level of uncertainty of ±0.0024 nm as that in ruby's experiments. The linear coefficient for the Sm 2+ :SrFCl luminescence line ( 5 D 0 → 7 F 0 ) is determined to be 1.123±0.002 nm/GPa. The obtained linear coefficient of ruby's R1 line (0.3722±0.002 nm/GPa) is in excellent agreement with that of Grasset [START_REF] Grasset | Calibration of the R ruby fluorescence lines in the pressure range 0-1 GPa and the temperature range 250-300K[END_REF] (0.371±0.006 nm/GPa) and that of Forman et al [START_REF] Forman | Pressure Measurement Made by the Utilization of Ruby Sharp-Line Luminescence[END_REF] (0.372±0.014 nm/GPa). Both of the previous studies [START_REF] Forman | Pressure Measurement Made by the Utilization of Ruby Sharp-Line Luminescence[END_REF][START_REF] Grasset | Calibration of the R ruby fluorescence lines in the pressure range 0-1 GPa and the temperature range 250-300K[END_REF] used reference pressure points that are calibrated from the primary piston gauges (see Table 2). The relative uncertainty in this study is ±0.5%, compared to ±1.6% [START_REF] Grasset | Calibration of the R ruby fluorescence lines in the pressure range 0-1 GPa and the temperature range 250-300K[END_REF] and ±3.8% [START_REF] Forman | Pressure Measurement Made by the Utilization of Ruby Sharp-Line Luminescence[END_REF] in previous studies. The linear coefficient of ruby's R2-line (0.3796±0.002 nm/GPa) is in reasonable agreement with those in previous studies [START_REF] Forman | Pressure Measurement Made by the Utilization of Ruby Sharp-Line Luminescence[END_REF][START_REF] Grasset | Calibration of the R ruby fluorescence lines in the pressure range 0-1 GPa and the temperature range 250-300K[END_REF] (Table 2). The relative uncertainty (±0.5%) is significantly improved, compared to ±2.4% [START_REF] Grasset | Calibration of the R ruby fluorescence lines in the pressure range 0-1 GPa and the temperature range 250-300K[END_REF] and ±3.7% [START_REF] Forman | Pressure Measurement Made by the Utilization of Ruby Sharp-Line Luminescence[END_REF] in previous studies.