Antoine Géry

A Delanoë

N Heutte

E Chosson

J Bonhomme

David Garon
email: david.garon@unicaen.fr

A novel qPCR based-method for detection and quantification of three recurrent species of Penicillium isolated from bioaerosols in mold-damaged homes

Keywords: Penicillium, qPCR, mold-damaged homes, indoor air

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

Introduction

In many industrialized countries, indoor air quality has become a major concern. Indeed, in these countries, it is estimated that people spend up to 90% of their time inside buildings (WHO, 1983) which can be exacerbated by confinement. Indoor air quality can be altered by humidity problems and the development of biological pollutants like molds [START_REF] Andersen | Associations between fungal species and water-damaged building materials[END_REF]. This deterioration of indoor air quality in the habitats has impacted on the quality of life, and can lead to economic consequences in terms of health expenditure and renovation costs.

According to the WHO (2015), 10-50% of buildings in Europe have moisture problems that facilitate the growth of molds and the formation of bioaerosols. Some of these molds can cause respiratory diseases or aggravation of asthma and allergies, and sometimes infections in immunocompromised people [START_REF] Douwes | Bioaerosol Health Effects and Exposure Assessment: Progress and Prospects[END_REF][START_REF] Fisk | Meta-analyses of the associations of respiratory health effects with dampness and mold in homes[END_REF][START_REF] Fisk | Association of residential dampness and mold with respiratory tract infections and bronchitis: a meta-analysis[END_REF][START_REF] Platt | Damp housing, mould growth, and symptomatic health state[END_REF][START_REF] Stark | Fungal levels in the home and allergic rhinitis by 5 years of age[END_REF][START_REF] Eduard | Fungal spores: a critical review of the toxicological and epidemiological evidence as a basis for occupational exposure limit setting[END_REF]. Some micromycetes are also known for their ability to produce mycotoxins that may possess cytotoxic [START_REF] Smith | In vitro coculture models to evaluate acute cytotoxicity of individual and combined mycotoxin exposures on Caco-2, THP-1 and HepaRG human cell lines[END_REF][START_REF] Zhang | Aflatoxin B1 and aflatoxin M1 induced cytotoxicity and DNA damage in differentiated and undifferentiated Caco-2 cells[END_REF] and/or genotoxic [START_REF] Domijan | In vitro genotoxicity of mycotoxins ochratoxin A and fumonisin B1 could be prevented by sodium copper chlorophyllin -Implication to their genotoxic mechanism[END_REF][START_REF] Liu | Evaluation of genotoxic risk and oxidative DNA damage in mammalian cells exposed to mycotoxins, patulin and citrinin[END_REF] properties.

It is estimated that molds of the genus Penicillium are present in at least 90% of degraded habitats [START_REF] Dallongeville | Concentration and determinants of molds and allergens in indoor air and house dust of French dwellings[END_REF]. In this study, we are particularly interested in three species of Penicillium frequently isolated from indoor air samples collected in mold-damaged homes [START_REF] Delanoë | Bioaerosols exposure assessment in mold-damaged houses in Normandy, France[END_REF]: Penicillium chrysogenum, Penicillium crustosum and Penicillium brevicompactum, which have been respectively found in 75%, 67%, and 63% of bioaerosols collected in our previous study [START_REF] Delanoë | Relationships between Exposure to Bioaerosols, Moldy Surface and Symptoms in French Mold-Damaged Homes[END_REF].

These three Penicillium species are opportunistic pathogens that can cause allergies or lung damage [START_REF] D'antonio | Necrotizing pneumonia caused by Penicillium chrysogenum[END_REF][START_REF] De La Cámara | Penicillium brevicompactum as the cause of a necrotic lung ball in an allogeneic bone marrow transplant recipient[END_REF][START_REF] Geltner | Invasive Pulmonary Mycosis Due to Penicillium chrysogenum: A New Invasive Pathogen[END_REF][START_REF] Lyratzopoulos | Invasive Infection due to Penicillium Species other than P. marneffei[END_REF] and endophthalmitis [START_REF] Eschete | Penicillium chrysogenum endophthalmitis: First reported case[END_REF] in immunocompromised patients. P. brevicompactum and P. crustosum are also considered as toxigenic species as P. crustosum synthesizes tremorigenic mycotoxins like penitrems [START_REF] El-Banna | Production of penitrem A by Penicillium crustosum isolated from foodstuffs[END_REF]Moldes-Anaya et al., 2012) and P. brevicompactum produces mycophenolic acid [START_REF] Patel | Bioreactor studies of production of mycophenolic acid by Penicillium brevicompactum[END_REF][START_REF] Patel | Production of mycophenolic acid by Penicillium brevicompactum-A comparison of two methods of optimization[END_REF].

The development of DNA sequencing in the 1990s allowed sequence-based identification.

Indeed, the internal transcribed spacer rDNA area (ITS) is now considered as the official barcode for fungi (Schoch et al., 2012) and is widely used as a sequenced marker to allow species identification of fungi. However, the ITS does not show enough variations to distinguish closely related species of fungi such as those belonging to the Penicillium genus.

Therefore, the use of beta-tubulin gene (benA) associated with ITS as a secondary barcode is recommended to ensure the identification of isolates from Penicillium genus [START_REF] Visagie | Identification and nomenclature of the genus Penicillium[END_REF].

Moreover, real-time PCR allows for the quantification of specific fungal DNAs and, thus, a better appreciation of bioaerosols content [START_REF] Wu | Application of PCR and probe hybridization techniques in detection of airborne fungal spores in environmental samples[END_REF][START_REF] Zeng | Detection and quantification of Cladosporium in aerosols by real-time PCR[END_REF]. Although it is time-consuming to develop such a standardized method to be used, this one then considerably reduces the analysis time and allows to detect and quantify target DNA of scarce fungal species, non-viable fungal elements, or non-culturable molds which is not achieved by cultural methods.

The assessment of human exposure to fungal bioaerosols remains difficult due to methodological difficulties (collection and analysis of bioaerosols) and complexity of bioaerosols (fungal diversity) [START_REF] Nevalainen | Indoor fungi: companions and contaminants[END_REF]. This study presents an original and rapid qPCR analysis method with the aim to detect and quantify DNA of three Penicillium species (P. brevicompactum (Pbrev), P. chrysogenum (Pchry), and P crustosum (Pcrus)) frequently isolated in mold-damaged homes.

Materials and methods

Fungal strains

Different fungal strains were used in this study (Table 1). Reference strains of P. brevicompactum (CBS 257.29), P. chrysogenum (CBS 306.48) and P. crustosum (CBS 115503) were purchased from Westerdijk Fungal Biodiversity Institute (Utrecht, The Netherlands). For each mold-damaged home, an aliquot of 1 mL of collection liquid and dilutions (10 -1 ; 10 -2 ; 10 -3 ) were deposited into Petri plates, and malt extract agar (MEA) (Merck, Darmstadt, Germany) supplemented with chloramphenicol (0.02 g/L) (Cooper, USA) was poured. Plates were incubated at 25 °C for 7 days, checked daily, and the number of colonies was counted and reported as Colony Forming Units per m 3 of air (CFU/m 3 ). Each different fungal colony was isolated and purified in MEA medium [START_REF] Delanoë | Relationships between Exposure to Bioaerosols, Moldy Surface and Symptoms in French Mold-Damaged Homes[END_REF]. In total, 25 fungal strains were also isolated from indoor air and were preserved in our laboratory's fungal collection. These isolates which belonging to Aspergillus and Penicillium genera were previously purified and identified using macroscopic, microscopic and molecular features [START_REF] Choi | Identification and Characterization of Fungi Contaminated in the Built-In Furniture of an Apartment Home[END_REF][START_REF] Domsch | Compendium of soil fungi[END_REF][START_REF] Houbraken | Classification of Aspergillus, Penicillium, Talaromyces and related genera (Eurotiales): An overview of families, genera, subgenera, sections, series and species[END_REF][START_REF] Klich | Identification of Common Aspergillus Species, Centraalbureau voor Schimmelcultures[END_REF][START_REF] Pitt | A Laboratory Guide to Common Penicillium Species[END_REF][START_REF] Pitt | The Genus Penicillium and Its Teleomorphic States Eupenicillium and Talaromyces[END_REF][START_REF] Samson | Introduction to Food and Airborne Fungi, Centraalbureau voor Schimmelcultures[END_REF][START_REF] Samson | Penicillium Subgenus Penicillium: New Taxonomic Schemes. Mycotoxins and Other Extrolites[END_REF][START_REF] Visagie | Identification and nomenclature of the genus Penicillium[END_REF][START_REF] Von Arx | The Genus of Fungi Sporulating in Pure Culture[END_REF]. DNA extraction from the bioaerosol collection liquid was performed from 5 mL centrifuged at 4500 g. The supernatant was removed and DNA extraction was performed on the pellet as described above.

DNA purification and quantification

Extracted DNA was purified using NucleoSpin gDNA Clean-up kit (Macherey-Nagel, Duren, Germany) following the instructions of the manufacturer. For each isolate, purified DNA extracted was quantified using NanoDrop 2000 (Thermo Fisher Scientific, Waltham, MA, USA). To assess DNA quality, optical density values (A260/A280 and A260/A230) were compared to the reference values (1.8-2.0 and 2.0-2.2) using NanoDrop [START_REF] Desjardins | NanoDrop Microvolume Quantitation of Nucleic Acids[END_REF]. DNA extracted from reference strains CBS 257.29 (Pbrev), CBS 306.48

(Pchry) and CBS 115503 (Pcrus) was then diluted with sterile ddH2O to a final concentration of 50 ng/µL.

Primers design

Primers were designed based on benA sequences downloaded on GenBank ® /NCBI and aligned on ClustalW2 ® software (Conway Institute UCD, Dublin, Ireland) [START_REF] Rodríguez | Design of Primers and Probes for Quantitative Real-Time PCR Methods[END_REF]. In order to ensure the specificity of primers (Table 2), the expected PCR products were compared using BLAST (Basic Local Alignment Search Tool, NCBI) to the sequences of the CoreNucleotide, dbEST and dbGSS databases. The expected PCR products all had a query coverage and percent identity of 100% for the corresponding species and no other species were identified in the request. For the standard range, the reaction mixture contained: 10 µL of SYBR™ Select Master Mix 2X, 1 µL of forward primer, 1 µL of reverse primer, 2 µL of pure genomic DNA (gDNA) of each Penicillium species reference (standard range : 0.01/0.1/1/10/100 ng of DNA) and ultrapure water to 20 µL. 2.4 µL of MgCl2 25 mM was added for Pbrev to reach a sufficient efficiency of 90%.

Statistical analysis

Descriptive statistics were calculated to provide information about the sample and paired ttest was also used to compare the two methods. Bland-Altman plots were used for descriptive evaluation of the concordance of the results from two methods. This was performed by plotting the difference for analysed variables between two methods against the mean results.

Only results at p < 0.05 were considered statistically significant. All statistical analyses were realized using SAS system version 9.4 (SAS Institute Inc. Cary, NC, USA).

Results

qPCR amplification

The amplified fragments from reference strains of Pbrev, Pchry and Pcrus showed bands around 200 bp, 125 bp and 100 bp respectively, without nonspecific bands (Figure 1), which was consistent with the length of expected fragments. The qPCR melting curves obtained for Pbrev, Pchry and Pcrus with this method showed three specific peaks with the following Tm values: 81.1 °C (Pcrus), 81.5 °C (Pchry) and 83.9 °C (Pbrev) (Figure 2). qPCR amplification using gDNA with different gradient concentrations demonstrated that there was a good linear correlation on standard curves between the cycle threshold and DNA concentration on the range from 0.01 ng/µL to 100 ng/µL (Figure 3). Detailed data are presented in supplementary material (Table S1). The reproducibility results showed that the coefficient of variation (CV) at CT values for different concentrations of Pbrev, Pchry and

Pcrus was less than one (Figure 2). Consequently, the intra-assay and inter-assay reproducibility of this method were good.

qPCR specificity

This qPCR method showed primers could specifically amplify benA from the 18 isolates of Penicillium brevicompactum, Penicillium chrysogenum, and Penicillium crustosum. No amplification was observed when the method was performed on gDNA of the other Pbrev Pchry Pcrus environmental isolates of Penicillium glabrum, P. granulatum, P. olsonii, Aspergillus versicolor and A. sydowii frequently isolated from indoor bioaerosols.

Comparison between spectrophotometry and qPCR techniques

Because of its simplicity and rapidity, spectrophotometry is commonly used to quantify DNA.

However, it indicates the concentration of total DNA in the DNA extract. To determine if our qPCR method can specifically quantify the DNA of these three Penicillium as finely as spectrophotometry, we quantified DNA extracts of each Penicillium with both methods and compared them.

For each Penicillium species, 30 DNA extracts obtained from our samples with concentrations between 5 and 100 ng/µL were performed in triplicates using Nanodrop and qPCR.

No significant difference could be found between these two methods (respectively Penicillium brevicompactum: p = 0.940; Penicillium chrysogenum: p = 0.817; Penicillium crustosum: p = 0.106). Bland-Altman plot analyses were also carried out to evaluate the bias between the mean differences of these two methods (Figure 4). 3.5. Tests on environmental samples DNA extractions were carried out from the agar plates obtained after culture of bioaerosols collected from 15 mold-damaged homes. The total DNA obtained was then tested to determine if Pbrev, Pchry and Pcrus could be detected using our technique. An example of culture plate before extraction was presented in supplementary material (Figure S1).

The DNA of these Penicillium species was found among the total extracted DNA. The macroscopic, microscopic and molecular study confirmed the presence of these Penicillium in the studied bioaerosols and highlighted other species as presented in Table 3. The DNA of these three species of Penicillium was also searched in the total DNA extracted directly from the collection liquid (as decribed in 2.2) without any prior culture step. The amount of DNA extracted this way was not sufficient to enable amplification to generate a signal different from the negative control. Thus, for the same 15 mold-damaged homes, none of these Penicillium species could be directly found in the bioaerosols collected.

Discussion

The development of specific molecular techniques for the identification of molds marked a turning point in the field of mycology. Although ITS and RPB fragments are widely used for this purpose, benA allows a finer identification between phylogenetically related Penicillium species [START_REF] Visagie | Identification and nomenclature of the genus Penicillium[END_REF]. Furthermore, the alignment of ITS and RPB fragments for these three Penicillium species does not show sufficient genotypic heterogeneity to allow for specific primer design.

In this study we developed an original qPCR based method for the identification of three species of Penicillium frequently found in the air of degraded homes [START_REF] Delanoë | Relationships between Exposure to Bioaerosols, Moldy Surface and Symptoms in French Mold-Damaged Homes[END_REF].

This identification is faster than the cultural approach and does not require the support of a sequencing platform. In addition, specificity tests showed that the primers used did not crossreact with the gDNA of other recurrent indoor mold species belonging to the genera Aspergillus and Penicillium.

In addition, this technique can be standardized and therefore routinely used in the laboratory to allow the identification of a large number of isolates in a short time, and then to assess human exposure to Penicillium strains in indoor environment.

Our method did not show any significant difference with spectrophotometry in its ability to quantify the target DNA of P. brevicompactum, P. chrysogenum and P. crustosum while spectrophotometry only measures total DNA. It also has the major advantage of being able to specifically detect and quantify the target DNA of these three Penicillium species at concentrations ranging from 0.01 to 100 ng/µL, i.e. at concentrations up to 100 times lower than the spectrophometry detection limit (2.5 ng/µL for Nanodrop 2000 TM ).

Although this method allows a rapid identification and quantification of the DNA of these three Penicillium by avoiding the many steps required for the isolation, purification and identification of each fungal colony, it requires a sampling technique that enables the collection of more fungal elements to be applicable to bioaerosols without a step of culture on agar plate.

Indeed, despite assays were lead on pre-amplification and nested-PCR methods our samples did not generate a signal different from the negative control. Next studies on bioaerosol analysis by qPCR would require a concentration of CFU/m 3 of air ten times higher than that observed in the mold-damaged houses included in our study where the maximum concentrations observed are respectively 38 CFU/m 3 for Penicillium brevicompactum; 2400 CFU/m 3 for P. chrysogenum and 38 CFU/m 3 for P. crustosum [START_REF] Delanoë | Relationships between Exposure to Bioaerosols, Moldy Surface and Symptoms in French Mold-Damaged Homes[END_REF]. Another approach would be to take air samples over much longer periods by equipping residents with portable pumps, for example.

Conclusion

This qPCR method allows to gain time throughout all the purification and identification steps and a specific quantification of DNA from Penicillium brevicompactum, Penicillium chrysogenum and Penicillium crustosum. In addition to its practicality, this method can easily be standardized due to its robustness and so open new prospects for the monitoring of specific indoor fungi, particularly in the field of the exposure to fungal bioaerosols.

(

  Macherey-Nagel, Duren, Germany). Fungal colony was introduced in a 2 mL microtube with glass beads. The microtube was then placed into a Qiagen TissueLyser with 400 μL of lysis buffer PL1 (Macherey-Nagel, Duren, Germany) for 15 min at 20 Hz, and then incubated with 10 µL of RNAse and 20 μL of proteinase K at 10 mg/mL (Sigma-Aldricht, St. Louis, MO, USA) (Macherey-Nagel, Duren, Germany) at 65 °C for 15 min. After that, 400 μL of chloroform (Sigma-Aldricht, St. Louis, MO, USA) were added to the mixture. The aqueous phase was recovered and extracted using the kit precipitation and washing buffer according to the protocol described by the supplier.

Figure 1 .

 1 Figure 1. PCR amplification of the benA fragment of three Penicillium (L: BenchTop 100 bp DNA Ladder (Promega, Madison, WI, USA)).

FigureFigure 3 .

 3 Figure 2. Tm peaks obtained for Pchry (81.1 °C), Pcrus (81.5 °C) and Pbrev (83.9 °C).

Figure 4 .

 4 Figure 4. Bland-Altman plot analysis ( : Bias; : CI Bias (95%); : CI (95%)).

Table 1 .

 1 Fungal strains used in this study.

	Fungal species	Isolate number
	Penicillium brevicompactum CBS 257.29, 122_HAB10, 389_HAB24, 846_HAB53,
		857_HAB54, 862_HAB55
	Penicillium chrysogenum	CBS 306.48, 18_HAB04, 634_HAB39, 708_HAB44,
		803_HAB50, 864_HAB55

DNA extraction was performed using a modified protocol of the Nucleospin™ Plant II kit

Table 2 .

 2 List of accession numbers and sequences of specific primers used for qPCR assays.

	Species	Strains	Accession Number	Primer sequences (5'-3')	Annealing temperature	Expected product length
				Forward (Bt_Pbrev_F3) :
		CBS 110067	AY674438
				AGTAAGTGGACGACTGTG
	Pbrev	CBS 110069	AY674435	Reverse (Bt_Pbrev_R4) :	61 °C	207 bp
		CBS 257.29	KF499573
				CTCCAAGTCGACGAGGA
				Forward (Bt_Pchry_F2) :
		CBS 282.97	JX996925
				AACAGTGATGGGGATTCTGG
	Pchry	CBS 306.48	JF909955	Reverse (Bt_Pchry_R5) :	64 °C	128 bp
		CBS 109613	KJ866978
				CGCCCGATCAGATGATGCA
	Pcrus	CBS 47184	AY674352 Forward (Bt_Pcrus_F2) :	65 °C	100 bp

® GreenER™ dye, ROX, AmpliTaq ® DNA Polymerase and oligonucleotides. The data collected were processed with QuantStudio™ Design & Analysis Software (Thermo Fisher Scientific, Waltham, MA, USA).

The program was composed of three stages: hold stage, PCR stage and melt curve stage. The hold stage consisted in two steps: temperature with a ramping rate of 1.6 °C/s up to 50 °C held 2 min (step 1); temperature with a ramping rate of 1.6 °C/s up to 95 °C held 10 min (step 2). The PCR stage consisted also in two steps: 15 sec at 95 °C (step 1); temperature decreased down by 1.6 °C/s to the annealing temperature (Table

2

) held 1 min before rising up anew by 1.6 °C/s to 95 °C (step 2) for 40 cycles. The melt curve stage consisted in 3 steps :

Table 3 .

 3 List of fungal species identified in 15 mold-damaged homes.

	Sample ID	qPCR identification Pbrev Pchry Pcrus	Species isolated and identified using culture step
					Actinomucor elegans, Aspergillus sydowii, Aspergillus versicolor,
	HAB01	-	+	+	Paecylomyces variotii, Penicillium chrysogenum, Penicillium
					crustosum
	HAB02	-	+	+	Aspergillus versicolor, Cladosporium cladosporioides, Penicillium chrysogenum, Penicillium crustosum, Penicillium simplicissimum
					Aspergillus sydowii, Cladosporium cladosporioides, Paecylomyces
	HAB03	+	+	+	variotii, Penicillium brevicompactum, Penicillium chrysogenum, Penicillium crustosum, Penicillium griseofulvum, Penicillium
					simplicissimum
					Aphanocladium album, Aspergillus versicolor, Cladosporium
	HAB04	+	+	-	sphaerospermum, Penicillium brevicompactum, Penicillium
					chrysogenum, Penicillium expansum, Penicillium waksmanii
	HAB05	+	+	+	Aspergillus flavus, Aspergillus versicolor, Penicillium brevicompactum, Penicillium chrysogenum, Penicillium crustosum, Penicillium olsonii
					Aspergillus flavus, Aspergillus glaucus, Aspergillus niger, Aspergillus
					sydowii, Aspergillus versicolor, Penicillium brevicompactum,
	HAB06	+	+	+	Penicillium chrysogenum, Penicillium crustosum, Penicillium olsonii,
					Penicillium purpurogenum, Penicillium verrucosum, Penicillium
					viridicatum
					Aspergillus europaeus, Aspergillus flavus, Aspergillus fumigatus,
					Botrytis cinerea, Cladosporium cladosporioides, Cladosporium
	HAB07	+	-	+	herbarum, Penicillium aurantiogriseum, Penicillium brevicompactum,
					Penicillium crustosum, Penicillium glabrum, Penicillium
					simplicissimum, Ulocladium chartarum
					Alternaria alternata, Aspergillus versicolor, Cladosporium
	HAB08	+	-	+	cladosporioides, Cladosporium sphaerospermum, Penicillium brevicompactum, Penicillium crustosum, Penicillium glabrum,
					Penicillium nalgiovense, Penicillium purpurogenum, Talaromyces flavus
					Actinomucor elegans, Aspergillus sydowii, Aspergillus ustus, Fusarium
	HAB09	-	-	-	oxysporum, Penicillium glabrum, Penicillium purpurogenum,
					Penicillium variabile
					Arthrinium phaeospermum, Aspergillus melleus, Aspergillus versicolor,
	HAB10	-	+	+	Cladosporium cladosporioides, Penicillium chrysogenum, Penicillium
					citrinum, Penicillium crustosum
					Aspergillus versicolor, Penicillium brevicompactum, Penicillium
	HAB11	+	+	+	chrysogenum, Penicillium crustosum, Penicillium expansum,
					Penicillium glabrum, Penicillium olsonii
					Aspergillus fumigatus, Aspergillus ustus, Aspergillus versicolor,
	HAB12	+	+	+	Penicillium brevicompactum, Penicillium chrysogenum, Penicillium crustosum, Penicillium digitatum, Penicillium expansum, Penicillium
					variabile
					Aspergillus pseudoglaucus, Cladosporium cladosporioides, Penicillium
	HAB13	+	+	-	brevicompactum, Penicillium chrysogenum, Penicillium glabrum,
					Penicillium viridicatum

Acknowledgements

This research was funded by the CONSEIL REGIONAL DE NORMANDIE, the AGENCE REGIONALE DE SANTE DE NORMANDIE (ARS), and the AGENCE DE L'ENVIRONNEMENT ET DE LA MAITRISE DE L'ENERGIE (ADEME, program Aactair).


Marie-Pierre Hory
email: mphory@iscparis.com.

Grégory Levieuge
email: gregory.levieuge@banque-france.fr.

Daria Onori
email: daria.onori@univ-orleans.fr.

Public spending, currency mismatch and financial frictions *

Keywords: JEL Classification: E62, F34, F41 Fiscal multiplier, Terms of trade, Currency mismatch, DSGE model, Financial frictions

In this paper, we demonstrate that the size of the fiscal multiplier depends both on currency mismatch and home bias. Our demonstration is based on a real two-country dynamic stochastic general equilibrium model with incomplete and imperfect international financial markets, external debt and domestic financial frictions. We show that if home bias is high, the terms of trade improve following a fiscal stimulus. This reduces the private real debt burden denominated in foreign currency, decreases the external financial premium born by firms, and stimulates investment. Thus, the higher the fiscal multiplier is, the larger the proportion of firms' debt denominated in foreign currency.

In contrast, the terms of trade deteriorate when home bias is low. This increases the real debt burden and external finance premium. Hence, in this case, the fiscal multiplier decreases as the share of firms' debt denominated in foreign currency increases.

Introduction

Various determinants of the size of the fiscal multiplier have been found in the literature, such as the level of public debt [START_REF] Huidrom | Why do fiscal multipliers depend on fiscal positions?[END_REF][START_REF] Nickel | Fiscal stimulus in times of high debt: Reconsidering multipliers and twin deficits[END_REF][START_REF] Ilzetzki | How big (small?) are fiscal multipliers?[END_REF][START_REF] Cimadomo | Transmission of government spending shocks in the euro area: Time variation and driving forces[END_REF], the exchange rate regime [START_REF] Born | Exchange rate regimes and fiscal multipliers[END_REF]Corsetti et al., 2012a), the position in the economic cycle [START_REF] Gechert | Which fiscal multipliers are regime-dependent? A meta-regression analysis[END_REF], the degree of development, trade openness or home bias [START_REF] Ilzetzki | How big (small?) are fiscal multipliers?[END_REF][START_REF] Ravn | Consumption, government spending, and the real exchange rate[END_REF].

In this paper, we show that the size of the fiscal multiplier may also depend on both the proportion of debt that is denominated in foreign currency and the degree of home bias. Our theoretical demonstration is based on a real two-country dynamic stochastic general equilibrium (DSGE) model with incomplete and imperfect international financial markets, external indebtedness and financial frictions due to asymmetric information. In a costly state verification framework (CSV) à la Townsend, firms have to bear an external finance premium (EFP), which increases with their debt-to-wealth ratio. While domestic net wealth is assumed to be entirely denominated in domestic goods, firms' debt is assumed to be -to some extent -denominated in foreign goods. Such a maturity mismatch may be at the origin of a financial accelerator mechanism à la [START_REF] Bernanke | The financial accelerator in a quantitative business cycle framework[END_REF], which in turn influences the macroeconomic impact of fiscal shocks.

Specifically, we show that the terms of trade improve following a fiscal stimulus if home bias is high. This reduces the private real debt burden denominated in foreign goods and decreases the EFP born by firms, thus stimulating investment. It follows that the fiscal multiplier is higher the larger the fraction of firms debt denominated in foreign goods. In contrast, we observe a deterioration of the terms of trade when home bias is low. This makes the real debt burden increase, leading to a deterioration of firms' balance sheets and hence to a higher EFP. As a result, the fiscal multiplier decreases as the share of firm debt denominated in foreign goods increases.

To the best of our knowledge, this is the first contribution capable of explaining varying levels of the fiscal multiplier by combining the effects of currency mismatch, financial frictions, and real exchange rate reactions in response to fiscal stimulus. In doing so, our analysis is closely related to three branches of the literature.

First, our paper is linked to monetary DSGE models with financial frictions and sticky prices. The seminal paper of [START_REF] Bernanke | The financial accelerator in a quantitative business cycle framework[END_REF] shows that in a CSV framework, the fiscal multiplier is higher when the EFP is positive. The fact that financial imperfections matter is also confirmed by more recent contributions [START_REF] Fernández-Villaverde | Fiscal policy in a model with financial frictions[END_REF][START_REF] Eggertsson | Debt, deleveraging, and the liquidity trap: A Fisher-Minsky-Koo approach[END_REF]. Furthermore, our analysis builds on a two-country model where firms' debt is denominated in both domestic and foreign currencies to appraise how this influ-1 ences the size of fiscal multipliers through the EFP. Existing works assume that either firms' debt is denominated in local currency only, as in [START_REF] Gertler | External constraints on monetary policy and the financial accelerator[END_REF], or that it is entirely denominated in foreign currency, as in [START_REF] Chang | Monetary policy in a dollarized economy where balance sheets matter[END_REF]. [START_REF] Batini | Monetary rules in emerging economies with financial market imperfections[END_REF] is, to the best of our knowledge, the only contribution assuming that domestic firms can borrow in both home and foreign currencies. Nonetheless, this paper does not focus on the size and determinants of the fiscal multiplier. Finally, to better focus on the basic transmission channel, we depart from these models by considering a real economy without price stickiness, similar to [START_REF] Cheng | Balance sheet effects, foreign reserves and public policies[END_REF]. In fact, in an open economy, the presence of nominal rigidities coupled with a central bank following a Taylor rule has important consequences for interest rate movements following a fiscal stimulus. This, in turn, generates nominal exchange rate movements (international Fisher effect) that modify international capital flows. Ignoring nominal features and neutralizing the effects of monetary policy allows us to concentrate only on the real consequences of a fiscal shock and hence to better understand the mechanisms at work, including the changes in relative prices.

Second, in this sense, our paper also relates to the literature on the response of the terms of trade and the real exchange rate to a public spending shock. While the traditional Mundell-Fleming-Dornbush framework predicts an appreciation, recent theoretical and empirical evidence is less clear-cut. Several empirical studies find that the real exchange rate depreciates in response to an increase in public spending [START_REF] Kim | Twin deficit or twin divergence? Fiscal policy, current account, and real exchange rate in the US[END_REF][START_REF] Monacelli | Openness and the sectoral effects of fiscal policy[END_REF][START_REF] Enders | How do fiscal and technology shocks affect real exchange rates?: New evidence for the United States[END_REF]. Some recent theoretical papers support this view. However, these contributions rely on specific assumptions regarding the characteristics and behavior of public and private agents1 that may have direct effects on the fiscal multiplier, not only through the exchange rate. [START_REF] Bouakez | Government spending, monetary policy, and the real exchange rate[END_REF], for example, find a depreciation of the real exchange rate that is related to the assumptions of sticky prices and of a "not-too-aggressive" domestic monetary policy. Other authors show that the response of the real exchange rate can be positive or negative, conditional on factors such as the exchange rate regime, country characteristics or the nature of the fiscal shock (Corsetti et al., 2012a;[START_REF] Kim | Country characteristics and the effects of government consumption shocks on the current account and real exchange rate[END_REF][START_REF] Forni | Government spending shocks in open economy VARs[END_REF][START_REF] Miyamoto | The effects of government spending on real exchange rates: Evidence from military spending panel data[END_REF].

Unlike this branch of the literature, we do not make any specific assumptions concerning the behavior of private and public agents, and we focus on real mechanisms. Furthermore, among country characteristics, we show that home bias plays a crucial role in the determi-nation of relative prices. In the context of currency mismatch, the change in relative prices affects the real debt burden, which ultimately influences the macroeconomic effects of public spending.

Finally, our paper can be related to the so-called "third generation models of currency crisis" [START_REF] Aghion | Currency crises and monetary policy in an economy with credit constraints[END_REF][START_REF] Aghion | A corporate balance-sheet approach to currency crises[END_REF][START_REF] Christiano | Monetary policy in a financial crisis[END_REF]. In essence, this literature demonstrates that the real impact of exchange rate movements may be amplified through balance sheet effects. As a rule, countries that are most likely to enter a crisis are those in which firms hold considerable foreign currency-denominated debt. Nonetheless, our contribution differs somewhat from these models in several respects. First, we concentrate on the effects of fiscal shocks. Second, the mechanism that we focus on does not rely on public debt but on private sector debt. Third, we consider the change in the balance sheets of private domestic firms not as a cause but as a consequence of terms of trade movements.

The remainder of the paper is organized as follows. The theoretical model is developed in Section 2. Section 3 presents the calibration. Section 4 shows the responses of the model to a public spending shock, depending on the degree of home bias and maturity mismatch. A discussion on the size of the fiscal multiplier and policy implications is presented in Section 5. Section 6 concludes the paper.

The model

We consider a real economy consisting of two countries of equal size: the home economy (H) and the foreign economy (F). Both are populated by a continuum of identical households with size normalized to one. These households consume a composite good (C t ), including home (C H,t ) and foreign goods (C F,t ). They also buy home and foreign bonds (B H,t and B F,t ). In each bloc, there are two types of firms: capital and goods producers. To make the model as simple as possible, we assume that each of them operates in competitive markets. The capital producers buy goods and transform them into capital that is sold to goods producers. Goods producers use labor and capital to produce a homogeneous final good that they sell to households and to capital producers. Importantly, home final goods producers can borrow to finance capital input. As in [START_REF] Bernanke | The financial accelerator in a quantitative business cycle framework[END_REF], because of asymmetric information, they have to bear an EFP. An important difference from [START_REF] Bernanke | The financial accelerator in a quantitative business cycle framework[END_REF] is that here, firms can borrow in both local and foreign currencies. The countercyclical EFP affects firms' cost of financing, thus modifying their investment decisions and, in turn, amplifying economic fluctuations. For simplicity, and without loss of generality, we assume that there is no asymmetric information between firms and their lenders in the foreign country. Thus, there is no financial accelerator in F.

The rest of the model is very standard. In what follows, we present the equations describing the behavior of the home country sectors in detail. The steady-state and the log-linearized version of the model are provided in the Appendix.

Households

We consider an infinite-horizon discrete-time economy populated by a constant mass of agents of size normalized to one in each country. The representative household in the home country is characterized by the following preferences:

E t ∞ t=0 β t U (C t , L t ) (1)
where E t indicates the expectation operator at time t, β ∈ (0, 1) is the discount factor, C t is the per capita consumption index, and L t is the number of worked hours. We assume that the utility function takes the following form:

U (C t , L t ) = C 1-σc t 1 -σ c - L 1+σ l t 1 + σ l (2)
where σ c > 0 is the inverse of the intertemporal elasticity of substitution of consumption and σ l > 0 is the intertemporal elasticity of substitution of labor. For the sake of simplicity and to focus on the essential mechanisms, we assume that foreign households share the same preferences as households in H. The home household faces the following budget constraint:

C t + P H,t P t B H,t + P F,t P t B F,t + T t = W t L t + R t-1 P H,t P t B H,t-1 + φ t-1 (d t-1 ) P F,t P t R * t-1 B F,t-1 (3)
where B H,t and B F,t are risk-free one-period bonds defined in terms of goods in the home (H) and the foreign (F) country,2 with relative prices

P H,t
Pt and

P F,t
Pt , respectively. P H,t is the price of the goods produced and sold at home, P F,t is the price of the goods produced in the foreign country and sold in the home economy (namely, imports), and P t is the domestic consumer price index (CPI). T t is a real lump-sum tax levied on households. W t represents the real wage rate. Moreover, we denote by R t and R * t the real interest rates on the domestic and foreign bond markets, respectively. Generally, an asterisk " * " designates variables in the foreign economy.

The factor φ t is a country premium borne by households that buy foreign bonds. Fol-lowing [START_REF] Benigno | Price stability with imperfect financial integration[END_REF] and Schmitt-Grohé and Uribe ( 2003), it increases with the economy's aggregate level of real foreign debt (B F,t ) as a percentage of domestic steady-state output

d t = P F,t B F,t
PtY , and it is defined as follows:

φ t (d t ) = exp -φ d P F,t B F,t P t Y (4)
where φ d > 0 is the country premium elasticity. We assume that φ (.) < 0. This means that the country premium increases with the aggregate level of foreign debt. In steady state, when the net foreign asset position is zero, φ(0) = 1. This country premium reflects frictions in international capital markets, such as the price to pay to access them, agency costs or even the possibility of default, and ensures the stationarity of the model (Schmitt-Grohé and Uribe, 2003). For analytical convenience, and without loss of generality, we suppose that home households can hold foreign bonds but that foreign households cannot hold home bonds [START_REF] Benigno | Consumption and real exchange rates with incomplete markets and non-traded goods[END_REF].

The representative household chooses C t , L t , B H,t and B F,t to maximize her utility subject to the budget constraint, leading to the following first-order conditions:

-Consumption and leisure are chosen to equalize the marginal rate of substitution between consumption and leisure to the real wage:

L σ l t C -σc t = W t (5)
-The Euler equation, reflecting the household's taste for consumption smoothing:

R t = 1 β E t C -σc t C -σc t+1 (6)
-The arbitrage equation between home and foreign bonds:

E t R t P H,t+1 P H,t -φ t (.)R * t P F,t+1 P F,t = 0 (7)
Finally, the standard transversality conditions must hold.

The per capita index of consumption, C t , is an aggregate of consumption goods produced in the home country (C H,t ) and consumption goods produced in the foreign country (C F,t ). It is defined as follows:

C t = w 1/µ C (µ-1)/µ H,t + (1 -w) 1/µ C (µ-1)/µ F,t µ/(µ-1) (8)
where µ > 0 is the elasticity of substitution between home and foreign goods and w ∈ (0, 1) captures the degree of home bias in the home bloc. Therefore, (1 -w) can be viewed as the degree of trade openness. The domestic and foreign demands for domestic goods are given by

C H,t = w P H,t P t -µ C t ; C F,t = (1 -w) P F,t P t -µ C t (9)
The CPI associated with the consumption index (Equation 8) is given by

P t = w(P H,t ) 1-µ + (1 -w)(P F,t ) 1-µ 1/(1-µ) (10)
In the same way, the foreign economy's CPI is defined as

P * t = (1 -w * )(P * H,t ) 1-µ * + w * (P * F,t ) 1-µ * 1/(1-µ * ) (11)
where P * F,t is the price of goods produced and sold in the foreign country and P * H,t is the price of goods produced by the home economy and sold in the foreign country, namely, the price of the home economy's exports.

We define the terms of trade (τ t ) as the relative price of imports to exports. Given the law of one price, according to which

P * F,t P F,t = P * H,t
P H,t = 1, the terms of trade can be expressed as:

τ t = P F,t P H,t . ( 12
)
Finally, using Equations ( 7) and ( 12), the (modified) uncovered interest rate parity (UIP) condition is obtained:

R t = φ t (d t )E t R * t τ t+1 τ t (13)
which differs from the standard UIP because of the presence of the interest rate premium φ t .

Firms

Both countries are populated by good and capital producers. To produce final goods, goods producers use labor provided by households and capital provided by capital producers. Domestic goods producers borrow in home and foreign goods to finance their inputs and bear an EFP that depends on their balance sheet structure, in line with the framework suggested by [START_REF] Bernanke | The financial accelerator in a quantitative business cycle framework[END_REF]. For the sake of simplicity, foreign firms are not subject to balance sheet effects and are only financed by households of country F, without agency premium. They all operate in competitive markets.

Capital producers

To produce new capital K t , capital producers invest a composite of final goods (denoted I t ) bought from home and foreign goods producers as follows:

I t = w 1/µ i i I µ i -1 µ i H,t + (1 -w i ) 1/µ i I µ i -1 µ i F,t µ i µ i -1 (14)
where w i ∈ (0, 1) measures the home bias of capital producers and µ I > 0 is the elasticity of substitution between home and foreign retail goods for capital producers. In producing new capital, these firms support internal adjustment costs, which are increasing and convex in I t /K t :

Ψ(I t , K t ) = Φ 2 I t K t -δ 2 K t ( 15
)
where δ ∈ (0, 1) is the depreciation rate of capital and Φ is a positive parameter.

For the sake of simplicity, we assume that firms and households have the same preferences for home and foreign goods, such that w = w i and µ = µ i . The price of I t is therefore equal to the CPI given by Equation ( 10). Next, the optimal intratemporal demands for domestic and foreign inputs are given by

I H,t = w P H,t P t -µ i I t and I F,t = (1 -w) P F,t P t -µ i I t (16)
Finally, the stock of capital evolves according to the usual law of motion:

K t+1 = I t + (1 -δ)K t (17)
Hence, profit optimization of capital producers with respect to I t defines the real price of capital, q t , as follows:

q t = 1 + ∂Ψ(I t , K t ) ∂I t = 1 + Φ I t K t -δ (18)

Goods producers

Domestic firms use capital and labor to produce and sell a homogeneous good in a competitive market. Their production technology is characterized by constant returns to scale and is represented by a Cobb-Douglas function with exogenous productivity shocks denoted

A t : Y t = A t K α t L 1-α t ( 19
)
where Y t is the quantity of goods produced by domestic firms. The capital intensity, α, lies between 0 and 1. These firms choose the quantities of labor and capital that maximize their profits. This yields the following first-order conditions, defining domestic real wages:

W t = P H,t P t (1 -α) Y t L t , ( 20
)
and the real return on capital over period t:

R k t =     α P H,t Pt Yt Kt -Φ 2 δ 2 -It Kt 2 + (1 -δ)q t q t-1     (21)
Equation ( 21) states that each additional unit of capital yields α P H,t Pt Yt Kt (corresponding to the marginal productivity of capital) to the firm minus the capital adjustment costs. This equation also assumes that capital could be resold at its depreciated value (1 -δ)q t . Home wholesalers borrow in both local and foreign currencies to finance their activity (contrary to foreign wholesale firms). Moreover, as in [START_REF] Bernanke | The financial accelerator in a quantitative business cycle framework[END_REF], they have to bear an EFP, Θ t , defined by

Θ t = Θ q t-1 K t N t (22)
with Θ (.) > 0, Θ(1) = 1 and Θ(∞) = ∞. N t is the net worth of a wholesale firm, which will be defined below. Moreover, the elasticity of the EFP to the capital-to-net worth ratio is denoted θ hereafter.

The representative firm borrows in home currency in proportion κ and in foreign currency3 in proportion (1-κ), with κ ∈ [0, 1]. Therefore, home and foreign interest rates are combined to obtain the expected marginal cost of borrowing:

E t R k t+1 = Θ t+1 κR t + (1 -κ) φ t (d t )E t R * t τ t+1 τ t ( 23
)
This equation states that the real return of capital must be equal to the cost of acquiring this capital. This cost is determined by the EFP, by the home interest rate in proportion κ, and by the foreign interest rate and the terms of trade in proportion 1 -κ.

Wholesalers accumulate net worth according to the following dynamics:

N t+1 = ξ e R k t q t-1 K t -Θ t κR t-1 + (1 -κ)φ t-1 (d t-1 )R * t-1 τ t τ t-1 (q t-1 K t -N t ) (24)
where 1 -ξ e is the probability that a firm will exit the market. The net worth is equal to the real return on capital held by the firm minus the financing cost of the acquired capital. Equation ( 24) shows that firms are exposed to changes in the terms of trade when they are indebted in foreign currency. For small values of κ, a decrease in the terms of trade (an appreciation) increases the firm's net worth, whereas an increase in the terms of trade (a depreciation) decreases its net worth. Finally, entrepreneurs who exit consume their remaining resources:

C e t = (1 -ξ e ) ξ e N t ( 25
)
In line with households, the optimal consumption of exiting entrepreneurs is

C e H,

Fiscal policy and market clearing

As is typical in the literature, public spending is financed through lump-sum taxes:

P t G t = T t ( 27
)
where G t is the total amount of public spending. We assume that the government consumes both local and foreign final goods and that composite public spending is aggregated in the same manner as private demand. Public spending follows an autoregressive process:

G t = ρ g G t-1 + ε gt ( 28
)
where

G t = Gt-G G
is the log-deviation of G t around its steady-state value G, ρ g ∈ (0, 1), and

ε gt is a fiscal shock.
The domestic market clearing condition is given by

Y t = w P H,t P t -µ (C t + C e t + I t + G t ) + (1 -w) P * H,t P * t -µ (C * t + I * t + G * t ) (29)
The equilibrium between the current account and the financial account allows the trade balance (T B) to be defined as follows:

T B t = P H,t Y t -P t C t -P t C e t -P t I t -P t G t -P t Ψ(I t , K t ) (30)
The home economy accumulates net foreign assets according to the following dynamics:

d t = P t-1 P t P H,t P H,t-1 φ t-1 τ t τ t-1 R * t-1 d t-1 + P H,t P t Y t Y - C t Y - C e t Y - G t Y - I t Y -Ψ(I t , K t ) (31)
Walras' law implies that the bond market equilibrium is reached when all other markets clear.

Calibration

The parameters of the model are calibrated with respect to consensus values in the literature. As noted above, the main differences between the two economies concern the financial accelerator mechanism (absent in country F for parsimony) and the denomination of debt (to varying degrees in foreign currency for country H but in domestic currency in F). As such, we can more clearly isolate the mechanisms at work and the impact of foreign currency denomination of debt on the fiscal multiplier. A complete summary of the parameter calibration is reported in Table 1 below. Note that for the sake of the analysis, some different values of κ and ω will be considered. Households Following [START_REF] Elekdağ | Balance sheets, exchange rate policy, and welfare[END_REF], the inverse of the intertemporal elasticity of substitution (σ c ) and the inverse of the Frisch elasticity of labor supply (σ l ) are fixed at 2 and 1, respectively. As is typical in the literature, the discount factor β is equal to 0.99. The elasticity of substitution between locally produced varieties, ζ, is equal to 6, following [START_REF] Bouakez | Government spending, monetary policy, and the real exchange rate[END_REF] and [START_REF] Kitano | Capital controls, monetary policy, and balance sheets in a small open economy[END_REF]. The elasticity of substitution between home and foreign goods, µ, is fixed at 1.5, as in [START_REF] Bouakez | Government spending, monetary policy, and the real exchange rate[END_REF]. Next, the consumption-to-GDP ratio (C/Y ) in steady state is fixed at 60%. Finally, the country premium elasticity φ d is assumed to be equal to 0.0007, in line with Schmitt-Grohé and Uribe (2003).

Firms Following [START_REF] Kitano | Capital controls, monetary policy, and balance sheets in a small open economy[END_REF], the capital intensity (α) is set to 0.35, which implies a labor intensity of 0.65. As is typical in the literature, the depreciation rate of capital δ is set to 0.025. The adjustment cost function parameter Φ is equal to 6, as in [START_REF] Chang | On the sources of aggregate fluctuations in emerging economies[END_REF].

Wholesale firms support an EFP, which depends on the capital-to-net worth ratio with an elasticity of 0.075, in line with [START_REF] Elekdağ | Balance sheets, exchange rate policy, and welfare[END_REF], for example. Wholesalers exit at the end of a period with probability 1 -ξ e , with ξ e = 0.985, as in [START_REF] Levieuge | The bank capital channel and counter-cyclical prudential regulation in a DSGE model[END_REF]. In steady state, the consumption of existing firms (C e ) is assumed to represent 2% of GDP. In steady state, the leverage ratio (K/N ) is equal to 3, following [START_REF] Devereux | Exchange rates and monetary policy in emerging market economies[END_REF], whereas investment represents 18% of GDP.4

Fiscal policy

The autoregressive parameter ρ g in the process driving the pattern of public spending shocks is set to 0.8, in line with most of the literature.

The effects of public spending

This section presents the real effects of public spending, especially on GDP, depending on the degree of home bias and on the proportion of external debt denominated in foreign currency. Because, according to the literature, the degree of home bias may influence the reaction of the real exchange rate to public spending, our analysis is conducted in two stages: we successively consider the case of an economy with a large and with a low home bias, i.e., with ω = 0.75 or 0.25, respectively. In each case, we examine the effects of a low vs. high share of debt denominated in foreign currency. Additionally, to be as clear as possible, we also refer to a configuration without financial friction, i.e., with θ = 0 (i.e., no financial accelerator). Considering these different configurations allows for a better understanding of the mechanisms at work and of the results.

As a preamble, note that financial frictions are an important feature of the model. In this respect, Equation ( 22), which defines the EFP, is crucial: it states that the EFP is decreasing in net wealth ("collateral effect") and increasing in q t-1 K t ("capital demand effect"). An important inherent mechanism to bear in mind, which is common to all the configurations under review, is the following: any decrease (increase) in investment induces less (more) capital accumulation and thus less (more) net wealth accumulation, which tends to increase (decrease) the EFP. This in turn exacerbates the initial decline (increase) in investment.

Finally, notwithstanding financial frictions, the effects of public spending are not expected to be highly beneficial in this model in real terms, notably given Ricardian households and the absence of nominal rigidities. Crowding-out effects of private investment are likely to be strong.

Large home bias

We first consider the case of an economy with an important home bias (ω = 0.75). Figure 1 reports the responses of the main variables of the model to a 1% increase in public spending. The red dotted line corresponds to the case in which firms are mainly indebted in foreign currency (κ = 0.1), while the blue solid line refers to a situation in which indebtedness is mainly denominated in local currency (κ = 0.9).

In the two cases, the increase in public spending triggers an increase in domestic demand, given the home bias, and thus a rise in domestic prices P H,t . This in turn has two effects. First, it makes domestic investment more expensive, as the price of I t is equal to the CPI given by Equation ( 10). This drives down domestic investment, as well as total investment, given the predominant weight of I H in I t (ω = 0.75 in Equation 14). This is the first source of the crowding-out effect.

Second, the increase in P H,t improves the terms of trade.5 Interestingly, this reduces the real debt burden when debt is mainly denominated in foreign currency (i.e., when κ = 0.1). In this case, firms' net worth increases, and as the collateral effect dominates the capital demand effect, firms benefit from a decrease in the EFP. As this mitigates the crowding-out effect, the response of the output to the fiscal shock is strictly positive. Given these favorable balance sheet effects, this configuration results in the highest multiplier that can be expected.

For comparison purposes, Figure 4 in the Appendix shows that in the absence of financial frictions (θ = 0), net wealth initially increases but without affecting credit conditions (by definition). Hence, the economy cannot benefit from any self-sustained positive balance sheet effects. As a result, net worth declines in the wake of reduced capital accumulation, and output is less stimulated than in the presence of the financial accelerator mechanism.

Finally, when the real debt burden consists primarily of domestic goods (i.e., κ = 0.9), the improvement in the terms of trade has no effect on the balance sheets of indebted firms.Therefore, the crowding-out effect is not dampened, contrary to the case in which κ = 0.1. Consequently, output increases to a lesser extent (by 32% less) than when real debt is mainly denominated in foreign currency. It even decreases five quarters after the shock, given the stronger decline in private investment.

Low home bias

We now assume that the domestic economy is characterized by a low home bias, or equivalently, by a large openness, with ω = 0.25. The impulse responses of the main variables of the model, under this configuration, are presented in Figure 2, conditional on low (κ = 0.9) and high (κ = 0.1) debt in foreign currency.

In this context of low home bias, an increase in public spending raises the demand for foreign goods. This increases the foreign goods price (P F,t ), with two main consequences. First, given that the price of investment goods I t , given by Equation ( 10), is mainly driven by the price of goods produced in the foreign country (as 1 -ω = 0.75), the rise in P F,t increases the price of investment goods I t . This drives down investment. Moreover, the subsequent decline in capital and wealth accumulation tends to increase the EFP. This worsens the crowding-out effect. Second, we observe a deterioration in the terms of trade, which has different consequences depending on the proportion of private debt that is denominated in foreign goods.

When debt is mainly denominated in foreign currency (κ = 0.1), the deterioration in the terms of trade increases the real debt burden. The worsening of firms' balance sheet position provokes a tightening of credit conditions, with a higher EFP. This contributes making investment even lower. As a result, we observe an immediate decrease in aggregate output in response to a fiscal shock. This depicts the worst configuration in terms of the fiscal multiplier.6

In contrast, we observe in Figure 5 in the Appendix that the response of output is not negative but positive in the absence of financial frictions, as investment does not suffer from the deterioration of firms' balance sheets. Once again, this demonstrates the importance of financial frictions in explaining the size (and even the sign) of the fiscal multiplier in an open economy with debt denominated in foreign currency.

Finally, when private debt consists primarily of domestic goods (κ = 0.9), credit conditions are tightened due to lower accumulation of capital and, hence, of net worth (as the collateral effect dominates the demand effect) in the wake of the increase in the price of investment. However, the EFP increases less than for κ = 0.1, as the deterioration of the terms of trade has little impact on the real debt burden. Thus, investment falls but only by half as much as in the previous case. As a result, the response of output is positive, at least during the first 10 periods after the fiscal shock.

Assessment and discussion of policy implications

Following convention in the literature, the responses of GDP are now transposed in terms of the fiscal multiplier, defined as ∆Y t /∆G t . Figure 3 represents this impact multiplier conditional on the degree of home bias and on the proportion of debt denominated in domestic currency. This figure, which complements the IRFs and the mechanisms described previously, deserves several comments. First, Figure 3 confirms that the level of the multiplier highly depends on the degree of home bias. A small home bias (dotted line) is associated with a low fiscal multiplier. This is due not only to the increase in domestic demand for imported goods, as in the textbook model, but also to balance sheet effects. Indeed, under financial frictions, financing conditions depend on both currency mismatch and the response of the terms of trade to public spending shocks. This is because, under low home bias, the terms of trade worsen, and the balance sheet structure of firms that are heavily indebted in foreign currency deteriorates. Negative balance sheet effects are combined with the standard crowding-out effect to make the fiscal multiplier very low. In this configuration, the higher the debt in foreign currency is, the lower the fiscal multiplier. The impact multiplier can even be negative when private debt is mainly denominated in foreign currency.

In contrast, the solid line in Figure 3 shows that being indebted in foreign goods is beneficial when home bias is strong. In this case, the terms of trade improve in the wake of an exogenous increase in public spending. Because this improves the quality of firms' balance sheets by reducing real debt, firms can benefit from better credit conditions. Hence, under this configuration, the higher the debt in foreign currency is, the higher the fiscal multiplier. Despite the absence of ingredients that are known to increase fiscal multipliers in theoretical models (e.g., nominal rigidities or zero lower bounds for policy rates) and despite the Ricardian behavior of the agents, strictly positive multipliers may be achieved in this case.

Finally, these results lead to rather nuanced normative conclusions regarding currency mismatch.7 From a fiscal multiplier perspective, policies designed to restrict debt denominated in foreign currency are not necessarily desirable. They may mitigate the crowding-out effects of public spending stimulus in the case of a small home bias. However, they may reduce the fiscal multiplier when the home bias is large.

Ultimately, the main issue concerns financial imperfections. As shown8 , in the absence of financial frictions, currency mismatch is less crucial for the size of the impact of public spending.

Concluding remarks

The literature reports various determinants of the size of the fiscal multiplier, such as the level of public debt, the position of the economy in the business cycle, the exchange rate regime, or the degree of trade openness. In this paper, we demonstrate that in the presence of financial frictions, currency mismatch and the degree of home bias simultaneously constitute an additional determinant of the effectiveness of public spending.

Our theoretical contribution is based on a real two-country dynamic stochastic general equilibrium model with incomplete and imperfect international financial markets and external indebtedness. The model also embeds financial frictions due to asymmetric information. Therefore, in a costly state verification framework, firms have to bear an external finance premium that increases with their debt-to-wealth ratio. While domestic net wealth is assumed to be entirely denominated in domestic goods, firms' debt is assumed to be (to some extent) denominated in foreign goods. This maturity mismatch may be at the origin of a financial accelerator mechanism that may influence the macroeconomic impact of fiscal shocks. We show that following an exogenous increase in public spending, the terms of trade can improve or deteriorate, depending on the degree of home bias of the domestic economy. If the home bias is high, the terms of trade improve. This reduces the private real debt burden denominated in foreign currency and decreases the external finance premium born by firms. Finally, this stimulates investment. Thus, the higher the fiscal multiplier is, the larger the fraction of firms' debt denominated in foreign currency. In contrast, we observe a deterioration of the terms of trade when home bias is low. This makes the real debt burden increase, leading to a deterioration of firms' balance sheets and hence to a higher external finance premium. As a result, the fiscal multiplier decreases as the share of firms' debt denominated in foreign currency increases.

These results lead to rather nuanced conclusions for policies addressing currency mismatch. From a fiscal multiplier perspective, measures designed to restrict debt denominated in foreign currency are not necessarily desirable. On the one hand, they may mitigate the crowding-out effects of public spending stimulus in the case of small home bias. On the other hand, they may reduce the fiscal multiplier when home bias is large. Finally, financial imperfections appear even more important: in the absence of financial frictions, currency mismatch turns out to be less crucial for the size of the impact of public spending.

The steady state

Any variable without a time index refers to its steady-state value.

Home economy

C = w 1/µ C µ-1/µ H + (1 -w) 1/µ C µ-1/µ F µ/µ-1 (32) C H = w P H P -µ C ; C F = (1 -w) P F P -µ C ( 33
) P = wP (1-µ) H + (1 -w)P 1-µ F 1/(1-µ) (34) τ = P F P H (35) I = w 1/µ I µ-1 µ H + (1 -w) 1/µ I µ-1 µ F µ 1-µ (36) I H = w P H P -µ I ; I F = (1 -w) P F P -µ I (37) I K = δ (38) W L Y = P H P (1 -α) (39) q = 1 (40) Y K = 1 α P P H R k -(1 -δ) (41) I Y = αδ R k -(1 -δ) P H P (42) R = 1 β (43) Θ = Θ K N (44) R = R * (45) R k = ΘR (46) C e = (1 -ξ e ) ξ e N ( 47
) P G = T (48)
Foreign economy

C * = (1 -w) 1/µ C * µ-1/µ H + w 1/µ C * µ-1/µ F µ/µ-1 (49) P * = (1 -w)P * (1-µ) H + wP * 1-µ F 1/(1-µ) (50)
I * = (1 -w) 1/µ I * µ-1 µ H + w 1/µ I * µ-1 µ F µ 1-µ (

Log-linearized model

Home economy

Total demand (following Equation 29): Household consumption (following Equation 6):

Y t =µ
C t = E t C t+1 - 1 σ c R t ( 63
)
Capital demand (following Equation 21):

R k t = 1 - 1 -δ R k mpc t - Φδ 2 R k K t + 1 -δ R k q t -qt-1 (64)
Expected cost of capital (following Equation 23):

R k t+1 =θ q t + K t+1 -N t+1 + Θκ R R k R t + Θ(1 -κ) R * R k R * t + τ t+1 -τ t -φ d d t ( 65
)
Real price of capital (following Equation 18):

q t = Φδ( I t -K t ) q (66)
Consumption of exiting firms (following Equation 25):

C e t = N t ( 67
)
Marginal productivity of capital (following Equation 21):

mpc t = Y t -K t -(1 -w) τ t ( 68
)
Production function (following Equation 19):

Y t = a t + α K t + (1 -α) L t ( 69
)
Labor supply (following Equation 5):

L t = 1 σ l W t -σ c C t (70)
Marginal productivity of labor (following Equation 20):

W t = Y t -L t -(1 -w) τ t (71)
Terms of trade (following Equation 13):

τ t = E t τ t+1 + R * t -R t -φ d d t ( 72
)
Net foreign asset accumulation (following Equation 31):

9 d t = 1 β d t-1 -(1 -w) τ t + Y t - C Y C t - C e Y C e t - I Y I t - G Y G t ( 73
)
Net worth accumulation (following Equation 24):

N t ξ e =R k K N R k t-1 + R k θ 1 - K N q t-1 + K t + R k θ K N -1 + 1 N t-1 -Θ (1 -κ) R * K N -1 τ t -τ t-1 + R * t-1 -φ d d t-1 -ΘκR K N -1 R t-1 (74)
Capital accumulation (following Equation 17):

K t+1 = δ I t + (1 -δ) K t (75)
Fiscal policy:

G t = ρ g G t-1 + ε gt (76)
Productivity shock: ât = ρ a ât-1 + ε at (77)

Foreign economy

Total demand: Household consumption:

Y * t =µ
C * t = E t C * t+1 - 1 σ c R * t ( 79
)
Capital demand:

R k * t = 1 - (1 -δ * ) R k * mpc * - Φδ * 2 R k * K * t + (1 -δ * ) R k * q * t -q * t-1 (80)
Expected cost of capital:

R k * t = R * t (81)
Real price of capital:

q * t = Φδ * I * t -K * t q * (82)
Marginal productivity of capital:

mpc * t = -(1 -w) τ * t + Y * t -K * t ( 83
)
Terms of trade:

τ * t = -τ t ( 84
)
Production:

Y * t = â * t + α K * t + (1 -α) L * t ( 85
)
Labor supply:

L * t = 1 σ * l W * t -σ * c C * t ( 86
)
Real wage:

W * = Y * t -L * t -(1 -w) τ * t ( 87
)
Capital accumulation:

K * t+1 =

Figure 3 :

 3 Figure 3: The fiscal multiplier against the share of domestic currency-denominated debt

  α * δ * R k * -(1 -δ * )

Table 1 :

 1 Baseline calibration of the parameters

	Parameter Definition	Value Source
	σ c	Inverse of intertemporal elasticity of substi-	2 Elekdağ and Tchakarov (2007)
		tution of consumption
	σ l	Inverse of Frisch elasticity of labor supply	1 Elekdağ and Tchakarov (2007)
	β	Discount factor	0.99 Usual
	φ d	Country premium elasticity	0.0007 Schmitt-Grohé and Uribe (2003)
	ζ	Elasticity of substitution between varieties	6 Bouakez and Eyquem (2015) and
			Kitano and Takaku (2015)
	α	Capital intensity	0.30 Kitano and Takaku (2015)
	δ	Depreciation rate of capital	0.025 Usual
	µ	Elasticity of substitution across domestic and	1.5 Bouakez and Eyquem (2015), Ki-
		foreign goods	tano and Takaku (2015)
	Φ	Adjustment cost function parameter	6 Chang and Fernández (2013)
	θ	Elasticity of external finance premium to the	0.075 Elekdağ and Tchakarov (2007)
		capital-to-net wealth ratio
	ξ e	Probability of firms to exit	0.985 Levieuge (2009)
	ρ g	Autocorrelation of public spending shocks	0.8 Usual

[START_REF] Ravn | Consumption, government spending, and the real exchange rate[END_REF] assume that the preferences of households and the government are characterized by deep habits; it is thus optimal for imperfectly competitive producers to reduce markups and prices in the short run to lock in higher demand in the future. Finally, the price of domestic consumption decreases relative to foreign consumption prices, i.e., the real exchange rate depreciates. See also[START_REF] Kollmann | Government purchases and the real exchange rate[END_REF] for another mechanism relying on supply-side effects. From a public debt consolidation view,Corsetti et al. (2012b) suggest that high public spending today induces expectations of future spending restraint. Thus, long-term real interest rates do not rise in response to a fiscal stimulus, and the real exchange rate depreciates.

Although the paper deals with a real economy, and hence bonds are denominated in domestic and foreign goods, throughout the paper, we will use the expression of debt denominated in domestic or foreign currency.

Explaining κ is beyond the scope of this paper. Nonetheless, an interesting extension would consist of rendering it endogenous.

For the foreign economy, I * /Y * is set to 20% since C e /Y is zero.

Note that, by construction, a decrease in τ indicates an improvement in the terms of trade.

The deterioration in the terms of trade and, therefore, the negative balance sheet effects are limited by the decline in output, as this implies less demand (abroad). However, this remains the worst case.

See, e.g., IMF (2011) for examples of countries that have implemented limits on currency mismatch.

See, e.g., Figure4in the Appendix.

Since d = 0, d t denotes d t -d. See[START_REF] Bouakez | Government spending, monetary policy, and the real exchange rate[END_REF].

Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:


H Pallud

Dufour

MSc Sébastien M D Boissonneau
email: sebastien.boissonneau@ap-hm.fr

Management of patients suffering from hemorrhagic intracranial metastases: Propositions to help the neurosurgeon in emergency situations based on a literature review

Keywords: [metastases], [brain metastases], [brain metastasis], [hemorrhage], [hematoma], [blood clot], [intracerebral hemorrhage], [intracranial hemorrhage]

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

Introduction

Brain metastases are the most common intracranial neoplasms in adult patients. They appear in 10 to 30% of patient with systemic cancer [START_REF] Brastianos | Clinical Discussion and Review of the Management of Brain Metastases[END_REF]. Hemorrhagic transformation leads most of the time to a decision that needs to be taken acutely, in an emergency setting and that is consequently not based in the multidisciplinary environment of the tumoral board. The frequency of spontaneous intracerebral hemorrhage in patients with intracranial neoplasms ranges between 1.4 to 10% (average 2.5%) [START_REF] Kondziolka | Significance of hemorrhage into brain tumors: clinicopathological study[END_REF][START_REF] Schrader | Spontaneous Intracranial Haematomas Caused by Neoplasms[END_REF][START_REF] Wakai | Spontaneous Intracranial Hemorrhage Caused by Brain Tumor[END_REF][START_REF] Fewel | Spontaneous intracerebral hemorrhage: a review[END_REF]. Intracerebral hemorrhage is more frequent in patients with cerebral metastases than in patients with gliomas (14% versus 0.8%, respectively) [START_REF] Maiuri | Intracranial hemorrhages in metastatic brain tumors[END_REF]. Brain metastases from melanoma, renal cell carcinoma, choriocarcinoma, and thyroid carcinoma have a well-known propensity for spontaneous hemorrhage [7]. A dramatic dreadful complication of an intracranial bleeding is the subsequent neurological and functional alteration that may strongly impact the quality of life (QoL) of the patient. The patient's QoL is indeed a crucial criterion to take into account before any neurosurgical procedures and to be weighted up against the functional prognosis and the potentially short overall survival expectancy for patients with brain metastases [START_REF] Stelzer | Epidemiology and prognosis of brain metastases[END_REF].

Based on the literature review, we herein summarize the epidemiology, clinical features, diagnostic evaluation, neurosurgical management and prognosis for adult patients harboring a brain metastasis-related intracerebral hemorrhage. The goal of this study is to come up with a few suggestions to help the neurosurgeon in their decision-making process in emergency settings.

Methods

A literature search was conducted on PubMed, Cochrane, and Google Scholar in 2019 to identify all studies, except pediatric studies, concerning brain metastases and intracerebral hemorrhage in the English language. The inclusive search dates were from 2000 through 2019 and specific search terms included

[metastasis], [metastases], [brain metastases], [brain metastasis], [hemorrhage], [hematoma], [blood clot], [intracerebral hemorrhage], [intracranial hemorrhage].
After the searches were completed, the abstract of each publication was reviewed to determine relevance or adequacy with our topic and selected studies were further analyzed for this review. We used the right reporting tool for practice guidelines in health care to strengthen the methodology [START_REF] Chen | A Reporting Tool for Practice Guidelines in Health Care: The RIGHT Statement[END_REF]. The review was conducted in accordance with PRISMA recommendations [START_REF] Moher | Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement[END_REF].

Results

A total of 455 articles in PubMed, 5 in Cochrane and 3 in Google Scholar were initially found with the above-mentioned search criteria. Of those 459 articles were retained after removing duplicates. 392 were then removed because of their non-adequacy with the topic of this article. Indeed, 9 articles were removed because they were not written in English language. So, 58 articles were analyzed and could serve as a basis to establish guidelines.

Currently, there are no surgical guidelines about the surgical management of brain hemorrhagic metastases. In the light of current guidelines for spontaneous stroke hematomas, we advocate an early decompression surgery (clot removal together with metastasis removal) to diminish mass effect, for patient with neurological deterioration and/or vigilance alteration [START_REF] Mendelow | Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial[END_REF][START_REF] Steiner | European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage[END_REF]. The need of a decompressive craniectomy associated with clot removal is still discussed with conflicting results in few non-randomized trials [START_REF] Ma | Decompressive craniectomy in addition to hematoma evacuation improves mortality of patients with spontaneous basal ganglia hemorrhage[END_REF][START_REF] Shimamura | Decompressive hemicraniectomy is not necessary to rescue supratentorial hypertensive intracerebral hemorrhage patients: consecutive single-center experience[END_REF]. In the randomized study STICH II,pertaining to patient suffering from an intracerebral hematoma, the authors do not report any increase of disability after surgical clot removing (Class III, Level of evidence B) [START_REF] Mendelow | Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial[END_REF], .The European Stroke Organization (ESO) guidelines for the management of spontaneous intracerebral hemorrhage, favor an early surgery for patients with a Glasgow Coma Scale score 9-12 (Class II, Level of evidence A) [START_REF] Steiner | European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage[END_REF]. In our review, the results of STITCH II study can't be extrapolated to patients with brain metastases, and the timing for surgery is still controversial. Indeed, these studies seem to be harmful for ultraearly clot removal (< 2 hours) for cerebral hematomas, because it could increase the risk of early re-bleeding (Class III, Level of evidence B). In the opposite, patients with cerebellar hematomas and with a brainstem compression, or a neurologically deterioration, and/or a hydrocephalus should benefit from an ultra-early surgical removal (Class I, Level of evidence B) [START_REF] Morgenstern | Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association[END_REF]. This reflection seems to be coherent with the current literature. The removal of hematoma in patient suffering from a neurological deterioration, should be performed. This removal could improve the onco-functional imbalance and avoid death but needs to be analyzed in the light of the oncological prognosis of the patient, with the consequences of the surgery. This is the reason why we cannot extrapolate the results of STITCH II study with these patients.

Pitfalls

A common diagnostic pitfall is the spontaneous intracranial hematoma (not directly related to a brain metastasis) caused by the systemic neoplasm. Shrader et al. reported in a prospective study of 2041 patients, that the frequency of tumor related with spontaneous intracranial hematoma is 7.2%, with a higher frequency for brain metastases. This point is pivotal for the daily management of patients with spontaneous intracranial hematoma, where a neoplastic disease should be searched for, even in patients with no past medical history of cancer [START_REF] Schrader | Spontaneous Intracranial Haematomas Caused by Neoplasms[END_REF][START_REF] Nawabi | Neoplastic and Non-Neoplastic Causes of Acute Intracerebral Hemorrhage on CT: The Diagnostic Value of Perihematomal Edema[END_REF].

Collision-Tumors

In the literature, exceptional cases reports were reported. Indeed, hemorrhagic brain metastases could also mimic a cavernous angioma. Such an atypical presentation was reported by Lu et al. in two cases of patients with metastatic melanoma [START_REF] Lu | Brainstem melanomas presenting as a cavernous malformation[END_REF]. Another kind of vascular brain abnormality is described in the literature. An association of a brain arteriovenous malformation with an intracranial metastasis is reported by Morollon et al. [START_REF] Morollón | Histology of a cerebral hemorrhage: AVM as a seat of a metastatic choriocarcinoma[END_REF], but also in the case of a brain arteriovenous fistulae [START_REF] Fadli | Metastatic and hemorrhagic brain arteriovenous fistulae due to a choriocarcinoma. Case report[END_REF].

Atypical cases

Moreover, neoplastic cranial aneurysm is a rare entity, and according to the primary tumor the risk of bleeding may prove not negligible and is higher than 80% for the vast majority of neoplasms. Neoplastic cranial aneurysms could rupture and bleed more frequently in the case of lung cancer, and a choriocarcinoma rather than a cardiac myxoma [START_REF] Zheng | Neoplastic cerebral aneurysm from metastatic tumor: a systematic review of clinical and treatment characteristics[END_REF].

Hemorrhagic brain metastases could show many kinds of imaging presentations. Indeed, Seki et al. reported in 2016 on one patient with dural metastasis mimicking a meningioma [START_REF] Seki | Intraparenchymal hemorrhage from dural metastasis of breast cancer mimicking meningioma[END_REF].

In rare cases, atypical presentation is chronic or acute subdural hematoma. This rate is around 0.5 to 4% in these patients [START_REF] Tseng | Dural metastasis in patients with malignant neoplasm and chronic subdural hematoma[END_REF][START_REF] Prasad | Dural metastases in chronic myeloid leukemia presenting as subdural hematoma[END_REF]. Another atypical presentation, was epidural hematoma in a patient with a skull metastasis from an ovarian cancer [START_REF] Kumar | Epidural hematoma secondary to solitary skull metastasis from an ovarian carcinoma[END_REF].

Another pitfall lies in the risk of patients who are diagnosed with subdural hematoma in the setting of a known cancer. Those patients could have a hemorrhagic dural metastasis misdiagnosed as a subdural hematoma. In case of leukemia or hemopathy, the subdural hematoma can be independent of the bleeding diathesis induced by the disease. This invasion of the dura-mater should lead to perform a dural biopsy during the surgical procedure of the hematoma evacuation [START_REF] Tseng | Dural metastasis in patients with malignant neoplasm and chronic subdural hematoma[END_REF][START_REF] Chye | Acute spontaneous subdural hematoma caused by skull metastasis of hepatocellular carcinoma: case report[END_REF]. Hirooka et al. reported a rare case of a patient with a subarachnoid hemorrhage who developed secondarily, a brain metastasis. Metastases from lung cancer represent the majority of brain metastases [START_REF] Hirooka | Brain Metastasis of Pleural Mesothelioma after a Subarachnoid Hemorrhage[END_REF], and malignant pleural mesothelioma, is a fatal neoplasm, but uncommon. This disease is a consequence of asbestos exposure for many years (more than 40 years). In this rare case, the authors hypothesize that subarachnoid hemorrhage would have led to a blood brain barrier disruption, and in fine permitted the development of a brain metastases [START_REF] Zheng | Neoplastic cerebral aneurysm from metastatic tumor: a systematic review of clinical and treatment characteristics[END_REF][START_REF] Hirooka | Brain Metastasis of Pleural Mesothelioma after a Subarachnoid Hemorrhage[END_REF].

Another atypical case revelation is during a long air travel: According to the authors the vasoactive factors could be modified by the pressure during a long airplane flight and led to a hemorrhage [START_REF] Goldberg | Hemorrhage within brain tumors in association with long air travel[END_REF].

Radiosurgery

Cases of fatal bleeding occurring just after, or during radiosurgery for brain metastases have been described but seemed to be truly exceptional and seems to be multifactorial, but there has not been to date compelling evidence of a clear association [START_REF] Redmond | Gamma Knife surgery for the treatment of melanoma metastases: the effect of intratumoral hemorrhage on survival[END_REF][START_REF] Yomo | Fatal tumoral hemorrhage after stereotactic radiosurgery for metastatic brain tumors: report of three cases and review of literature[END_REF]. Few risk factors of delayed bleeding seem to be associated like a peri-tumoral minor oozing of blood before radiosurgery, the use of anticoagulant drug, the use of antiangiogenic drug, and the hemorrhagic predisposition of the primitive neoplasms (melanoma, renal neoplasm) [START_REF] Wowra | Repeated gamma knife surgery for multiple brain metastases from renal cell carcinoma[END_REF].

Neurosurgical management: Propositions

In the light of these element we propose a flowchart to help the neurosurgeon in their decision-making process in acute settings. (Figure 2). We hope that these propositions may improve the complex management of these patients: Patients without a clear oncological past medical history should systematically benefit from of a pathological analysis of the clot which was removed in emergencies.

Patients with a clear oncological history and a life expectancy superior to 3 months, should have a skull bone biopsy in case of epidural hematoma. A dura-mater biopsy should be done in case of subdural hematoma, and "en bloc" resection should be done as much as possible, thanks to the surgical dissection plane to be found around the hematoma.

Patients with a life expectancy of less than 3 months should be oriented for best supportive care (Figure2).

Discussion

Little is known in the literature about the management and the outcomes of patients with hemorrhagic brain metastases. And coagulation status in cancer patients can be altered by different factors:

-Chemotherapy or bone marrow invasion could induce thrombocytopenia [START_REF] Berg | Thrombocytopenia in adult cancer patients receiving cytotoxic chemotherapy: results from a retrospective hospital-based cohort study[END_REF].

-The coagulation factors may be affected by liver metastases [START_REF] Campagna | Chemotherapy Complications[END_REF][START_REF] Duwe | Hepatotoxicity following systemic therapy for colorectal liver metastases and the impact of chemotherapy-associated liver injury on outcomes after curative liver resection[END_REF].

-Targeted therapies, especially tyrosine-kinase inhibitors, seem to increase the frequency of fatal intracranial hemorrhage in patients with brain metastases [START_REF] Faivre | Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer[END_REF][START_REF] Pouessel | High Frequency of Intracerebral Hemorrhage in Metastatic Renal Carcinoma Patients with Brain Metastases Treated with Tyrosine Kinase Inhibitors Targeting the Vascular Endothelial Growth Factor Receptor[END_REF].

-Inhibitors of angiogenesis, like bevacizumab (frequently used in renal cancer), which is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF), could induce coagulopathy and increase the risk of hemorrhage [START_REF] Elice | Side effects of anti-angiogenic drugs[END_REF] .The risk of spontaneous tumor hemorrhage related to Bevacizumab administration is still an unsolved issue but seems to be very low in clinical trials [START_REF] Carden | What is the risk of intracranial bleeding during anti-VEGF therapy?[END_REF][START_REF] Besse | Bevacizumab safety in patients with central nervous system metastases[END_REF][START_REF] Wang | Retrospective study on bevacizumab in the treatment of non-small cell lung cancer with brain metastases[END_REF].

Moreover, cancer is a global disease with many consequences on the immune system, with systemic inflammatory response [START_REF] Hanahan | Hallmarks of Cancer: The Next Generation[END_REF] which leads to a kind of hyper-metabolism for the patient and should not be viewed as a single focal lesion for the patient,. This is the reason why patients under anticoagulation therapy, like anti-vitamin K (AVK), or low molecular weight heparin, could have an increased risk of hemorrhage [START_REF] Akl | Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer[END_REF].

The survival prognosis of the systemic cancer and the functional prognosis have to be discussed with the referring oncologist, the medical team, and the patient's family. For example, patients suffering from melanoma with brain metastasis who have genetic mutation of BRAF V600E, have a better survival prognosis and should benefit from a more aggressive therapeutic management [START_REF] Chapman | Diffusion tensor imaging predicts cognitive function change following partial brain radiotherapy for low-grade and benign tumors[END_REF][START_REF] Flaherty | Improved survival with MEK inhibition in BRAF-mutated melanoma[END_REF][START_REF] Carron | Stereotactic radiosurgery combined with anti-PD1 for the management of melanoma brain metastases: A retrospective study of safety and efficacy[END_REF][START_REF] Gaudy-Marqueste | Survival of melanoma patients treated with targeted therapy and immunotherapy after systematic upfront control of brain metastases by radiosurgery[END_REF][START_REF] Gaudy-Marqueste | On demand Gamma-Knife strategy can be safely combined with BRAF inhibitors for the treatment of melanoma brain metastases[END_REF] . The genomic heterogeneity of brain metastases, and the molecular profile could be an opportunity for specific therapies [START_REF] Dagogo-Jack | Brain Metastasis: Clinical Implications of Branched Evolution[END_REF][START_REF] Shonka | Targeted Treatment of Brain Metastases[END_REF] to improve outcomes and reduce morbidity [START_REF] Preusser | Brain metastases: pathobiology and emerging targeted therapies[END_REF].

Obviously, patients with only few weeks/days of life expectancy should be managed conservatively and benefit from palliative care. The QoL, and particularly the quality of the "last years of life" should remain a key element for the neurosurgeon and the medical oncologists.

Only one study reports the surgical outcomes of hemorrhagic brain metastases. Yoo et al, reported a retrospective series of 21 patients with hemorrhagic metastases (single metastasis in 15 cases, oligo-metastatic condition in 6 cases) with a mean time to progression of 20.8 months and with a median survival time of 11.7 months after surgery. An interesting point is the fact that, the local recurrence after resection of a hemorrhagic metastasis is low: 12 month-free survival is higher than 80% in this series. The progression-free survival reported in the Yoo's paper, seems to be associated with an "en bloc" resection [START_REF] Yoo | Surgical Outcomes of Hemorrhagic Metastatic Brain Tumors[END_REF] (Class II, Level of evidence C).

The functional prognosis should be taken into consideration by neurosurgeons before going for surgery in a patient with brain hemorrhagic metastases. The functional anatomy of human brain white matter pathway should be incorporated in the choice of the surgical approach in order to perform a minimal cortectomy and to gain access to the brain metastases and the clot through an intra-parenchymal "safe" corridor. The shortest pathway through the brain to the clot is not always the best option as it may disrupt main eloquent subcortical pathways [START_REF] Voets | Brain white matter fibre tracts: a review of functional neuro-oncological relevance[END_REF].

Indeed, patients with a glioblastoma seems to be more at risk of developing a brain hemorrhage than patients with brain metastases, according to Zwicker et al. [START_REF] Zwicker | A meta-analysis of intracranial hemorrhage in patients with brain tumors receiving therapeutic anticoagulation[END_REF]. Moreover, anticoagulation use seems to be quite safe for low molecular weight heparin and Oral Factor Xa Inhibitor [START_REF] Young | Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D)[END_REF][START_REF] Klerk | The Effect of Low Molecular Weight Heparin on Survival in Patients With Advanced Malignancy[END_REF].

Conclusion

The current literature pertaining to the neurosurgical management of acute bleeding in brain metastasis is scant and the level of evidence remains low (experts 'opinions; class C) we suggest a flowchart to assist in dealing with those difficult patients [START_REF] Abettan | Between hype and hope: What is really at stake with personalized medicine?[END_REF].

In line with the literature, it appears the benefit of removing hemorrhagic BM really exist when the neurological condition of the patient acutely deteriorates. In the setting of an intracranial bleeding, the possibility of an underlying secondary tumor should be investigated regardless of the existence of an oncological past medical history or not. Multidisciplinary team management of those patients, performed in close interaction with medical oncologists is pivotal to the optimal care in the era of personalized medicine