Andrea Zerboni
email: andrea.zerboni@unimi.it

Michele Degli Esposti

Ying-Li Wu

Filippo Brandolini

Guido S Mariani

Federica Villa

Paolo Lotti

Francesca Cappitelli

Marzia Sasso

Agostino Rizzi

Michele Degli Esposti

G Diego Gatta

Mauro Cremaschi

Age, palaeoenvironment, and preservation of prehistoric petroglyphs on a boulder in the oasis of Salut (northern Sultanate of Oman)

Keywords: Rock art, Rock weathering, Microscopy, Climate change, Radiocarbon, Sultanate of Oman

scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

The preservation of rock art in open-air contexts -as much as other cultural heritages [START_REF] Howard | Managing global heritage in the face of future climate change: the importance of understanding geological and geomorphological processes and hazards[END_REF] -is tricky, especially in locations where extant climatic and environmental settings are different respect to those present at the time of the production of rock art galleries [START_REF] Darvill | Open-air rock-art conservation and managment[END_REF][START_REF] Giesen | Condition assessment and preservation of open-air rock art panels during environmental change[END_REF][START_REF] Groom | Rock Art Management and Landscape Change: Mixed Field Assessment Techniques for Cultural Stone Decay[END_REF]. This is especially true in arid and semiarid regions, where Holocene climatic changes have deeply and repeatedly reshaped the environment. In such contexts, open-air rock art galleries are, at the same time, a record for past climates as much as a feature threatened by new environmental conditions [START_REF] Cremaschi | L'arte rupestre del Tadrart Acacus: testimone e vittima dei cambiamenti climatici[END_REF]Zerboni, 2012). As a consequence, rock art (paintings and engravings) may suffer strong weathering and taphonomic processes -including physical, chemical and biological weatheringand in some cases can be completely erased. For these reasons, the understanding of the processes leading to rock art preservation and/or destruction and its paleoenvironmental context are as important as its cultural, archaeological, and artistic implications [START_REF] Whitley | Introduction to rock art research[END_REF][START_REF] Dorn | Petroglyphs in Petrified Forest National Park: Role of rock coatings as agents of sustainability and as indicators of antiquity[END_REF][START_REF] A N U S C R I P T A C C E P T E D Accepted Manuscript 24 Dorn | The Rock Art Stability Index[END_REF]Allen et al., 2011;[START_REF] Bednarik | The use of weathering indices in rock art science and archaeology[END_REF][START_REF] Giesen | Condition assessment and preservation of open-air rock art panels during environmental change[END_REF].

Studies promoting the understanding of preservation of rock art preservation and its environmental context remained scanty for a long time. Recently, however, an increased awareness that the understanding of rock art and its decay requires multidisciplinary approaches promoted the development of some projects focused on the assessment of rock art preservation and the study of the interface between rocks and pigments. Some studies considered the many processes affecting rock art and their rock supports [START_REF] Cerveny | A weathering-based perspective on rock art conservation[END_REF][START_REF] Hall | Deterioration of San rock art: new findings, new challenges[END_REF][START_REF] Hall | Light penetration into Clarens sandstone and implications for deterioration of San rock art[END_REF][START_REF] Mol | The writing's in the wall: a review of new preliminary applications of electrical resistivity tomography within archaeology[END_REF][START_REF] Groom | The applicability of repeat photography in rock art conservation: a case study of mixed methods in the Arkansan Ozarks[END_REF][START_REF] Groom | Rock Art Management and Landscape Change: Mixed Field Assessment Techniques for Cultural Stone Decay[END_REF][START_REF] Gallinaro | Rock art between preservation, research and sustainable development -A perspective from Southern Ethiopia[END_REF], and applied indices describing the stability of rock art [START_REF] A N U S C R I P T A C C E P T E D Accepted Manuscript 24 Dorn | The Rock Art Stability Index[END_REF][START_REF] Allen | Practicing Physical Geography: an Actor-Network View of Physical Geography Exemplified by the Rock Art Stability Index[END_REF][START_REF] Groom | RASI Survey of Sites in Petrified Forest National Park[END_REF][START_REF] Allen | Evaluation of Grenada's "Carib Stones" via the Rock Art Stability Index[END_REF]. In other cases, studies are dedicated to understanding the age and paleoenvironmental significance of rock art [START_REF] Cremaschi | The rock varnish in the Messak Sattafet (Fezzan, Libyan Sahara), age, archaeological context, and palaeoenvironmental implication[END_REF][START_REF] Dorn | Petroglyphs in Petrified Forest National Park: Role of rock coatings as agents of sustainability and as indicators of antiquity[END_REF][START_REF] Cremaschi | L'arte rupestre del Tadrart Acacus: testimone e vittima dei cambiamenti climatici[END_REF]2012;[START_REF] Bednarik | The use of weathering indices in rock art science and archaeology[END_REF]Macholdt et al., in press). For that reason, in this paper we examine some engravings recently discovered in the northern part of the Sultanate of Oman (oasis of Salut), with the main aim to decipher their age and significance in relation to the local and regional archaeological background, and to reconstruct the main environmental processes leading to the decay or preservation of petroglyphs.

Several petroglyphs' panels were discovered in the region and the most of them show the same slightly varnished, usually dotted pecking technique, and the same iconographic repertoire commonly witnessed in other parts of the Arabian Peninsula (e.g., [START_REF] Jung | On representations of camels and camel-riders in the rock art of Northern Yemen[END_REF][START_REF] De Ceuninck | Les pétroglyphes du Fujairah, Emirates Arabes Unis[END_REF];

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4 Ziolkowski, 1998Ziolkowski, , 2007;;[START_REF] Bednarik | The Saudi Arabian rock art mission of November 2001[END_REF][START_REF] Khan | The rock art of Saudi Arabia across twelve thousand years[END_REF][START_REF] Khan | Rock Art of Saudi Arabia[END_REF][START_REF] Bednarik | Scientific study of Saudi Arabian rock art[END_REF][START_REF] Bednarik | Scientific investigations into Saudi Arabian rock art: a review[END_REF][START_REF] Fossati | Current finds in rock art research of Oman: a review and update[END_REF]. However, the finding discussed here represents a so far unique discovery within the regional archaeological context and deserves a specific geoarchaeological investigation. In fact, this rock art panel comprises a series of engravings that differs in pecking technique from the most widespread ones, and notably from the large majority of the rock art present in the same oasis.

Although being generally strongly abraded by environmental processes, where they are sheltered by a dark, biomineralized rock crust, they are better preserved. The same rock crust allowed dating engravings and elucidating their palaeoenvironmental history.

The study area

Geographic, climatic and geologic background

The rock art panel here investigated consists of engravings on a limestone boulder outcropping on the southern slope of a hill belonging to Jabal Hammah, in the vicinity of the archaeological site of Salut (Fig. 1) in the northern Sultanate of Oman (Degli Esposti et al., 2018b). The Geologic Map of Oman, 1.250,000, sheet NF4007 -NIZWA, reports the toponym Jabal Hammah, although locals currently refer to the same hill as Jabal Salut, which is the toponym used in most of the archaeological literature cited here. The area is located between the modern villages of Bisya (2 km to the South) and Bahla (20 km to the North), and stands at the margin of the palaeo-oasis of Salut, which developed in the Early and Middle Holocene along Wadi Sayfam (Cremaschi et al., 2018a).

A variety of sedimentary, metamorphic, and igneous rocks outcrop in this region (Geologic Map of Oman, 1.250,000, sheet NF4007 -NIZWA); the area is delimited to the North by the massif being part of the Mid-Late Cretaceous Samail Ophiolite, and to the West and to the South by Permian to Cretaceous sedimentary formations (limestone and radiolarite). The bedrock of the hill hosting the engraved boulder consists of the Late Jurassic to Cretaceous Wahrah Formation [START_REF] Glennie | Geology of the Oman Mountains[END_REF], which includes lithoclastic, oolithic, marly limestone, chert, and silicified limestone (Béchennec, 1986). Pleistocene and Holocene deposits cover part of the region, including large alluvial fans and fine sediments covering most of the bottom of the alluvial plain along the main wadis (see details in Cremaschi et al., 2018a).

The present climate of Northern Oman is arid to semi-arid and controlled by the seasonal development of the monsoon winds. Rainfall originates from Mediterranean frontal systems in winter and spring [START_REF] Weyhenmeyer | Cool glacial temperatures and changes in moisture source recorded in Oman groundwaters[END_REF][START_REF] Weyhenmeyer | Isotope study of moisture sources, recharge areas, and groundwater flow paths within the eastern Batinah coastal plain, Sultanate of Oman[END_REF], and varies between 150-250 mm/yr [START_REF] Alsharhan | Hydrogeology of an Arid Region: the Arabian Gulf and Adjoining Areas[END_REF][START_REF] Fleitmann | Holocene ITCZ and Indian monsoon dynamics recorded in stalagmites from Oman and Yemen (Socotra)[END_REF]. On the contrary, palaeoclimate studies based on

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speleothems from the Hoti Cave (at ca. 45 km from the study site; [START_REF] Neff | Strong coherence between solar variability and the monsoon in Oman between 9 and 6 ka ago[END_REF][START_REF] Fleitmann | Holocene ITCZ and Indian monsoon dynamics recorded in stalagmites from Oman and Yemen (Socotra)[END_REF] suggest that in the early Holocene (between ca. 10.5 and 9.5 ka BP) precipitations increased, triggered by the northward shift of the mean latitudinal position of the summer ITCZ and the associated Indian Summer Monsoon (ISM) rainfall belt. After ~7.8 ka BP to present, the mean summer ITCZ continuously migrated southward triggering the gradual decrease in intensity and duration of the ISM season. Other records from southern Oman and Socotra suggest a marked decrease in precipitation at ca. 2 ka BP, thus confirming a general decrease in intensity of the Indian Ocean monsoon in the late Holocene [START_REF] Fleitmann | Holocene ITCZ and Indian monsoon dynamics recorded in stalagmites from Oman and Yemen (Socotra)[END_REF].

Archaeological background

The archaeological record of the region of the Sultanate of Oman roughly comprised between the cities of Nizwa and Bahla was initially surveyed in the 1970ies [START_REF] Hastings | Oman in the third millennium BCE[END_REF][START_REF] De Cardi | Excavations and survey in Oman, 1974-1975[END_REF], but systematic archaeological investigation started later (e.g. [START_REF] Orchard | The work of the Al-Hajar project in Oman[END_REF]. A project of extensive archaeological research which entailed the excavation of the major archaeological sites in the oasis (Husn Salut; Salut-ST1; Jabal Salut necropolis; Qaryat Salut) was established in 2004, when the work of the Italian Mission to Oman started tracing the outlines of the regional evolution of human occupation [START_REF] Phillips | Works of the Italian Mission at Salut: a concise overview of ten years of investigation[END_REF]Degli Esposti, 2015a;[START_REF] Avanzini | Husn Salut and the Iron age of south east Arabia. Excavations of the Italian Mission To Oman 2004-2014[END_REF][START_REF] Tagliamonte | New data from the renewed excavation at Salūt: the Iron Age settlement (Qaryat Salūt)[END_REF]. Extensive stratigraphic excavations were combined with a programme of surveys conducted over the plain surrounding the sites, as well as the surrounding hillocks (e.g. [START_REF] Phillips | Further consideration of Bronze and Iron Age Settlement patterns at Salut[END_REF][START_REF] Condoluci | Iron age settlement patterns at Salut, ca. 1300-300 BC[END_REF], which led to the identification of several open-air sites, including some rock art panels and isolated representations (Fig. 1).

Locally, the earliest human traces in the area can be dated back to the Palaeolithic, whereas scatters of lithics suggest the Neolithic exploitation of the region (Fig. 2). However, the most evident and systematic occupation of the area and exploitation of natural resources corresponds to the Early Bronze Age (second half of the 3 rd millennium BCE). At that time, three monumental stone tower sites were erected along the eastern side of Wadi Sayfam, being an expression of a specific culture that displays homogeneous characters throughout the Oman peninsula, from Musandam in the north to the Masirah Island in the south [START_REF] Orchard | Third millennium oasis towns and environmental constraints on settlement in the Al-Hajar region[END_REF][START_REF] Degli Esposti | Excavations at the Early Bronze Age site «ST1» near Bisyah (Sultanate of Oman): notes on the architecture and material culture[END_REF]. A demographic decrease apparently marked the first half of the 2 nd millennium BCE, while a reverse trend started around the end of the 15 th century BCE, as indicated by the establishment of a dense network of Iron Age sites, clustering around the citadel of Salut [START_REF] Avanzini | An outline of recent discoveries at Salut in the Sultanate of Oman[END_REF][START_REF] Phillips | Archaeological survey in wadi Bahla (Sultanate of Oman): an Iron Age site on Jabal al-Agma, near Bisyah[END_REF][START_REF] Condoluci | Iron age settlement patterns at Salut, ca. 1300-300 BC[END_REF]. Archaeological excavation suggests that this settlement, somehow precocious compared to other areas of southeast Arabia, lasted beyond the end of the Early Iron Age period, that is, beyond c. 300 BCE and likely until the 1 st century CE (Degli Esposti et al., 2018a[START_REF] Waagen | New technology and archaeological practice. Improving the primary archaeological recording process in excavation by means of UAS photogrammetry[END_REF]. During this long phase the palaeo-oasis of Salut reached its greatest spatial extent and apogee of agricultural land use. Around the end of the 1 st century CE, the palaeo-oasis of Salut was abandoned for several centuries. After that, the citadel of Salut witnessed three distinct periods of Islamic occupation: (i) Early Islamic (ca. 9 th /10 th century CE); (ii) Middle Islamic (ca. 12 th /13 th century CE); and (iii) Late Islamic (after the 16 th century CE) [START_REF] Whitcomb | The archaeology of Oman: a preliminary discussion of the Islamic periods[END_REF][START_REF] Avanzini | Salut, Sultanate of Oman report[END_REF][START_REF] Avanzini | Husn Salut and the Iron age of south east Arabia. Excavations of the Italian Mission To Oman 2004-2014[END_REF]. Geoarchaeological evidence indicates that the major phases of expansion of settlements in the area were related to the establishment of efficient systems for water management sustaining intensive cultivation (Cremaschi et al., 2018a).

Materials and methods

Description of the rock art panel

The petroglyphs discussed in this paper were engraved on the vertical flank of a large boulder on the southwestern slope of Jabal Hammah (Fig. 34), northeast of Husn Salut. The Jabal Hammah is a rocky monocline relief dotted by several prehistoric tombs [START_REF] Condoluci | High places in Oman: the IMTO excavations on Jabal Salut. Quaderni di Arabia Antica 3[END_REF]Degli Esposti et al., in press). On the southwestern slope of the hill, several blocks and boulders belonging to the Wahrah Formation are present, corresponding to the remains of an ancient rockfall triggered by undersapping processes that eroded the underlying marls. In the central part of the rockfall, the engraved boulder stands up. Several smaller blocks stand at its foot, possibly adjusted to increase its stability or to allow carving the engravings (Fig. 4). Other large boulders found along the slope of the hill were artificially stabilised, but they do not display engravings. On the contrary, in the same area several small, isolated engraved blocks were found. The large boulders and the small ones possibly correspond to a sort of landmark and are part of the same archaeological landscape.

We distinguished three engraved figures carved on the boulder surface (Fig. 5). Despite two of them being remarkably less well preserved, all can be recognised as representing the same motif: a standing man holding in his right hand a long shaft ending in a hemi-circular item, possibly the representation of a halberd (henceforth we refer to this item as halberd). The three figures are sketchily made with simple traits ("stick men"), with outstretched arms and open legs. Other petroglyphs are scattered in the surroundings of Jabal Hammah and they include horse riders, various animals, and several signs. The most of the latter are common in the region, as suggested by several comparisons (e.g., [START_REF] Jung | On representations of camels and camel-riders in the rock art of Northern Yemen[END_REF][START_REF] De Ceuninck | Les pétroglyphes du Fujairah, Emirates Arabes Unis[END_REF][START_REF] Haerinck | Petroglyphs at Sinadil in the Hajjar mountains (southeast Arabia)[END_REF]Ziolkowski, 1998Ziolkowski, , 2007;;[START_REF] Khan | The rock art of Saudi Arabia across twelve thousand years[END_REF][START_REF] Khan | Rock Art of Saudi Arabia[END_REF][START_REF] Fossati | Current finds in rock art research of Oman: a review and update[END_REF]. Although other examples of complete motifs of the standing man with halberd have not been found so far in the area of Salut, we spotted a few representations of the single halberd (Fig. 6). Interestingly, these engravings were made using the continuous pecking technique instead of the dotted technique that distinguishes the great majority of the rock art in the area; this is a further similarity to our case study. Three isolated halberds are on the southern face of a boulder employed in the building of one of the structures that is part of an Early Bronze Age tower (T2) standing some 600 meters north of the Iron Age complex of Salut (Degli Esposti, 2015b). The engraving was manufactured after the block was inserted in the masonry structure; however, it is hard to define the real chronological correlation between the engravings and the age of the tower T2. A few stone seals found during archaeological excavations provide additional, indeed scarce, parallels. A cylinder seal found at the Bronze Age tower ST1 in the area of Salut, dated to the Iron Age re-occupation of the site, bears a representation closely resembling the halberds shown on the discussed boulder [START_REF] Degli Esposti | The excavation of an Early Bronze Age tower near Salut (Bisyah, Sultanate of Oman): the Iron Age levels[END_REF], 2015b). Moreover, another cylinder seal from Ra'a al Jinz RJ-2, dated by its excavators between 2500 and 2250, is carved with an identical figure [START_REF] Cleuziou | Ra's al-Jinz and the prehistoric coastal cultures of the Ja'alān[END_REF].

Field survey, photographic recording, and analyses

The engraved boulder discussed here was located by one of the authors (MC) during a survey of the rock art panels over the hills surrounding the citadel of Salut. The boulder and the surrounding area were carefully inspected and engravings digitally recorded and drawn. Moreover, a 3D model of the boulder was elaborated with Structure-from-Motion (SfM) photogrammetry. This technique uses an automated process to obtain point clouds, triangular meshes and full 3D textured models from images (Peña-Villasenín et al., in press) and has been applied with relevant results in field archaeology [START_REF] De Reu | Towards a three-dimensional cost-effective registration of the archaeological heritage[END_REF][START_REF] Galeazzi | Towards the Definition of Best 3D Practices in Archaeology: Assessing 3D Documentation Techniques for Intra-Site Data Recording[END_REF][START_REF] Waagen | New technology and archaeological practice. Improving the primary archaeological recording process in excavation by means of UAS photogrammetry[END_REF] as well as in rock art studies [START_REF] Sanz | A simple methodology for recording petroglyphs using low-cost digital Reference Shelf[END_REF]Plisson and Zotkina, 2015;[START_REF] Robert | Applications of digital photography in the study of Paleolithic Cave art[END_REF][START_REF] Bea | Geometric Documentation and Virtual Restoration of the Rock Art Removed in Aragón (Spain)[END_REF], being the most

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appropriate solution for macroscopic 3D recording in the field in terms of time and cost of execution. Moreover, for the majority of rock art sites, SfM 3D-modelling has proved to be a valuable, cost-effective alternative to Terrestrial Laser Scanner (TLS) [START_REF] Johnson | Using photogrammetry to interpret human action on Neolithic monument boulders in Ireland's Cavan Burren[END_REF][START_REF] Jalandoni | Testing the value of low-cost Structure-from-Motion (SfM) photogrammetry for metric and visual analysis of rock art[END_REF]. In this paper, we applied a low-cost and high flexible SfM approach [START_REF] Jalandoni | Testing the value of low-cost Structure-from-Motion (SfM) photogrammetry for metric and visual analysis of rock art[END_REF] to elaborate a 3D model for metric analysis and digital tracing of rock art motifs (Supplementary Material). In our case study, we took 156 pictures with a Canon EOS 100D from different perspectives and elevations with at least 60% overlap and markers with a known distance were placed near the boulder; Tab. 1 presents camera location parameters used in the elaboration of the 3D model. The 3D model was generated and scaled using Agisoft Metashape photogrammetric software [START_REF] Agisoft | Agisoft Metashape User Manual: Standard Edition[END_REF].

As described in the following parts (sections 4.1 and 4.2), the best-preserved part of the rock art panel is covered by a dark, hard mineral coating. The same coating covers or fills small natural depressions along the boulder and along vertical discontinuities (fractures). To establish the nature and age of the weathering crust, we collected it in correspondence of several linear fractures on the sides of the boulder not related to engravings. Several small crust and bedrock samples were removed with a small chisel.

Rock samples were cut perpendicular to the crust surface, polished, and thin section prepared according to the procedure described in [START_REF] Murphy | Thin Section Preparation of Soils and Sediments[END_REF]. Micromorphological observation under plane-polarized light (PPL) and cross-polarized light (XPL) of thin sections were conducted with an optical petrographic microscope Olympus BX41 equipped with a digital camera (Olympus E420); during interpretation, we followed the concepts discussed in Cremaschi et al., 2018b. Micromorphological studies of thin sections also employed a Cambridge 360 scanning electron microscope (SEM) imaging both secondary and back-scattered electrons. Energy dispersive X-ray analysis (EDS Link Isis 300) required to carbon coat the thin sections. Energy dispersive X-ray spectroscopy worked with an accelerating voltage of 20 kV, filament intensity 1.70 A, and probe intensity of 280 pA. Every analysed element was previously standardised by using several single element standards (Micro-Analysis Consultants Ltd); elemental concentrations measured by EDS are reported as oxide weights normalized to 100%.

Several fragments of the crust were collected and glued on glass fibers mounted on a goniometer head. An Oxford Diffraction Xcalibur 4-circle diffractometer, equipped with a Mo-Kα X-ray tube (λ = 0.7107 Å) and a CCD area detector and operating at 50 kV and 30 mA, were used for X-ray diffraction investigations. The diffraction patterns were collected by exposing each

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sample for 45 or 120 seconds during a full rotation of the goniometer head around the vertical axis.

The collected images were integrated into a 2θ-Intensity diffraction pattern adopting the routines implemented in the software Crysalis (Rigaku Oxford Diffraction, 2018). The phase assignment was done based on the collected powder diffraction patterns, using the 'Xpert HighScore suite [START_REF] Degen | The Highscore Suite[END_REF].

Several samples of rock crust were observed with a Confocal Laser Scanning Microscope (CLSM) after fluorescent staining. Confocal images were collected using a Nikon A1 laser scanning confocal microscope and a 20x/0.75NA (WD 1 mm) Plan Apo λ objective. Fluorescence was excited and collected using different combinations of the following laser lines and emission parameters: (i) autofluorescence from photosynthetic pigments was viewed in the red channel using the 633 nm line of an Ar/HeNe laser in the emission range of 650 to 750 nm; (ii) The total biofilm biomass was visualized by DAPI (4′,6-diamidino-2-phenylindole, Invitrogen) staining according to manufacturer instructions. This dye was excited with a 405 nm laser with emission collected in the range of 430-480; (iii) metabolically active cells of the biofilms were viewed in the green channel by staining the samples with Calcein AM (FilmTracer™ calcein green biofilm stain, Invitrogen) according to manufacturer instructions. This dye was excited with a 488 nm laser with emission collected in the range of 500-550 nm; (iv) extracellular polysaccharides were detected by Con A staining (Concanavalin A, Alexa Fluor 488 conjugate, Invitrogen) according to manufacturer instructions. This dye was excited with a 488 nm laser with emission collected in the range of 500-550 nm; (v) extracellular proteins were detected by Bodipy staining (BODIPY® 630/650-X, Invitrogen) according to manufacturer instructions. This dye was excited with a 633 nm laser with emission collected in the range of 650-700 nm. CLSM was used in reflectance mode with the 488 nm argon line for relief imaging of specimens. Captured images were analysed with the software NIS-Elements (Nikon) for 3D reconstructions of biofilms.

Based on both SEM and optical microscopes observations, one sample of weathering surface not experiencing mechanical or biogeochemical weathering (Sowers, 2000) was selected for accelerator mass spectrometry radiocarbon dating (AMS-14 C), as organic carbon generally occurs trapped under the Mn-rich rock varnish at the rock interface [START_REF] Dorn | Accelerator mass spectrometry radiocarbon dating of rock varnish[END_REF]. The sample for dating was prepared according to the protocol described in Zerboni (2008). A portion of the same sample was analysed for total organic carbon (TOC) by titration using chromic acid to measure the oxidizable organic carbon [START_REF] Walkley | An examination of Degtjareff method for determining soil organic matter and a proposed modification of the chromic acid titration method[END_REF]. The sample was dated at the facility of the

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University of Georgia (USA). AMS-14 C age result was calibrated using the INTCAL13 calibration curve [START_REF] Reimer | IntCal13 and Marine13 radiocarbon age calibration curves 0-50,000 years cal BP[END_REF] and results reported with 95.4% and 68.2% accuracy.

Results

Description of the rock surface of the boulder

The surface of the boulder, as much as many other rock surfaces in the area, displays evidence of weathering processes. Physical and chemical deterioration are the most evident effects of weathering. In the area, blocks are often disaggregated by thermal stress, and the surface of limestone rocks dotted by small-scale solution pits, karren, and microkarren (sensu [START_REF] Ginés | Karst Rock Features: Karren Sculpturing[END_REF] (Fig. 7). One further karst-related feature is evident at the micro-scale (Fig. 8); under the microscope, boulders and blocks display dissolved surfaces with etch pits [START_REF] Fiol | El Rillenkarren: un tipus particular de biocarst? Primares dades[END_REF]. In this case, where the dominant lithotype is a siliceous limestone, the formation of alveolar microdepressions at the rock surface is controlled by the dissolution and removal of micritic mud among silicified grains (Fig. 8). Moreover, on the considered boulder evidence of calcium carbonatebearing case hardening (Smith, 1988;[START_REF] Dorn | Rock Coatings[END_REF] is present. In fact, along the margins of the boulder, we occasionally notice the occurrence of a few mm thick coating of sparitic calcite combined with iron oxides and occasionally clay minerals (Fig. 8).

As a consequence of the abovementioned processes, the surface of the boulder is rough and limestone dissolution levelled the micro-relief of engravings, leading to their removal. The groves of the engravings are best preserved in few places, where dark, few mm-thick crusts are present (Fig. 9). The same crust is evident also in correspondence of natural depressions, cracks, and fractures along the same boulder, and on many other rocks outcropping along Jabal Hammah (Fig. 9). At the macro-scale, the crust is metallic, smooth, massive, and hard; its [START_REF] Munsell® | Soil Color Charts[END_REF] color varies between 10R 2.5/1 and 10YR 2/2 (reddish black-very dark brown). Moreover, a very thin layer of a darkish coating covers the whole rock surfaces of subaerially exposed rocks (Fig. 7).

Generally, the color of this coating is 10YR 4/1 (dark gray) and contrast with the yellowish color of the fresh Wahrah Formation limestone (10YR 7/6, yellow). The thin rock coating is widespread in the area, but at some places dismantled by recent wind erosion.

Under the petrographic microscope, the dark crust consists of a continuous layer draping the discontinuities between the residual siliceous grains and filling the alveolar depressions at the rock surface (Fig. 10). This results in an irregular thickness of the crust along the rock surface, higher in correspondence of alveolar voids and thinner on grains. At PPL and XPL, the dark

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coating is massive and opaque, with a few reddish reflections along some silicified ooids; reddish parts of the coating show a moderate birefringence under XPL. Conversely, the thin rock coating widespread on all exposed rock surfaces displays almost the same thickness of a few tens of microns (rarely thicker) and a dark brownish color under PPL to a light to dark brown color and very weak birefringence under XPL (Fig. 8). This coating covers also the dark crust and has analogies with dust films [START_REF] Rivard | Varnish, sediment, and rock controls on spectral reflectance of outcrops in arid regions[END_REF][START_REF] Dorn | Rock Coatings[END_REF] enriched with local constituents and others originating from the aerosol.

The higher magnification of the SEM better illustrates the occurrence of alveolar voids due to dissolution on top of rock surfaces (Fig. 11), the continuity of the thin dust film (Fig. 11), and the occurrence of coating infilling and draping discontinuities (Fig. 12). The thickness of the dust film never exceeds 100 µm and is dark brown under the SEM; the EDS analysis suggests a composition dominated by Si (~50-60%), Al (~16-20%), Fe (~9%), and Mg (~8-11%), and enrichments of such alkalis as K (~2.5-5%) and Na (~2-2.5%). This layer adheres to the rock surface, but it did not tightly grow on it (Fig. 11); chemical data suggest that this layer consists mostly of clay minerals, possibly Fe-oxides stained, and enriched in alkalis form the aerosol [START_REF] Cremaschi | L'arte rupestre del Tadrart Acacus: testimone e vittima dei cambiamenti climatici[END_REF], thus confirming the attribution to dust film. The thickness of the dark crust found in the engravings' furrows and sampled along discontinuities of the block varies from a few up to 500 µm. SEM images in Fig. 12 illustrate the different properties of the samples and help in discriminating between the micritic matrix, siliceous ooids, and many components of the crust. The outer part of the crust consists of a convolute to botryoidal mixture of crystals; EDS analysis detected major concentrations of the following elements: Si (~36-44%), Al (~17-20%), Fe (~10-13%), Mg (~6.5-10%), K (~3%), Na (~2.5%), and Ca (~2.5-1.5%). This layer is up to 100 µm thick and dotted by whitish features enriched in Mn (~7-16%); it can be interpreted as a layer of clay minerals enriched in Mn and Fe oxides -a rock varnish [START_REF] Dorn | Rock Coatings[END_REF][START_REF] Dorn | Rock varnish[END_REF]. The subsequent part under the SEM appears white and bright; in fact, it is enriched in Fe (~85-90%), with a lower content of Si (~8%), Na (~1.5%), Mg (~1%), and Al (<1%). Towards the bottom of the crust, the Fe content decreases up to ~65%, but we noticed an enrichment of Ca (~7.5%), and P (~5.5%). In rock coatings, concentrations of Ca and P showing parallel trends generally indicate the presence of calcium phosphates minerals, ultimately related to biologic processes [START_REF] Reneau | Elemental relationships in rock varnish stratigraphic layers, Cima Volcanic Field, California, implications for varnish development and the interpretation of varnish chemistry[END_REF][START_REF] Dorn | Rock Coatings[END_REF][START_REF] Cremaschi | L'arte rupestre del Tadrart Acacus: testimone e vittima dei cambiamenti climatici[END_REF].

The analysis of the X-ray powder diffraction patterns reveals a heterogeneous spatial distribution of the mineral phases making up the weathering crust. Overall, in addition to the

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12 ubiquitous contribution of quartz, which can be assigned to the underlying siliceous ooids, the observed diffraction peaks from the collected patterns were assigned to birnessite -ideally (Na,Ca,K)0.5(Mn 4+ ,Mn 3+ )O4•1.5H2O -and, locally, hydroxyapatite and halite, whereas two samples clearly show also the occurrence of an amorphous phase. The identification of amorphous phases is compatible with the occurrence of mixtures of Mn and Fe oxides and hydroxides that are common in rock coatings, whereas birnessite is one of the most common crystalline phase in Mnbearing rock varnish [START_REF] Potter | The manganese-and iron-oxide mineralogy of desert varnish[END_REF][START_REF] Dorn | Rock Coatings[END_REF]. The detection of hydroxyapatite is compatible with the occurrence of Ca and P, and has been described in rock varnish [START_REF] Nriagu | Phosphate minerals: their properties and general modes of occurrence[END_REF][START_REF] Dorn | Rock Coatings[END_REF].

CLSM observations

Representative images of the biofilm biomass and the extracellular organic matter (EOM) retrieved on the rock surfaces are presented in Fig. 13a and Fig. 13b Phototrophs (red signal) appear as few isolated coccoid cells on the rock surfaces, while chemotrophs (green + blue signals) dominate the biofilm community. The fraction of metabolically active cells in the biofilms is distinguished by coupling the results from DAPI staining (blue signal) with those obtained from Calcein AM staining (green signal) (Fig. 13a). In fact, while the DNAbinding dye DAPI shows the total biofilm biomass (active and non-active cells), the green fluorescent viability dye Calcein AM can measure intracellular esterase activity, which is an indicator of both cellular metabolic activity and cell membrane integrity. Thus, the green signal in Fig. 13a represents the fraction of active cells in the biofilm, which is about 30% of the total biomass. The fluorescent signals in Fig. 13b indicate the EOM retrieved on the rock surfaces. The green signal, derived from the lectin-binding dye Con A, reveals the presence of extracellular glycoconjugates (i.e. polysaccharides, including those ones covalently linked to proteins and/or lipids) covering the lithic surfaces. BODIPY® 630/650-X is an amine-reactive dye used to label the primary amines of proteins, amine-modified oligonucleotides, and other amine-containing molecules. The resulting red signal shows the presence of extracellular proteinaceous materials accumulating on the rock surfaces and partially overlapping the green signal of glycoconjugates.

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Overall, the microbiological investigations reveal that: i) the lithic substrates are colonised by a monolayer of cells growing in small clusters that follow rock fissures and cracks; ii) chemotrophs comprise the largest proportion of the biofilm community in all the specimens analysed, and iii) only a small fraction (about 30%) of the biofilm community is metabolically active; moreover, iv) a thin layer of extracellular organic materials rich in glycoconjugates cover most of the rock surfaces.

Radiocarbon dating

Rock varnishes and rock crusts can be radiocarbon dated if they are biomineralized and if they still preserve organics trapped within weathering products [START_REF] Dorn | Accelerator mass spectrometry radiocarbon dating of rock varnish[END_REF][START_REF] Dorn | New approach to the radiocarbon dating of rock varnish, with examples from drylands[END_REF][START_REF] Cremaschi | L'arte rupestre del Tadrart Acacus: testimone e vittima dei cambiamenti climatici[END_REF]. The latter generally act as a sealing, allowing the isolation of the carbon systems from external contaminations. A sample of crust collected on the boulder -although not in correspondence of engravings -displaying a TOC content of ca. 1.5 g/kg was submitted to AMS-14 C dating. The analyses rendered the age of 2600±60 uncal. years BP (see calibration in Tab. 2). This age refers to the growth of the rock crust; thus it is a limit ante quem for the making of engravings.

Discussion

Engravings in the regional context

In the recent years, a number of studies highlighted the rich rock art record of the Arabian Peninsula (e.g. Anati, 1968Anati, -1974;;[START_REF] Shari | Dhofar: its ancient writings and inscriptions[END_REF][START_REF] Nayeem | The Rock Art of Arabia: Saudi Arabia, Oman, Qatar, the Emirates & Yemen[END_REF][START_REF] Crassard | Prehistoric rock art in Hadramawt: the site of Ali-1 in Wâdî Bin 'Alî (Yemen)[END_REF][START_REF] Jennings | Rock art landscapes beside the Jubbah palaeolake, Saudi Arabia[END_REF][START_REF] Bednarik | Scientific investigations into Saudi Arabian rock art: a review[END_REF][START_REF] Guagnin | An illustrated prehistory of the Jubbah oasis: Reconstructing Holocene occupation patterns in north-western Saudi Arabia from rock art and inscriptions[END_REF], and in particular of the Sultanate of Oman (e.g. Clarke, 1975aClarke, , 1975b;;[START_REF] Preston | An introduction to the anthropomorphic content of the rock art of Jebel Akhdar[END_REF][START_REF] A N U S C R I P T A C C E P T E D Accepted Manuscript 26 Jäckli | Rock art in Oman. An introductory presentation[END_REF][START_REF] Insall | The petroglyphs of Shenah[END_REF][START_REF] Yule | The Hasat Bin Salt in the al-Zahirah Province of the Sultanate of Oman[END_REF][START_REF] Khan | The rock art of Saudi Arabia across twelve thousand years[END_REF]Al-Jahwari and ElMahi, 2013;[START_REF] Fossati | Current finds in rock art research of Oman: a review and update[END_REF][START_REF] Tokunaga | Early Islamic and Ancient North Arabian graffiti and petroglyphs in Tabūk province -Saudi-Japanese al-Jawf/Tabūk Archaeological Project (JTAP)[END_REF]. Nevertheless, the engravings of human figures with halberd are almost unique in the region; at least, a few engraved items that can be interpreted as isolate halberds exist. In fact, no fitting comparison is known from South East or South Arabia.

One similar engraving was found north of Timna in the Arabah Valley (Negev Desert), among the representations of a densely decorated panel with petroglyphs belonging to different ages [START_REF] Rothenberg | Rock drawings in the Ancient Copper Mines of the Arabah -new aspects of the region's history[END_REF]. At this site, a "stick man" in the same outstretched position as those at Salut and holding a double-pointed-head item is present. This figure has some similarities with the one represented at Salut. However, the head of this item (tool or weapon) is less curved, and the man holds it from one end of the head and not from the shaft. Given the context, the famous mining

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14 area of the Arabah (e.g. [START_REF] Rothenberg | Timna. Valley of the Biblical copper mines[END_REF][START_REF] Rothenberg | Chalcolithic copper smelting[END_REF], this tool could be reasonably interpreted as a pickaxe.

Formation of rock coatings

The microscopic, chemical, and mineralogical investigation on the rock surface of the boulder with engravings and the identification of an equivalent of the rock crust preserving engravings suggests the occurrence, along time, of many and contrasting weathering processes. Different climatic conditions triggered each weathering process and led to the formation of specific weathering products.

The dissolution of the rock surfaces and the formation -at the micro-scale -of alveolar etching pits are related to karst process. This requires moderate water availability, higher than the present day one. In fact, the effects of karst processes along Jabal Hammah seem quite significant and not compatible with the present hydroclimate. In fact, the so-called arid karst is controlled by intense evapotranspiration at the surface, low rate of CO2 enrichment of solutions, and fast percolation of water, resulting in less intense surface karstification and more intense underground dissolution [START_REF] Kranjc | Arid Karst or Karst in Arid Countries? The Egyptian[END_REF]. The greyish layer covering all subaerially exposed rock surfaces in the area of Jabal Hammah is a dust film [START_REF] Dorn | Rock Coatings[END_REF], consisting of fine mineral particles originating from the aerosol and the deflation of surrounding soils aggraded on rock by the wind. Its accretion is related to arid environmental conditions and today its formation could be still active.

Finally, the crust grown along the engravings' furrows can be defined as a complex and multi-layered Fe-and Mn-bearing rock varnish. Its formation required several processes including microorganism-promoted biomineralization. The distribution of this weathering surface is more limited than the dust film, and it seems to be more common on the sheltered portions of siliceous limestone. This is compatible with other data suggesting that rock varnish growth occurs preferentially on silica-bearing rocks [START_REF] Dorn | Rock Coatings[END_REF][START_REF] Dorn | Rock varnish[END_REF]. At Salut, rock varnish consists, like many varnishes developed in warm deserts, of a thick accumulation of poorly layered and oxidesimpregnated clay minerals. In our case, a large part of the rock varnish is impregnated by Feoxides, which represents the central part of the varnish, whereas its outer part mostly consists of the classical Mn-rich rock varnish. The association of iron films with manganese-rich accretions is common in arid and semiarid regions (e.g., [START_REF] Engel | Chemical data on desert varnish[END_REF][START_REF] Hooke | Desert varnish: an electron probe study[END_REF][START_REF] Hein | Bacterially mediated diagenetic origin for chert-hosted manganese deposits in the Franciscan Complex, California Coast Ranges[END_REF][START_REF] Cremaschi | The rock varnish in the Messak Sattafet (Fezzan, Libyan Sahara), age, archaeological context, and palaeoenvironmental implication[END_REF]. Both iron and manganese oxides are likely the result of intense biomineralization occurred in presence of clays under environmental settings wetter than today,

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and interrupted by the onset of severe arid climate [START_REF] Kiersch | Small-scale structures and other features of the Navajo Sandstone, northern part of the San Rafael Swell, Utah[END_REF][START_REF] Dorn | Rock Coatings[END_REF][START_REF] Dorn | Rock varnish[END_REF]. This is the same environmental context of Mid-Late Holocene rock varnish formed in the Sahara [START_REF] Cremaschi | The rock varnish in the Messak Sattafet (Fezzan, Libyan Sahara), age, archaeological context, and palaeoenvironmental implication[END_REF][START_REF] Cremaschi | L'arte rupestre del Tadrart Acacus: testimone e vittima dei cambiamenti climatici[END_REF]. Moreover, Krumbrein (1969[START_REF] Krumbein | Biologische Entstehung von wiistenlack[END_REF] observed rock varnish on silicified limestone from the Negev Desert and, similarly to our case, dissolution created surface pores that were occupied by iron and manganese deposits.

The agent promoting the accumulation of rock varnish could not be unquestionably identified, but we think that a biological mediation occurred. For instance, the surrounded features in the Fe-rich layer are similar to the product of biomineralization [START_REF] Dorn | Rock Coatings[END_REF]. Moreover, a number of studies suggest that a plethora of microbial communities including bacteria, algae, fungi, and endolithic and epilithic lichens play a role in iron and manganese fixation on both limestone and siliceous bedrocks (Scheffer et al., 1963;[START_REF] Krumbein | Ober den Einfluss der Mikroflora auf die Exogene Dynamik (Verwitterung und Krustenbildung)[END_REF][START_REF] Krumbein | Biologische Entstehung von wiistenlack[END_REF][START_REF] Ascaso | The pedogenic action of Parmelia conspersa, Rhizocarpon geographicum and Umbilicaria pustulata[END_REF][START_REF] Friedmann | Endolithic microorganisms in the Antarctic cold desert[END_REF][START_REF] Dorn | Rock Coatings[END_REF]. Confocal microscopy images confirmed the presence of a metabolically active microbial community on rock surfaces. These findings also suggest the attribution of rock varnish to biomineralization through the activity of chemotrophs.

Age of rock art and weathering processes, and palaeoenvironmental implications

Once defined the main processes implied in the chemical weathering of rock surfaces and in the decay of engravings, we can try to delineate a tentative relative chronology of events, which can be improved considering the radiocarbon dating and the comparison with regional palaeoclimatic data.

The single radiocarbon age available refers to the formation of rock varnish. The attribution of the result of radiocarbon dating to rock varnish is suggested by the occurrence of phosphates, whose formation is related to biological processes, trapped within the Fe-and Mn-rich layers. As a consequence, the age of rock varnish formation represents a terminus ante quem for the age of engravings. The AMS-14 C result is also useful in reconstructing the palaeoenvironmental context of rock art.

The oldest process that occurred in the region is the dissolution of limestone, promoted by wet environmental conditions. In the area, most of the Holocene was wetter than today, and arid environmental conditions started in the Late Holocene (e.g. [START_REF] Fleitmann | Holocene ITCZ and Indian monsoon dynamics recorded in stalagmites from Oman and Yemen (Socotra)[END_REF], also contributing to the abandonment of Early Bronze Age sites and to the transition to a different settlement pattern during the Middle Bronze Age, around c. 2000 BCE (e.g., [START_REF] Magee | The Archaeology of Prehistoric Arabia. Adaptation and Social Formation from the Neolithic to the Iron Age[END_REF]. The larger water availability recorded in the Early Bronze Age phase prompted the onset of intensive

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16 agriculture and the creation of complex water-management systems (Cremaschi et al., 2018a), and probably allowed the biomineralization of rock varnish in the alveolar voids produced by pristine dissolutions. Likely, the rock surface studied here was engraved during this period. In fact, the available radiocarbon date indicates this happened before 2600±60 uncal. years BP, which means at least before the central part of the local Early Iron Age (overall commonly dated between 1300 and 300 BCE). This is compatible with the identification of a similar representation on an architectonic element of the Early Bronze Age tower T2 at Salut, although it only includes isolated halberds and no human figure (Degli Esposti, 2015b).

On the contrary, the subsequent Middle and Late Bronze Age, as well as the Early Iron Age, are marked by a progressive reduction of rainfall [START_REF] Fleitmann | Holocene ITCZ and Indian monsoon dynamics recorded in stalagmites from Oman and Yemen (Socotra)[END_REF]. During this arid period, marked by short-timed wet episodes, biological processes triggering biomineralization were interrupted. Archaeological evidence related to water management and excavation of deep wells confirms the reduction of environmental humidity at the beginning of this long period (Cremaschi et al., 2018a). Likely, short-timed resumption of rainfall occurring in the last three millennia of the Holocene (for instance, in Medieval times) conveyed sufficient water to occasionally reactivate karst dissolution and promote the levelling of the engravings' furrow. Fortunately, the presence of the weathering crust had a case-hardening effect on the underlying rock (sensu [START_REF] Kiersch | Small-scale structures and other features of the Navajo Sandstone, northern part of the San Rafael Swell, Utah[END_REF][START_REF] Twidale | Granite landforms[END_REF][START_REF] Dorn | Rock Coatings[END_REF] preserving engravings up to today. Finally, in the last centuries of severe arid conditions, the wind accreted the thin dust film covering all rock surfaces.

Other means of dating the engravings are admittedly of little help. Comparative dating cannot be used as precise complete parallels are unknown, while the most common isolated halberds also lack a safe date. Stylistic issues seem to be a poor tool, given the overall naïve appearance of the wide majority of the rock art in the region (e.g. Ziolkowski, 2007).

Representations of weapons/tools or animals for which dated archaeological counterparts or the age of first domestication are known would be common benchmarks for dating: suffice it to mention the ubiquitous representations of camel-riders and the currently accepted date for the domestication of this animal in ancient Near East around 1000 BCE [START_REF] Magee | When was the was the dromedary domesticated in the ancient Near East?[END_REF]. Unfortunately, there is no evidence in the archaeological record of the area of tools or weapons with a similar shape to the "halberds" depicted in the discussed engravings. The only possible candidate, a tool that actually recalls a small pick-axe, was first known from Mleiha in the Sharjah Emirate [START_REF] Mouton | La péninsule d'Oman de la fin de l'Âge du fer au début de la période Sassanide[END_REF] [START_REF] Degli Esposti | The Late Iron Age of central Oman (c. 300BC-300AD) -new insights from Salūt[END_REF]. The deriving chronology, however, fixed between mid-2 nd and 1 st century BCE, is strongly incoherent with the radiocarbon determination. [START_REF] Fossati | Current finds in rock art research of Oman: a review and update[END_REF] has recently proposed a tentative, broad phasing for the rock art of Oman (see also Fig. 2). There, "Dagger in T shape" are generally linked with 3 rd and 2 nd millennium BCE engravings. One anchoring point of this hypothesis is the affinity with Yemenite warrior stele, where similar signs actually represent daggers (e.g. [START_REF] Newton | Aspects of Bronze Age art of southern Arabia: The pictorial landscape and its relation to economic and socio-political status[END_REF]. It is clear from the case discussed here, as well as from the Arabah Valley comparison mentioned above, that these T signs cannot be univocally interpreted when found in isolation, and in the present case they surely do not represent daggers. A broad date into the 2 nd millennium BCE would, nevertheless, be consistent with the other evidence discussed here.

Fossati's (2017) 6 th phase, comprising the long period from the 1 st millennium BCE to the present, is distinguished by the widespread representation of warriors (often mounted). If the halberds depicted in the Salut boulder indeed are weapons (nothing precludes different interpretations, such as ceremonial items), their date could thus fit in at the very beginning of this long phase, and possibly suggest an earlier start for it.

Conclusion

In this paper, we describe a previously unknown iconography in the rock art of the Sultanate of Oman -the man with the halberd -, which does not fit any comparison with the engravings and paintings known in the region, although representations of isolated halberds (also called "Capital T" signs) are, conversely, rather well known (e.g. Ziolkowski, 2007;[START_REF] Fossati | Current finds in rock art research of Oman: a review and update[END_REF], and are also found scattered over the same oasis of Salut.

We suggest that lithological and environmental reasons are in charge of the scarcity of coeval engravings. The formation of rock varnish is the factor that triggered the preservation of engravings on Jabal Hammah. This process was promoted by the lithology of the boulderlimestone with silicified ooids -as Si-bearing rocks favour the growth of rock varnish. At Jabal Hammah rock varnish was not found on non-silicified limestone surfaces, which are, therefore, more prone to karst dissolution. In such a case, engravings may have been erased. In the area, the few other representations of isolated halberds were found in more protected contexts, as in the case of the engravings on the architectonic element of the tower T2. There, the block in the wall was buried after the abandonment of the site and, therefore, the rock surface and engravings did not undergo weathering and dissolution. At Jabal Hammah, the formation of a biomineralized In the case of the studied boulder, the interplay of contrasting chemical and biochemical processes (conservative vs. destructive processes) permitted the preservation of engravings, gave the opportunity to radiocarbon date them, and offered fresh data to reconstruct the complex archaeological landscape of the palaeo-oasis of Salut. Our work also confirms (i) the importance of weathering surfaces as proxy data of past environmental conditions [START_REF] Dorn | Rock varnish[END_REF]Cremaschi et al., 2018b), and (ii) the great potential that combined geoarchaeological investigation on rock art and its rock support [START_REF] Cremaschi | The rock varnish in the Messak Sattafet (Fezzan, Libyan Sahara), age, archaeological context, and palaeoenvironmental implication[END_REF][START_REF] Cremaschi | L'arte rupestre del Tadrart Acacus: testimone e vittima dei cambiamenti climatici[END_REF]Zerboni, 2012) has in paleoenvironmental reconstruction.

In a broader perspective, our results suggest that in some cases the absence of rock art evidence is not evidence of rock art absence. Destructive natural processes may have acted dismantling or rejuvenating rock surfaces, thus erasing engravings or paintings. Other case studies confirm this general assumption. For instance, in the hyperarid central Sahara, where prehistoric rock art panels and galleries dating to wetter periods of the Holocene are common, some rock shelters settled in prehistoric times do not present any rock art representations, as in the case of the Takarkori Cave [START_REF] Cremaschi | Takarkori rock shelter (SW Libya): an archive of Holocene climate and environmental changes in the central Sahara[END_REF]. This is the consequence of climate-driven processes that contributed to the continuous abrasion and dismantling of the friable sandstone surface of the vault of the rock shelter and to the loss of rock art, whose existence is suggested by archaeological evidence discovered in the anthropogenic infilling of the cave [START_REF] Di Lernia | Colour in context. Pigments and other coloured residues from the Early-Middle Holocene site of Takarkori (SW Libya)[END_REF]). Future regional rock art studies shall seriously take into account this conclusion.

List of tables

Table 1. Camera location parameters used to generate the 3D model of the boulder with rock art. Table 2. AMS-14 C dating results on rock crust; calibration according to [START_REF] Reimer | IntCal13 and Marine13 radiocarbon age calibration curves 0-50,000 years cal BP[END_REF].

List of figures

  -preserved figure, the uppermost, a faintly visible vertical stroke may indicate the penis, which is also vaguely visible in the central figure. The engravings were made with a continuous pecking, lowering the engravings' groves of a few millimetres under the original surface.

  respectively. The images correspond to the Maximum Intensity Projection (MIP) 3D reconstructions obtained from confocal images series with the dedicated NIS-Elements software. The fluorescent signals in Fig. 13a visualise cells in the biofilms. It is possible to observe a patchy distribution of small cell aggregates following the topography of the rock surfaces.

  , and most recently several examples have been excavated in the Salut plain necropolis (Degli

  from complete erosion triggered by karst dissolution. Many of the blocks and boulders of the area of Salut, however, display strong evidence of this process that might have erased other engravings.

  Hauptmann zum 65 Geburstag. Internationale Archäologie 12, Verlag Marie Leidorf, Rahden/Westf., 443-450. Zerboni, A., 2008. Holocene rock varnish on the Messak plateau (Libyan Sahara): Chronology of weathering processes. Geomorphology 102, 640-651. DOI: 10.1016/j.geomorph.2008.06.010. Zerboni, A., 2012. Rock art from the central Sahara (Libya): a geoarchaeological and palaeoenvironmental perspective. In: Huyge, D., Van Noten, F., Swinne, D., (Eds.), Proceedings of the International Colloquium 'The signs of Which Times? Chronological and Palaeoenvironmental Issues in the Rock Art of Northern Africa (Brussels, 3-5 June 2010). Royal Academy for Overseas Sciences, Brussels, pp. 175-195. Ziolkowsky, M., 1998. A study of the petroglyphs from Wadi al-Hayl, Fujairah, United Arab Emirates. Arab. Arch. and Epigr. 9, 13-89. Ziolkowsky, M., 2007. Rock on art: petroglyph sites in the United Arab Emirates. Arab. Arch. and Epigr. 18, 208-238.

Fig. 1 .

 1 Fig. 1. The study area on GoogleEarth™ satellite imagery; the star is the position of the boulder, dots are other rock art stations, the triangle is the position of the citadel of Salut. Note the monocline pattern of the Jabal Hammah. The inset indicates the position of the area in the Sultanate of Oman.

Fig. 2 .

 2 Fig. 2. Regional cultural periods on the basis of the current archaeological literature, compared with the periodization of rock art in Oman (Jabal Akhdar) as suggested by Fossati (2017).

Fig. 3 .

 3 Fig. 3. (A) General view of the western slope of the Jabal Hammah (the arrow indicates the position of the boulder). (B) A detail of the slope with the engraved boulder in its presentday landscape. (C) A view of the citadel of Salut from the Jabal Hammah.

Fig. 4 .

 4 Fig. 4. Different views of the engraved boulder after 3D reconstruction (see the text for details).

  Fig. 5. (A) Pictures of the main panel of engravings representing men with halberd, and (B) a detail of the best preserved figure. (C, D) Interpretative drawing of the panel of men with halberd.

Fig. 6 .

 6 Fig. 6. (A-C) Local comparisons for the representation of the man with halberd; (A) represents the engravings found on the masonry of the Bronze Age tower T2. (D) An example of a different iconography in the local rock art.

Fig. 7 .

 7 Fig. 7. Some examples of limestone surfaces displaying evidence of karst dissolution. Arrows in A and B indicate the deepest micro-karren (linear features); arrows in B and C indicate dissolution surfaces marked by small and irregular depressions C.

Fig. 8 .

 8 Fig. 8. Optical images of a cross section of samples from the engraved boulder: (A) Alveolar microdepressions at the rock surface, note the dissolution of micritic mud (PPL). (B) Sparitic calcite of the case hardening (XPL). (C) Cross section of a limestone surface covered by the thin dust film (PPL) and (D) a detail of the dust film (XPL).

Fig. 9 .

 9 Fig. 9. Field pictures of the rock crust developed in the groves of one of the engraved figures (A); note the incoming inversion of the relief due to karst dissolution and the crust sheltering the engraving from complete levelling. (B-E) Examples of the same crust developed elsewhere on the same boulder.

Fig. 10 .

 10 Fig. 10. Optical images of a cross section of samples of rock crust. (A) General view illustrating the distribution of the crust draping silicified ooids and infilling voids among them (PPL). (B) A detail of the crust in XPL illustrating its optical properties; note the occurrence of completely and partially silicified ooids and the removal of part of the micritic mud due to dissolution. (C) The crust at high magnification illustrating intergranular spaces filled by varnish material (PPL). (D) The same in XPL, note the presence of reddish and birefringent material (indicated by the arrows).

Fig. 11 .

 11 Fig. 11. Scanning Electron Microscope images of a cross section of rock surface: (A) alveolar voids due to dissolution (etching pits are indicated by the arrows); (B) thin dust film indicated by the arrows.

Fig. 12 .

 12 Fig. 12. Some examples of Scanning Electron Microscope images of the rock varnish. (A) General view of the varnish infilling dissolution pit and draping grains (indicated by the arrows); (o) silicified ooids and (m) micritic mud are indicated. (B) Accumulation of rock varnish inside intergranular spaces. (C) The multi-layered rock varnish descried in the text; (o) silicified ooids, (m) micritic muds, (Mn) layer of clay mineral with Mn and Fe oxides, (Fe) Fe-rich

Fig. 13 .

 13 Fig. 13. (A) Confocal laser scanning imaging of the biofilm; colours key: phototrophs, red (autofluorescence); metabolically active chemotrophs, green (Calcein AM); total chemotrophs, blue (DAPI); stone, grey (reflection). (B) Confocal laser scanning imaging of the extracellular organic matter retrieved on the rock surfaces; colours key: extracellular glycoconjugates, green (Con A); extracellular amine-containing molecules, red (BODIPY® 630/650-X); stone, grey (reflection).

Table 1 .

 1 Camera location parameters used to generate the 3D model of the boulder with rock art.

	Number of pictures	156	Camera stations	156
	Altitude	2.67 m	Tie points	128,354
	Ground resolution	0.647 mm/pix Projections	400,483
	Coverage area	13 m 2	Reprojection error	1.48 pix

Table 2 .

 2 AMS-14 C dating results on rock crust (calibration according to[START_REF] Reimer | IntCal13 and Marine13 radiocarbon age calibration curves 0-50,000 years cal BP[END_REF].

	Sample Latitude	Longitude	TOC	Laboratory code δ	13 C	pMC	AMS 14 C age	AMS 14 C age cal. 95.4%	AMS	14 C age cal. 68.2%
			(g/Kg)				years uncal BP years cal BC years cal BP years cal BC years cal BP
	Salut 1 N25°54'38.8"	E 12°14'48.9"	1.45-1.5 UGAMS 32708 -25.34	72.39±0.52	2600±60	901-541	2850-2490 836-590	2785-2539

Acknowledgments

We would like to express our gratitude to the Office of the Adviser to His Majesty the Sultan for Cultural Affairs, Muscat, and to A. Avanzini, Director of the Italian Mission to Oman (IMTO), whose help made the geoarchaeological research in the region possible. In particular, the Office of the Adviser to His Majesty the Sultan for Cultural Affairs asked M. Cremaschi to perform the rock art survey of the area surrounding the citadel of Salut in year 2016. F. Berra is thanked for helping with the interpretation of the petrography of limestone. Comments from Guest Editors and two reviewers increased the clarity of the manuscript. This research was supported by the Italian


MD, PhD Laurent Lam
email: laurent.lam@iplesp.upmc.fr

PhD; Patrizia Carrieri
email: pmcarrieri@aol.com

PhD Gilles Hejblum
email: gilles.hejblum@iplesp.upmc.fr

BS Jonathan Bellet
email: jonathan.bellet@iplesp.upmc.fr

MD Marc Bourlière
email: mbourliere@hopital-saint-joseph.fr

MD Fabrice Carrat
email: fabrice.carrat@iplesp.upmc.fr

Real-World Economic Burden of Hepatitis C and Impact of Direct-Acting Antivirals in France: A Nationwide Claims Data Analysis

Keywords: antiviral, HBV, hepatitis B virus, HCV, hepatitis C virus, HIV, human immunodeficiency virus, LTD, long-term disease, SNDS, Système National Health Care Costs, Antiviral Agents, Hepatitis C, Chronic, Administrative Claims, Healthcare

Background & Aims: The economic impact of managing patients with hepatitis C virus (HCV) infection remains unknown. This study aimed to assess the economic burden of chronic HCV infection from a national health insurance perspective and the impact of direct-acting antivirals (DAAs) using nationwide real-world data.

Methods: Patients with chronic HCV infection were identified from the French Health Insurance Claims Databases (SNDS) and matched for age and sex to the general population. Health resource utilization and reimbursements were summarized according to healthcare expenditure items from 2012 to 2021. The economic burden attributable to chronic HCV infection was evaluated over a 10-year period. Finally, the impact of DAAs was estimated using economic data derived from the SNDS.

Results: A total of 145,187 patients with chronic HCV infection were identified.

Among the patients eligible for DAA therapy, 81.5% had received DAA by the end of 2021. Over a 10-year period, managing patients with chronic HCV infection resulted in an additional cost of €9•71 billion (95% confidence interval [CI]: €9•66-€9•78 billion) or €9,191 (95% CI: €9,134-€9,252) per patient per year compared to the general population. After DAA therapy, patients with chronic HCV infection had a higher economic burden than the general population, with an additional cost of €5,781 (95% CI: €5,540-€6,028) per patient at the fifth year post-DAA therapy.

Conclusions:

A significant economic burden persists among patients with HCV infection after DAA treatment. The high proportion of patients not treated with DAA therapy supports reinforcing policies for universal access.

Lay Summary -Key Points

• The economic burden of chronic Hepatitis C virus (HCV) infection and the impact of direct-acting antivirals (DAAs) have not been evaluated nationally using extensive real-world data from French claims databases.

• Our results showed a significant and persistent economic burden even after successful treatment with DAAs, underscoring the necessity for ongoing efforts to develop strategies to mitigate this persistent burden in patients with chronic HCV infection.

• Given the large number of patients not treated with DAAs, policies promoting universal access to DAAs must be strengthened to achieve HCV viral eradication.

Introduction

The clinical management of patients with chronic hepatitis C virus (HCV) infection aims to limit the progression of liver fibrosis, liver-related complications, and the extrahepatic burden associated with HCV infection. [START_REF] Lavanchy | The global burden of hepatitis C[END_REF] To this end, direct-acting antivirals (DAAs) have been proven effective in reducing liver complications and mortality and achieving sustained virologic response. Consequently, a universal access policy for DAAs was implemented in France in 2017 owing to their proven efficacy and tolerability. [START_REF] Carrat | Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study[END_REF][START_REF] Pol | Impact of extending direct antiviral agents (DAA) availability in France: an observational cohort study (2015-2019) of data from French administrative healthcare databases (SNDS)[END_REF] Nevertheless, universal access to DAAs could result in a significant economic burden and threaten the long-term sustainability of healthcare systems, given the large number of patients chronically infected with HCV and the high cost of these medications. [START_REF] Kamal-Yanni | Hepatitis C drug affordability[END_REF] To evaluate this burden, it is imperative to evaluate the health resource utilization associated with managing patients with chronic HCV infection in the DAA era and perform a comprehensive assessment from the national health insurance perspective.

Previous economic models assessing the budgetary impact and cost-effectiveness of DAAs in France had several limitations, including relying on input parameters from clinical trials performed in selected patients with chronic HCV infection or studies not conducted in the French setting. [START_REF] Leleu | Cost-effectiveness of sofosbuvir in the treatment of patients with hepatitis C[END_REF][START_REF] Deuffic-Burban | Cost-effectiveness and budget impact of interferon-free direct-acting antiviral-based regimens for hepatitis C treatment: the French case[END_REF] In addition, most models focused on the costeffectiveness of specific DAA regimens rather than examining the overall impact of DAAs on the economic burden of hepatitis C in France. [START_REF] Leleu | Cost-effectiveness of sofosbuvir in the treatment of patients with hepatitis C[END_REF][START_REF] Maunoury | Cost-effectiveness analysis of elbasvirgrazoprevir regimen for treating hepatitis C virus genotype 1 infection in stage 4-5 chronic kidney disease patients in France[END_REF] Furthermore, it is essential to gather updated data on the actual proportion of patients who received DAA therapy in the national cohort of patients with chronic HCV infection to identify future efforts to achieve the HCV elimination goal set for France in 2025. [START_REF] Pol | Is elimination of HCV realistic by 2030: France[END_REF] The French national claims databases are a valuable resource for estimating the real-world economic burden of chronic HCV infection and the impact of DAA regimens. [START_REF] Rachas | The Economic Burden of Disease in France From the National Health Insurance Perspective: The Healthcare Expenditures and Conditions Mapping Used to Prepare the French Social Security Funding Act and the Public Health Act[END_REF] In this study, we examined reimbursement data from the French health insurance claims databases (SNDS) to estimate the economic burden of chronic HCV infection from 2012 until the end of 2021. Additionally, we evaluated the proportion of patients with chronic HCV infection treated with DAAs and the impact of DAA therapy on healthcare resource utilization from a national health insurance perspective.

Patients and methods

Study design and population

We analyzed the SNDS from January 1, 2010, to December 31, 2021, to identify patients with chronic HCV infection. A multi-criteria algorithm was used to identify a national cohort of patients with chronic HCV infection in France. This algorithm was previously validated using the reference viral hepatitis status as defined in the data from hepatitis B virus (HBV)-or HCV-infected patients enrolled between August 2012 and December 2015 in the French hepatology centers (ANRS CO22 HEPATHER) cohort. [START_REF] Lam | Performance of algorithms for identifying patients with chronic hepatitis B or C infection in the french health insurance claims databases using the ANRS CO22 HEPATHER cohort[END_REF] It combines various criteria related to chronic HCV infection management, including notification of long-term diseases (LTD, which refers to any severe or costly illness that entitles the patient to full reimbursement of medical expenses), hospital stay, medications related to HCV infection, laboratory tests, and medical procedures. This multi-criteria algorithm revealed a sensitivity of 96% and a specificity of 85%, with the viral status of patients from the ANRS CO22 HEPATHER cohort used as the gold standard. Of note, the specificity was calculated using HBVinfected patients as the control group.

To compare the economic data of individuals with chronic HCV infection with those of the general population, we randomly selected a sample of more than 5•5 million individuals without HCV infection from the SNDS. The cohort of patients with chronic HCV infection aged 18-85 years was then matched 1:1 to individuals from the general population based on birth year and sex to estimate the costs attributable to chronic HCV infection and its associated comorbidities. Patients with chronic HCV infection were matched with individuals from the general population on the date of entry into the cohort to adjust for potential changes in management and healthcare costs over time. All identified individuals were analyzed from January 1, 2012, to December 31, 2021 (Fig. 1).

Data sources

The primary data source was reimbursement data from French claims databases known as the SNDS (système national des données de santé). [START_REF] Tuppin | Value of a national administrative database to guide public decisions: From the système national d'information interrégimes de l'Assurance Maladie (SNIIRAM) to the système national des données de santé (SNDS) in France[END_REF] The SNDS covers over 99% of the French population and includes extensive reimbursement data related to inpatient and outpatient hospitalizations, dispensed medications, medical procedures, and laboratory diagnostic tests. Additionally, it provides data on LTD and the date of death.

Covariates and outcomes

Reimbursement data were examined from January 1, 2012, to December 31, 2021.

These included direct and indirect medical expenses reimbursed by the French National Health Insurance in both outpatient and inpatient settings, such as hospital stays in public and private institutions, medications dispensed in retail or hospital pharmacies (including expensive medications such as DAAs prescribed during the prioritized access period), medical devices, medical procedures, ambulatory laboratory tests, disability pensions, physician visits, transportation, work-related accidents, and occupational diseases. Baseline characteristics of the patients were established using specific International Classification of Diseases 10th Revision (ICD-10) codes in the SNDS, as shown in Supplementary Table 1.

Assessment of the economic impact of DAA

The proportion of patients who received DAA therapy and the changes over time were estimated by determining the annual number of patients eligible for DAA therapy and those treated with DAAs. Owing to the unavailability of laboratory test results in the French claims database, the following conditions were used to define patients eligible for DAA therapy each year: 1) being identified as a patient with chronic HCV infection in the French claims database based on the previously described validated multi-criteria algorithm; 2) being alive during the respective year;

3) no previous treatment with DAAs; and 4) no evidence of cure with interferon and ribavirin; that is, patients treated with interferon and ribavirin and not retreated with DAAs over the study period were considered as biologically cured patients and were not deemed eligible for DAA therapy. We identified all dispensed DAAs using specific medication codes for DAA regimens, including those obtained from ambulatory and hospital pharmacies (Supplementary Table 2).

Changes in medical expenses before and after DAA therapy were estimated, and the annual reimbursement per patient with chronic HCV infection was summarized over the consecutive years pre-and post-DAA therapy. The average reimbursement per individual for the matched general population was deduced from the overall economic burden to evaluate the specific burden attributable to chronic HCV infection management.

Ethics statement

French decree no. 2021-848 granted the authors permanent access to the SNDS.

The study adhered to the principles of the Declaration of Helsinki and French law on biomedical research and was approved by INSERM CepiDC. All data were anonymized, and no informed consent was obtained for the SNDS analysis.

Statistical analyses

Aggregated reimbursement data were descriptively summarized annually according to 12 healthcare expenditure categories. Specific reimbursements per person per year were calculated for patients with chronic HCV infection and the general population. The confidence intervals (CIs) were estimated using a bootstrap approach (10,000 iterations). For all patients with chronic HCV infection, follow-up began on the date of the first recorded evidence of the disease in the SNDS and continued until the date of death or 12/31/2021, whichever occurred first. All analyses were performed using the R version 4.1.2 (R Core Team).

Public and patient involvement

There was no public or patient involvement in the design of this study. All data collected from the SNDS were anonymized, and the study results were not intended for direct dissemination to the study participants.

Role of the funding source

The funding source was not involved in the study design, data collection and analysis, report writing, or decision to submit the paper for publication.

Results

Participants

In the French claims databases, we identified 145,187 patients who received care for chronic HCV infection between January 1, 2010, and December 31, 2021 (Fig. 1).

After excluding patients with an uncertain date of birth or death, 145,038 patients with chronic HCV infection were included. Of these, 141,141 were individually matched to a random cohort of the general population by sex and year of birth. The median age of the individuals was 52 years (interquartile range [IQR]: 45-60 years), and 61% were male (Supplementary Table 3). The total follow-up period analyzed in this study was 2,205,476 person-years, with a median follow-up time of 10 years (IQR: 7-10 years).

Economic burden of chronic HCV infection

Over 10 years, the cumulative amount reimbursed for the management of chronic HCV infection was €11•93 billion (95% CI: 11•87-11•99 billion), with an average reimbursement of €11,129 (95% CI: 11,069-11,185) per patient per year (Supplementary Table 4). Contrastingly, the total expenditure for the general population between January 1, 2012, and December 31, 2021, was €2•22 billion (95% CI: 2•21-2•23 billion). Therefore, the additional cost attributable to the management of chronic HCV infection was €9•71 billion (95% CI: €9•66-€9•78 billion) (Table 1). The additional cost per patient with chronic HCV infection compared with the matched general population cohort was €9,191 (95% CI: €9,134-€9,252) per year. The economic impact of DAA therapy Fig. 3 illustrates the changes in reimbursements for chronic HCV infection before and after DAA therapy. The total amount reimbursed per patient with chronic HCV infection increased significantly, by more than six-fold (516%), from the year preceding DAA therapy to the year of DAA initiation, reaching €46,439 (95% CI: €46,193-€46,677) per patient (Supplementary Table 5). Notably, the healthcare reimbursements per patient with chronic HCV infection were €7,533 (95% CI: €7,342-€7,733) in the year before DAA initiation and €8,193 (95% CI: €7,966-€8,442) in the fifth year after DAA initiation.

Compared to the general population, patients with chronic HCV infection treated with DAAs face a higher economic burden post-DAA therapy. The additional reimbursement expenditure associated with managing patients with chronic HCV infection compared with the matched general population was €5,781 (95% CI: €5,540-€6,028) in the fifth year after DAA therapy (Table 2). Except for medications, the amount reimbursed for managing patients with chronic HCV infection was similar on average in the years before and after DAA initiation (Table 2 andSupplementary Table 6).

DAA treatment uptake

The proportion of patients with chronic HCV infection treated with DAAs increased progressively after 2013 before reaching a quasi-plateau in 2019. By the end of 2021, the proportion of eligible patients with chronic HCV infection who received DAA treatment was 81.5% (Fig. 4).

Discussion

To the best of our knowledge, this study provides the first comprehensive assessment of the national economic burden of chronic HCV infection based on realworld data from French claims databases. It also evaluates the overall economic impact of DAA therapy at the national level. After analyzing data from more than 140,000 patients with chronic HCV infection over a 10-year period, three key findings emerged. First, the total reimbursement for managing patients with chronic HCV infection from 2012 to 2021 was approximately €12 billion. Second, by the end of 2021, the proportion of DAA treatment had reached 81.5% among eligible patients with chronic HCV infection in France. Third, even after receiving DAA therapy, patients with chronic HCV infection continue to bear a significant economic burden over the long term compared with the general population.

Several studies have investigated the economic burden of chronic HCV infection across different countries. [START_REF] Stepanova | Economic Burden of Hepatitis C Infection[END_REF][START_REF] Razavi | Chronic hepatitis C virus (HCV) disease burden and cost in the United States[END_REF][START_REF] Fukuda | Healthcare Expenditures for the Treatment of Patients Infected with Hepatitis C Virus in Japan[END_REF][START_REF] Ki | Healthcare Costs for Chronic Hepatitis C in South Korea from 2009 to 2013: An Analysis of the National Health Insurance Claims' Data[END_REF] A study based on Japanese nationwide administrative claims data explored healthcare expenditures among patients with HCV at different stages of the disease. [START_REF] Fukuda | Healthcare Expenditures for the Treatment of Patients Infected with Hepatitis C Virus in Japan[END_REF] The authors found that despite a 29% decrease in healthcare expenditures after HCV cure, the economic burden of chronic HCV infection remained high after DAA exposure. Notably, this study did not determine the total healthcare expenditures of patients with HCV. It only documented cases of healthcare expenditure for which HCV infection was recorded in claims databases, which may have underestimated the real economic burden of the disease and its related comorbidities. In France, a previous study quantified the economic burden of extrahepatic manifestations of chronic HCV infection. [START_REF] Cacoub | Direct medical costs associated with the extrahepatic manifestations of hepatitis C virus infection in France[END_REF] In two other French studies, economic data related to the burden of chronic HCV infection considered only hospital expenditures obtained from an analysis of the French National Hospital database. [START_REF] Abergel | Chronic hepatitis C: Burden of disease and cost associated with hospitalisations in France in 2012 (The HEPC-LONE study)[END_REF][START_REF] Rotily | How did chronic hepatitis C impact costs related to hospital health care in France in 2009?[END_REF] Contrastingly, our study aimed to explore the overall burden associated with the clinical management of chronic HCV infection and related diseases through direct and indirect medical resource utilization. To our knowledge, no study has assessed the real-world economic burden of chronic HCV infection and its manifestations in the DAA era from a national health insurance perspective in France. Since healthcare coverage of chronic conditions is insured by the French national health insurance, previous economic results derived from commercially insured adults in other countries cannot be generalized to the French setting. [START_REF] Gordon | Impact of disease severity on healthcare costs in patients with chronic hepatitis C (CHC) virus infection[END_REF] To date, most of the evidence regarding the economic burden of HCV infection has relied on assumptions derived from the literature or expert opinion. [START_REF] Cacoub | Direct medical costs associated with the extrahepatic manifestations of hepatitis C virus infection in France[END_REF] By accessing the SNDS, we conducted a detailed analysis of claims databases using reliable reimbursement amounts. Notably, the use of the incremental costing method and the construction of a matched cohort from the general population without chronic HCV infection allowed us to determine the exact economic burden directly attributable to chronic HCV infection. [START_REF] Shih | Use of Claims Data for Cost and Cost-Effectiveness Research[END_REF] Compared with the matched general population without HCV infection, our findings revealed a persistent economic burden in patients with chronic HCV infection, even years after DAA therapy. This additional burden could be partly attributed to the specific profile of patients with chronic HCV infection, which often includes comorbidities associated with injection drug use and alcohol use disorders, [START_REF] Coye | Hospital Costs of Injection Drug Use in Florida[END_REF][START_REF] Schwarzinger | Contribution of alcohol use disorders on the burden of chronic hepatitis C in France, 2008-2013: A nationwide retrospective cohort study[END_REF] as well as healthcare costs related to managing liver complications and extrahepatic manifestations of chronic HCV infection. Furthermore, our study revealed the limited impact of DAAs on the economic burden of hospital stay in patients with chronic HCV infection. Although the beneficial impact of DAAs on liver-related complications is well established, their extrahepatic impact is not fully understood. [START_REF] Lam | Impact of direct-acting antiviral treatment for hepatitis C on cardiovascular diseases and extrahepatic cancers[END_REF] Further research is needed to determine whether the causes of healthcare expenditure differ before and after HCV treatment. Our results indicate that patients with chronic HCV infection remain at a higher risk of adverse clinical events, potentially leading to costly health management even after achieving a virological cure following DAA therapy. In a recent study analyzing 21,790 patients successfully treated for HCV with DAAs in British Columbia, Scotland, and England, the authors observed that the overall liver and drug-related mortality rates were significantly higher than those observed in the general population. [START_REF] Hamill | Mortality rates among patients successfully treated for hepatitis C in the era of interferon-free antivirals: population based cohort study[END_REF] Consistently, our data suggest that the total burden of liver disease and general comorbidities associated with HCV infection cannot be fully mitigated with interferon-free antiviral regimens. Further research is essential to establish strategies that could mitigate the economic burden after HCV treatment. Policies aimed at reducing drug and alcohol misuse, along with enhanced surveillance and management of comorbidities in HCV patients, have the potential to significantly impact this burden positively. Additionally, the development of integrated care models that combine medical treatment for addiction with support services like mental health counseling, could lead to improved health outcomes and potentially reduce the economic burden following HCV treatment. Notably, our results do not support economic estimates based on the assumption that patients who have been virologically cured of HCV would exhibit health service utilization patterns similar to those without HCV infection. [START_REF] Roebuck | Assessing the burden of illness of chronic hepatitis C and impact of direct-acting antiviral use on healthcare costs in Medicaid[END_REF] Consequently, our results highlight the need for further comprehensive cost-effectiveness and cost-utility studies that accurately account for the persistent economic burden after HCV treatment, as revealed by the analysis of real-world data from claims databases.

A recent study, which compiled data from clinical trials and observational cohorts, estimated the proportion of patients with chronic HCV infection who received DAA treatment across several countries. [START_REF] Nguyen | Global treatment rate and barriers to direct-acting antiviral therapy: A systematic review and meta-analysis of 146 studies and 1 760 352 hepatitis C virus patients[END_REF] Nevertheless, because the authors derived the proportion of patients who received DAA treatment from studies conducted in different years, this estimate may not accurately represent the current proportion of DAA treatment. In our study, we identified all DAAs at the national level among the national cohort of patients with chronic HCV infection. This approach allowed us to provide updated and robust estimates of the proportion of patients receiving DAA therapy in France. Importantly, the WHO has designated 2030 as the target year for achieving global HCV eradication, and France aims to eradicate HCV by 2025. [START_REF] Pol | Is elimination of HCV realistic by 2030: France[END_REF] Consequently, the significant proportion of patients not treated with DAA therapy supports reinforcing policies for universal access to DAAs.

Our study employed a previously validated algorithm to identify all patients with prevalent chronic HCV infection by analyzing nationwide claims databases until the end of 2021. The number of patients with chronic HCV infection identified in this study via the SNDS aligns with prevalence estimates from national surveys and studies that conducted blood sample analyses in the general population. [START_REF] Brouard | French hepatitis C care cascade: substantial impact of direct-acting antivirals, but the road to elimination is still long[END_REF][START_REF] Brouard | HCV and HBV prevalence based on home blood self-sampling and screening history in the general population in 2016: contribution to the new French screening strategy[END_REF] It is important to note that our estimate of specificity was 85% and that we cannot totally exclude the possibility of classification error. Nevertheless, the algorithm was determined using HBV-infected patients as a control group and not using a representative sample of the HCV-negative population from the SNDS. Given that HBV-and HCV-infected patients had similar clinical characteristics and reimbursement data, the specificity of 85% should be considered very conservative.

If this algorithm were applied to a representative sample of the SNDS, the risk of false positives and misclassifications would be much lower and the specificity would approach 100%. The significant percentage of patients with chronic HCV infection still not being treated with DAAs by the end of 2021 highlights the need for future efforts to identify better the social and structural barriers to care for this population. A previous study investigating the barriers to DAA initiation among patients with chronic HCV infection in the United States identified various factors, including fear of adverse events, belief in the need for alcohol abstinence before DAA initiation, and lower prioritization of chronic HCV infection compared to other illnesses. [START_REF] Brothers | Perceptions Towards HCV Treatment with Direct Acting Antivirals (DAAs): A Qualitative Analysis with Persons with HIV/HCV Co-infection Who Delay or Refuse Treatment[END_REF] In France, alcohol use disorders and the low density of HCV specialists at the regional level have been identified as factors delaying the initiation of DAAs in people who use drugs. [START_REF] Marcellin | France removes hepatitis C treatment prescriber restrictions-But what is the impact of the delay for key populations?[END_REF][START_REF] Barré | Untreated alcohol use disorder in people who inject drugs (PWID) in France: a major barrier to HCV treatment uptake (the ANRS-FANTASIO study)[END_REF] Our study has several strengths. First, it used real-world data collected directly from French claims databases, which provide a precise assessment of the economic burden of chronic HCV infection and the impact of DAAs. The analysis assessing the impact of DAA therapy was highly robust, as it was based on economic observational data directly captured through the SNDS rather than external data not adapted to the French context. Second, the cohort of patients with chronic HCV infection was identified using a validated algorithm specifically developed to evaluate the public health burden of this disease. [START_REF] Lam | Performance of algorithms for identifying patients with chronic hepatitis B or C infection in the french health insurance claims databases using the ANRS CO22 HEPATHER cohort[END_REF] Third, the study investigated direct and indirect medical costs, including disability pensions, work-related accidents, occupational diseases, and transportation costs.

This study has two main limitations. First, we cannot entirely exclude the possibility of coding errors in the reimbursement data within the SNDS. Second, our results only captured the economic burden of chronic HCV infection from the French National Health Insurance perspective and did not include indirect nonmedical costs and out-of-pocket payments, including amounts reimbursed per additional health insurance. Thus, economic burden from a societal perspective could not be defined in this study.

In conclusion, this study is the first to assess the economic burden of chronic HCV infection from a national health insurance perspective. It revealed that a high economic burden persists in patients with chronic HCV infection even after DAA therapy. It is crucial to acknowledge the persistent economic burden caused by patients with chronic HCV infection, even after achieving HCV cure, and to establish specific interventions to alleviate this ongoing burden. The proportion of untreated patients at the national level underscores the need for reinforcing policies for universal access to DAAs. Further research is needed to evaluate the costeffectiveness of DAA therapy using real-world data from the SNDS.

Fig. 2

 2 Fig. 2 details the changes in reimbursements for chronic HCV infection over time

Figure Legends:Fig. 1 .Fig. 2 .

 12 Figure Legends:

Fig. 3 .

 3 Fig. 3. Annual Reimbursement Changes Before and After Direct-acting

Fig. 4 .

 4 Fig. 4. Proportion of Patients With Chronic Hepatitis C Virus Infection Who

Table 1 . Economic Burden Attributable to Chronic Hepatitis C Virus Infection in France From 2012 to 2021 by Healthcare Sector

 1

	Cumulative amount	Amount per patient
	reimbursed (€)	per year (€)

Table 2 . Reimbursement Attributable to the Management of Chronic Hepatitis C Virus Infection After Direct-acting Antiviral Therapy (per Patient per Year)

 2

	Years relative to DAA treatment initiation
	0	+ 1	+ 2	+ 3	+ 4	+ 5

  Cumulative number of CHC patients eligible for DAA therapy Cumulative number of CHC patients treated with DAAs Cumulative percentage of CHC patients treated with DAAs

	€16,000 €50,000 Number of patients									DAA treatment proportion
	€14,000 €45,000 120,000				149 excluded:							100%
	€12,000 €40,000 100,000				-149 birth date or death date miscoded or unknown			90% 80%
	€10,000 €35,000 80,000												70%
	€25,000 €6,000 €8,000 €30,000 60,000												40% 60% 50%
	€4,000 40,000												30%
	€2,000 €20,000 20,000												20%
	€15,000												10%
	€0 2012 0 €10,000	2013 2014	2014 2015	2016	2015	2017	2016 2018	2017 2019	2018 2020	2019 2021	2020 0%	2021
			Hospital pharmacy / expensive medications	Retail pharmacy
	€5,000		Hospital stays in public healthcare institutions	Disability pensions
			Medical procedures / visits (outpatient hospital)	Medical devices (outpatient)
	€0	-5	Transportation Hospital stays in private healthcare institutions -4 -3 -2 -1	Outpatient medical laboratory Physician visits (outpatient) 0 1 2	3	4	5
			Medical procedures (outpatient)	Work-related accidents / occupational diseases Years relative to DAA treatment initiation
				Hospital pharmacy / expensive medications	Retail pharmacy
				Hospital stays in public healthcare institutions	Disability pensions
				Medical procedures / visits (outpatient hospital)	Medical devices (outpatient)
				Transportation						Outpatient medical laboratory
				Hospital stays in private healthcare institutions	Physician visits (outpatient)
				Medical procedures (outpatient)		Work-related accidents / occupational diseases

grants from INSERM-ANRS; personal fees from Sanofi, outside the submitted work. MB reports grants and personal fees from AbbVie, Gilead and Roche, outside the submitted work, and personal fees from Gilead, AbbVie, GSK, Janssen, Roche, MSD, Intercept, Atea Pharmaceuticals, Precision Biosciences outside the submitted work. PC received research grants from MSD and INTERCEPT unrelated to this work. LL, JB, GH have nothing to disclose.

Funding/Support: The research conducted on the SNDS received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. to the nature of this research based on the French administrative health care database, data that support the findings of this study are not available due to ethical and legal restrictions.

data were anonymized, and no informed consent was obtained for the SNDS analysis.


Anne-Laure Marchand

Christophe Robin

Christophe Nguyen

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