Bernard Albat

Michel Brunel

Claude Humeau

Maurice Navarro

Yves Allieu

Bernard Canaud

Claude Jaffiol

Henri Navratil

Robert Alric

Paul-André Chaptal

Charles Janbon

Jacques Othoniel

Bernard Arnaud

Albert-Jean Ciurana

François Janbon

Michel Pages

Gérard Asencio

Jacques Clot

Daniel Jarry

Claude Peguret

Jacques Astruc

Pierre Costa

Jacques Jourdan

Jacques Pelissier

Charles Aussilloux

Françoise D'athis

Bernard Klein

Boris Guiu

Hayot Maurice

Physiologie Houede

Nadine Cancérologie

Jung Boris

Médecine Intensive-Réanimation Kalfa

Nicolas Chirurgie

Klouche Kada

Laurence Lachaud

Thierry Parasitologie

embryologie Jean-Philippe Histologie

L E Bactériologie-Virologie ; Hygiène Hospitalière

Vincent Moing

Maladies

Florence Cardiologie

Matecki Stéfan

Physiologie Moranne

Olivier Néphrologie

Morel Jacques

Rhumatologie Navarro

Jean-Luc Pasquie

Perez Cardiologie

Antonia Martin

Perney Pascal

Michel Prudhomme

Pujol Anatomie

Louis Jean

Diane Pneumologie

Pascal Pédopsychiatrie

Tu-Anh Anatomie

Pédiatrie

Céline Bourgier

Cancérologie

Delphine Capdevielle

PERSONNEL ENSEIGNANT Professeurs Honoraires

Keywords: Severe acute pancreatitis, hypertriglyceridemia, mortality, ICU

Objectives: Hypertriglyceridemia induced acute pancreatitis (HTG-AP) is a severe condition seen in Intensive Care Unit (ICU), associated with high mortality. Recent clinical data suggest that therapeutic plasma exchanges (TPE) might improve HTG-AP's course.

Objective: To describe this emergent pathology in ICUs and to find HTG-AP's prognosis factors.

Methods:

This retrospective, observational cohort study was conducted among 12 different ICUs in France from 2010 to 2020. Data were recorded from medical files for each patient. We evaluated factors influencing survival status at day 28 using a multivariable logistic regression analysis.

Results: 95 adult patients with an HTG-AP diagnosis were enrolled in the study.

Mortality rate was 13.3% at day 28. Death at day 28 was associated with worse SOFA (Odds Ratio (OR)=2.545, IQ[1.284-5.044], p=0.0074) and RANSON score (OR=1.313, IQ[1.028-1.677], p=0.029) at admission. Median ICU length-of-stay was 7 (1-96) days in the survival group versus 2 (1-97) days in the non-survival group (p=0.1009). The triglyceride (TG) level was not associated with mortality in our univariate and multivariate analysis (p=0.2283). Only 37% of patients were treated by TPE in this study, without significant impact on mortality (OR=1.011, IQ (0.973-1.05), p=0.1227).

Conclusion:

In this first French cohort of HTG-AP patients in ICU, TG level at admission and TPE are not associated with mortality.

A la team Coeur Brisé, anesthechill de profession, c'était un plaisir de partager ce semestre avec vous via Whatsapp, trop de travail oblige.

Aux équipes avec qui j'ai eu la chance de travailler :

A la Réanimation Chirurgicale de Nîmes, j'ai découvert ce monde complexe de la réanimation avec vous. Toujours encadrée, vous m'avez accompagné dans la découverte de cette spécialité passionnante, vous avez su me guider dans la réflexion face à chaque problème, et me permettre de progresser à vos côtés. Avec vous, j'ai appris la rigueur et le travail en équipe. Merci pour le temps que vous consacrez à notre formation, ce semestre est un des plus riches de mon internat.

Aux anesthésistes du CH de Perpignan, vous m'avez fait découvrir et aimer ce monde si particulier du bloc opératoire. En 6 mois, vous avez transformé l'étudiante empotée en apprentie anesthésiste dégourdie et efficace. J'y ai découvert une belle étendue de notre spécialité, encadrée par une équipe bienveillante et toujours dans une super ambiance.

A l'équipe de la maternité de Nîmes, merci pour votre accueil dans l'équipe. Travailler 6 mois avec vous m'a donné le gout de l'anesthésie obstétricale et l'envie d'approfondir cette belle spécialité. Merci pour votre bienveillance et votre confiance au quotidien qui m'ont aidé à prendre de l'assurance et à me sentir à l'aise. Je garde un super souvenir de ce semestre et de tous ces repas en équipe.

Aux réanimateurs de Perpignan, merci pour ce semestre d'été si enrichissant et si varié. C'est une chance de découvrir à chacun votre manière de travailler, j'ai beaucoup appris. Merci de m'avoir donné l'opportunité de faire mes premiers pas en solo. Merci pour tous les moments en équipe, le café du matin, le pot de fin de semestre, j'ai des souvenirs plein la tête. Merci aussi à toute l'équipe paramédicale qui s'investit et qui donne vie à ce service, vous êtes incroyables.

A l'équipe d'anesthésie pédiatrique, et l'équipe d'anesthésie de Saint Roch, merci pour cette grande découverte du monde des petits. Grâce à votre formation et votre compagnonnage, j'ai réussi à ré apprendre l'anesthésie avec de nouveau repères (de petits repères), c'est passionnant.

A

INTRODUCTION

Acute pancreatitis (AP) is a common cause of abdominal pain leading to hospitalization [START_REF] Whitcomb | Clinical practice. Acute pancreatitis[END_REF]. Nearly 20% of these patients will develop severe AP with local or systemic complications and mortality rate reaching up to 20-30% (2,3). AP's incidence is increasing mostly due to gallstones (4,5). In the meantime, the number of cases of hyper triglyceridemic acute pancreatitis (HTG-AP) has also increased rapidly over the past 20 years (6-9). Many recent studies showed that hypertriglyceridemia (HTG) was responsible for 10-20% of AP, even becoming the second leading cause after gallstones, before alcohol (6,10-13). The American practice guidelines and the Endocrine Society state that a plasma level of triglycerides (TG) > 10,0 g/L is necessary to cause AP ( 14), even if the pathophysiology underlying HTG-AP is not well understood. Hypothesis are based on the toxicity of free fatty acids on acinar cells and the vascular endothelium. A TG rate above 1000 mg/dL forms chylomicrons, which increase blood viscosity, impairs blood flow, and causes ischemia.

HTG-AP mainly occurs in younger patients, male, with higher fat intake and in obese patients. Besides, a higher incidence of complications (renal failure, shock, and infection) and higher length of hospital stay (LOS) have been associated with HTAG-AP compared to patients with AP due to other aetiologies [START_REF] Valdivielso | Current knowledge of hypertriglyceridemic pancreatitis[END_REF][START_REF] Tai | A Retrospective Research of the Characteristic of Hypertriglyceridemic Pancreatitis in Beijing, China[END_REF][START_REF] Pascual | Association of elevated serum triglyceride levels with a more severe course of acute pancreatitis: Cohort analysis of 1457 patients[END_REF][START_REF] Qiu | Comparison of Existing Clinical Scoring Systems in Predicting Severity and Prognoses of Hyperlipidemic Acute Pancreatitis in Chinese Patients: A Retrospective Study[END_REF][START_REF] Huang | Incidence and clinical features of hyperlipidemic acute pancreatitis from Guangdong, China: a retrospective multicenter study[END_REF][START_REF] Hamada | Clinical Impact of Elevated Serum Triglycerides in Acute Pancreatitis: Validation from the Nationwide Epidemiological Survey in Japan[END_REF].

HTG is probably under-estimated because it is not systematically investigated in daily practice if alcohol abuse or gallstone have been previously found. However, when HTG is associated with one of these aetiologies, poorer outcomes (persistent systemic inflammatory response syndrome (SIRS), persistent organ failure and mortality) were reported. [START_REF] Wang | Elevated Serum Triglycerides in the Prognostic Assessment of Acute Pancreatitis: A Systematic Review and Meta-Analysis of Observational Studies[END_REF][START_REF] Sue | Effect of Serum Triglycerides on Clinical Outcomes in Acute Pancreatitis: Findings From a Regional Integrated Health Care System[END_REF] Triglycerides levels are also correlated with the risk of pancreatitis and severity [START_REF] Pascual | Association of elevated serum triglyceride levels with a more severe course of acute pancreatitis: Cohort analysis of 1457 patients[END_REF].

International guidelines on the management of AP are currently available [START_REF]/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis[END_REF].

Standard therapy involves the use of lipid-lowering agents (fenofibrate, gemfibrozil, niacin, omega3 fatty acids), low-molecular-weight heparin and insulin infusion in diabetic patients [START_REF] Altinkaya | Insulin and Heparin Therapies in Acute Pancreatitis due to Hypertriglyceridemia[END_REF][START_REF] Pulipati | Hypertriglyceridemia-associated acute pancreatitis: Response to continuous insulin infusion[END_REF]. To date, there is no strong guidelines supporting standard medical therapies due to a lack of evidence.

Therapeutic plasma exchange (TPE) could provide positive effects on HTG-AP by reducing TG plasma levels during the acute phase [START_REF] Berglund | Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline[END_REF]. It could also be helpful in prevention of recurrence [START_REF] Chen | Therapeutic plasma exchange in patients with hyperlipidemic pancreatitis[END_REF][START_REF] Kyriakidis | Management of acute severe hyperlipidemic pancreatitis[END_REF]. Some authors have recommended its use in severe HTG-AP (TG > 10,0 g/L) only after standard medical therapies failed [START_REF] Padmanabhan | Guidelines on the Use of Therapeutic Apheresis in Clinical Practice -Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue[END_REF] and have enhanced the need for early therapy initiation to observe some benefits [START_REF] Stefanutti | Timing clinical events in the treatment of pancreatitis and hypertriglyceridemia with therapeutic plasmapheresis[END_REF][START_REF] Furuya | Plasma exchange for hypertriglyceridemic acute necrotizing pancreatitis: report of two cases[END_REF]. Despite such promising findings, the effects of TPE on HTG-AP have never been specifically assessed and its indication in critically ill patients with AP remains uncertain [START_REF] Dichtwald | Hypertriglyceridemia Induced Pancreatitis: plasmapheresis or conservative management?[END_REF][START_REF] Gubensek | Comparable Triglyceride Reduction With Plasma Exchange and Insulin in Acute Pancreatitis -A Randomized Trial[END_REF].

In this article, we aimed to identify the main determinants associated with 28-day mortality in HTG-AP patients admitted to ICUs. The second objectives were to assess the potential impact of TPE on clinical outcomes and to provide a description of HTG-AP management practices.

MATERIALS AND METHODS

STUDY DESIGN, POPULATION, AND DATA

COLLECTION

This retrospective, observational, multicentre study was conducted in 12 French

Intensive care units (ICUs) from 11 university hospitals and 1 teaching hospital.

The diagnosis of AP was defined based on Atlanta revised classification [START_REF] Zhu | A Study on the Etiology, Severity, and Mortality of 3260 Patients With Acute Pancreatitis According to the Revised Atlanta Classification in Jiangxi, China Over an 8-Year Period[END_REF].

Hypertriglyceridemia is defined by a TG plasma level > 2,00 mmol/L (1,75 g/L) for men and > 1,60 mmol/L (1,40 g/L) for women. We considered the highest TG plasma level observed within the first 48h of ICU admission for the diagnosis of HTG-AP.

All patients admitted to the ICU for a diagnosis of HTG-AP between January The main endpoint of this study was mortality at 28 days.

RESULTS

PATIENT CHARACTERISTICS

A total of 95 patients with HTG-AP were enrolled during the study period (January 1 st , 2010 to December 31 st , 2020). Baseline characteristics of patients from the whole cohort, and comparisons between patients alive (n=82) or dead (n=13) at day 28 are shown in TABLE 1.

No significant difference was observed in the remaining baseline and clinical data, All data concerning the hospitalization in ICU are listed in TABLE 2.

including
Median time between symptom onset and ICU admission was 3.3 days (0-71).

Median ICU LOS was 13.8 (1-97) days and median hospital LOS 27.9 (1.0-168) days. The mortality rate was 15.3% during hospitalisation and 13.3% at day 28. Recurrence within 3 months occurred in 13 (13%) patients. Non survivors at day 28 exhibited a significantly higher SAPS II score, higher SOFA score, higher Balthazar score, higher necrosis score, higher need for MV, higher infusion of vasopressors, and need for CRRT.

Median TG plasma level was 18.8 g/L (6.0-43.8). There was no significant difference for TG levels at admission (p=0.2283) between groups.

Complications were led by respiratory complications (25.3%), mainly acute respiratory distress syndrome (ARDS) (70.8%) and ventilation associated pneumoniae (VAP) (58.3%). AP related complications occurred in 24.5% of the cases: 47.8% were intra-abdominal infections, which required percutaneous intervention in 52.2% of them;

43.5% were related thromboembolic or haemorrhagic complications, 26.1% mesenteric ischemia and 17.4% digestive fistula. A compartmental abdominal syndrome was diagnosed in 43.5% of patients with complications.

FACTORS ASSOCIATED WITH VITAL STATUS AT DAY 28

In an univariate analysis, vital status at day 28 was associated with significantly higher SAPS II (p= 0.0002), SOFA (p<0.0001), Balthazar (p= 0.0040) and Ranson (p <0.0001) scores and associated with the presence of necrosis (p=0.0008). All factors tested in the univariate analysis are presented in TABLE 2.

Pancreatic complications (p=0.0024), mesenteric ischemia (p=0.0086) and respiratory complications (p=0.0173) were associated with mortality at day 28. OR were calculated using random effects logistic regression. The regression was based on 95 patients for 28-day mortality. Recent studies reported that mortality of severe AP decreased, in the last years, to around 20% [START_REF] Adiamah | A systematic review of the epidemiology, pathophysiology and current management of hyperlipidaemic pancreatitis[END_REF][START_REF] Leppäniemi | WSES guidelines for the management of severe acute pancreatitis[END_REF][START_REF] Jabaudon | Thoracic Epidural Analgesia and Mortality in Acute Pancreatitis: A Multicenter Propensity Analysis[END_REF]. Early and standardized therapies including mini-invasive approach of infected necrosis may explain this survival improvement [START_REF] Kiss | The effect of serum triglyceride concentration on the outcome of acute pancreatitis: systematic review and metaanalysis[END_REF][START_REF] Wang | Relationship between Plasma Triglyceride Level and Severity of Hypertriglyceridemic Pancreatitis[END_REF].

Alive at

FOCUS ON TPE

Interestingly, we observed that death occurred mostly within the first days of admission with multiorgan failure being the main driver. Patients were hospitalized very soon after first symptoms' onset, highlighting that the diagnosis did not trigger delays.

Currently, it is well established that HTG is a trigger of intense systemic inflammatory response syndrome leading for some patients to ARDS, vasoplegic shock and consecutive organ failures [START_REF] Tsuang | Hypertriglyceridemic pancreatitis: presentation and management[END_REF][START_REF] Linares | Acute pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia[END_REF]. Death is caused mostly by infectious complications, especially in prolonged ICU LOS [START_REF] Swaroop | Severe acute pancreatitis[END_REF].

HTG-AP is associated with higher severity than other aetiology. Lifestyle therapies and treatment with fibrates and statins could be proposed for hypertriglyceridemia but currently specific treatment for HTG-AP and standardization of their therapeutic management are lacking. [START_REF]/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis[END_REF][START_REF] Berglund | Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline[END_REF][START_REF] Jaber | Guidelines for the management of patients with severe acute pancreatitis, 2021[END_REF][START_REF] Pancreatic | Guidelines for diagnosis and treatment of acute pancreatitis in China (2021)[END_REF].

Free fatty acids are toxic to vascular endothelium and acinar cells and chylomicrons increase blood viscosity. TPE has been proposed to purify plasma, but the studies show contradictory results [START_REF] Dichtwald | Hypertriglyceridemia Induced Pancreatitis: plasmapheresis or conservative management?[END_REF][START_REF] Rawla | Hypertriglyceridemia-induced pancreatitis: updated review of current treatment and preventive strategies[END_REF][START_REF] Horibe | Continuous Regional Arterial Infusion of Protease Inhibitors Has No Efficacy in the Treatment of Severe Acute Pancreatitis: A Retrospective Multicenter Cohort Study[END_REF]. Clinical improvement may be expected from such technique, but the lack of recommendations leads to heterogeneous practices among centres.

Several studies have showed a positive impact of TPE on the evolution of HTG-AP. Zheng and al. showed that TPE helps to reduce TG level rapidly with a reduction rate of 71% at 24h, without finding significant differences in clinical outcomes. Zhu and al. confirmed it in a prospective cohort [START_REF] Zheng | Dynamic changes of lipid profile in severe hypertriglyceridemia-induced acute pancreatitis patients under double filtration plasmapheresis: a retrospective observational study[END_REF][START_REF] Chen | Rapid reduction in triglyceride levels by therapeutic plasma exchange in patients with hypertriglyceridemic pancreatitis[END_REF]. In Click's systematic review [START_REF] Click | The role of apheresis in hypertriglyceridemia-induced acute pancreatitis: A systematic review[END_REF], improvement after TPE was obtained for 94% of patients. It was judged on clinical and biological criteria and on regression of organ failure [START_REF] Click | The role of apheresis in hypertriglyceridemia-induced acute pancreatitis: A systematic review[END_REF][START_REF] Gavva | Therapeutic plasma exchange for hypertriglyceridemia induced pancreatitis: A rapid and practical approach[END_REF]. In our cohort it was not associated with survival at day 28. Our cohort differs from previous studies by the large proportion of critically ill HTG-AP patients.

A perspective to prevent severe AP associated to HTG could be to treat asymptomatic patients beyond TG > 10 g/l, using TPE [START_REF] Stefanutti | Timing clinical events in the treatment of pancreatitis and hypertriglyceridemia with therapeutic plasmapheresis[END_REF][START_REF] Chang | Double Filtration Plasma Apheresis Shortens Hospital Admission Duration of Patients With Severe Hypertriglyceridemia-Associated Acute Pancreatitis[END_REF][START_REF] Şimşir | Therapeutic plasma exchange in hypertriglyceridemic patients[END_REF].

Its features are debated in the literature. In our study, it seems that double filtration plasmapheresis (DFPP) with albumin replacement was used as much as TPE. DFPP could be a good alternative to TPE, limiting the consumption of blood products and costs [START_REF] Lu | The role of double filtration plasmapheresis in hypertriglyceridemic pancreatitis: A propensity score matching analysis[END_REF].

We can also notice that recommended medical treatment of HTG such as fibrates or statins were prescribed in few patients instead of heparin and insulin infusions [START_REF] Alagözlü | Heparin and insulin in the treatment of hypertriglyceridemia-induced severe acute pancreatitis[END_REF].

Physiopathology hypotheses propose that they improve the reduction of chylomicrons and TG by stimulating lipoprotein lipase synthesis and activity [START_REF] Padmanabhan | Guidelines on the Use of Therapeutic Apheresis in Clinical Practice -Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue[END_REF].

Our study has some limitations.

First, this is a small, uncontrolled observational retrospective study. Time between first symptoms and admission in ICU varies between patients, potentially leading to an overestimation of severity.

Second, our analysis did not find any impact of TPE on patient survival. The lack of correlation could be related to the small number of patients in this subgroup limiting the interpretation of the results. Larger cohorts are needed to compare HTG-AP to other causes of pancreatitis in ICU and to assess TPE efficacy.

Third, HTG-AP admission in ICU increases between 2010 and 2020. Unfortunately we had no insight on standard care delivered in ICUs, that may have impacted prognosis.

CONCLUSION

To conclude, in this first French cohort with HTG-AP patients in ICU, mortality rate of 15% is determined mostly by severity and AP-related scores at admission. The TG level at admission did not impact mortality. The place of TPE in care is still to determine with larger prospective studies. ➢ Je donnerai mes soins gratuits à l'indigent et n'exigerai jamais un salaire au-dessus de mon travail.

➢ Admis (e) dans l'intérieur des maisons, mes yeux ne verront pas ce qui s'y passe, ma langue taira les secrets qui me seront confiés, et mon état ne servira pas à corrompre les moeurs, ni à favoriser le crime.

➢ Respectueux (se) et reconnaissant (e) envers mes Maîtres, je rendrai à leurs l'instruction que j'ai reçue de leurs pères.

➢ Que les hommes m'accordent leur estime si je suis fidèle à mes promesses. Que je sois couvert (e) d'opprobre et méprisé (e) de mes confrères si j'y manque.

  1 st of 2010 to December 31 st 2020 were retrospectively analysed. Patients under the age of 18 years and those with AP from other aetiologies were not included in the analysis. If patients presented more than one episode of HTG-AP during the inclusion period, only the first episode was considered. Individual patient data were retrospectively and anonymously collected from medical records into an electronic Case Report Form in the Research Electronic Data Capture (REDCap) platform (30,31). At admission, data about baseline demographics and characteristics, clinical and biological variables, organ failure and treatments were collected. Major outcomes during hospitalization were obtained including survival status at day 28, main complications of AP (e.g., organ failure, sepsis) and therapeutic interventions (e.g., mechanical ventilation, vasopressor support, continuous renal replacement therapy, antibiotic therapy, or TPE).

Figure 1 :

 1 Figure 1: Forrest plot of RANSON, SOFA, TG, and age's odd ratios

FIGURE 2 :

 2 FIGURE 2: Kaplan-Meyer survival estimates during the 28 days following

Figure 5 :Figure 6 :➢

 56 Figure 5: Forrest plot of RANSON, SOFA, TG, necrosis and age's odd ratios

PROFESSEURS DES UNIVERSITES -Médecine générale 1re classe :

	COLOMBO Pierre-Emmanuel ROSSI Jean François MULLER Laurent (Anesthésiologie-réanimation et médecine péri-opératoire) Cancérologie ; radiothérapie Hématologie ; transfusion
	COSTALAT Vincent ROUBILLE François PERRIGAULT Pierre-François (Anesthésiologie-réanimation et médecine péri-opératoire) Radiologie et imagerie médicale Cardiologie
	DAIEN Vincent SEBBANE Mustapha QUANTIN Xavier (Pneumologie) Ophtalmologie Médecine d'urgence
	DORANDEU Anne SIRVENT Nicolas ROUBERTIE Agathe (Pédiatrie) Médecine légale et droit de la santé Pédiatrie
	FAILLIE Jean-Luc SOLASSOL Jérôme VIEL Eric (Soins palliatifs et traitement de la douleur) Pharmacologie fondamentale ; pharmacologie clinique ; addictologie Biologie cellulaire
	STERKERS Yvon FUCHS Florent	Gynécologie-obstétrique ; gynécologie médicale Parasitologie et mycologie Maîtres de Conférences des Universités -Praticiens Hospitaliers
	GABELLE DELOUSTAL Audrey STOEBNER Pierre	Neurologie Dermato-vénéréologie
	GAUJOUX Viala Cécile SULTAN Ariane MCU-PH Hors classe -Echelon Exceptionnel Rhumatologie Nutrition
	GODREUIL Sylvain THOUVENOT Éric MARTRILLE Laurent	Bactériologie-virologie ; hygiène hospitalière Neurologie Médecine légale et droit de la santé
	GUILPAIN Philippe THURET Rodolphe RICHARD Bruno	Médecine Interne, gériatrie et biologie du vieillissement; addictologie Urologie Médecine palliative
	HERLIN Christian TUAILLON Edouard IMMEDIATO DAIEN Claire VENAIL Frédéric MCU-PH Hors classe	Bactériologie-virologie; hygiène hospitalière Chirurgie plastique, reconstructrice et esthétique, brulologie Oto-rhino-laryngologie Rhumatologie
	JACOT William VILLAIN Max BADIOU Stéphanie	Ophtalmologie Cancérologie ; Radiothérapie Biochimie et biologie moléculaire
	JEZIORSKI Eric VINCENT Denis BOULLE Nathalie	Pédiatrie Médecine interne ; gériatrie et biologie du vieillissement, médecine générale, addictologie Biologie cellulaire
	LALLEMANT Benjamin VINCENT Thierry CACHEUX-RATABOUL Valère	Oto-rhino-laryngologie Immunologie Génétique
	LATTUCA Benoît CARRIERE Christian	Cardiologie Bactériologie-virologie ; hygiène hospitalière
	LE QUINTREC DONNETTE Moglie CHARACHON Sylvie	PROFESSEURS DES UNIVERSITES Bactériologie-virologie ; hygiène hospitalière Néphrologie
	LETOUZEY Vincent 1 re classe : FABBRO-PERAY Pascale	Gynécologie-obstétrique ; gynécologie médicale Epidémiologie, économie de la santé et prévention
	LONJON Nicolas COLINGE Jacques (Cancérologie, Signalisation cellulaire et systèmes complexes) Neurochirurgie GIANSILY-BLAIZOT Muriel Hématologie ; transfusion
	LOPEZ CASTROMAN Jorge LAOUDJ CHENIVESSE Dalila (Biochimie et biologie moléculaire) Psychiatrie d'Adultes ; addictologie
	LUKAS Cédric VISIER Laurent (Sociologie, démographie) Rhumatologie
	MENJOT de CHAMPFLEUR Nicolas	Radiologie et imagerie médicale
	MILLET Ingrid	Radiologie et imagerie médicale
	MURA Thibault	Biostatistiques, informatique médicale et technologies de la communication
	NAGOT Nicolas LAMBERT Philippe	Biostatistiques, informatique médicale et technologies de la communication
	OLIE Emilie AMOUYAL Michel	Psychiatrie d'adultes; addictologie
	PARIS Françoise	Biologie et médecine du développement et de la reproduction ; gynécologie médicale PROFESSEURS ASSOCIES -Médecine Générale
	PELLESTOR Franck CLARY Bernard	Histologie, embryologie et cytogénétique
	POUDEROUX Philippe GARCIA Marc	Gastroentérologie ; hépatologie ; addictologie
	RIGAU Valérie	Anatomie et cytologie pathologiques
	RIVIER François	Pédiatrie	PROFESSEURS ASSOCIES -Médecine
	ROGER Claire BESSIS Didier (Dermato-vénéréologie) Anesthésiologie-réanimation et médecine péri-opératoire
	MEUNIER Isabelle (Ophtalmologie)

MCU-PH de 1 re classe

	PANABIERES Catherine CHAUMONT-DUBEL Séverine	Biologie cellulaire Sciences du médicament et des autres produits de santé
	RAVEL Christophe DELABY Constance	Parasitologie et mycologie Biochimie et biologie moléculaire
	SCHUSTER-BECK Iris GUGLIELMI Laurence	Physiologie Sciences biologiques fondamentales et cliniques
	THEVENIN-RENECéline HENRY Laurent	Immunologie Sciences biologiques fondamentales et cliniques
	MCU-PH de 2 éme classe HERBET Guillaume Neurosciences
	BARATEAU Lucie LADRET Véronique	Physiologie Mathématiques appliquées et applications des mathématiques
	BERGOUGNOUX Anne LAINE Sébastien	Génétique Sciences du Médicament et autres produits de santé
	BOETTO Julien LE GALLIC Lionel	Neurochirurgie Sciences du médicament et autres produits de santé
	CHIRIAC Anca LOZZA Catherine	Immunologie Sciences physico-chimiques et technologies pharmaceutiques
	DE JONG Audrey MAIMOUN Laurent	Anesthésiologie-réanimation et médecine péri-opératoire Sciences physico-chimiques et ingénierie appliquée à la santé
	DESHAYES Emmanuel MOREAUX Jérôme	Biophysique et médecine nucléaire Science biologiques, fondamentales et cliniques
	DU THANH Aurélie MORITZ-GASSER Sylvie	Dermato-vénéréologie Neurosciences
	FITENI Frédéric MOUTOT Gilles	Cancérologie ; radiothérapie Philosophie
	GATINOIS Vincent PASSERIEUX Emilie	Histologie, embryologie et cytogénétique Physiologie
	GOUZI Farès RAMIREZ Jean-Marie	Physiologie Histologie
	HERBAUX Charles RAYNAUD Fabrice	Hématologie, transfusion Sciences du Médicament et autres produits de santé
	HUBERLANT Stéphanie TAULAN Magali	Gynécologie-obstétrique ; Gynécologie médicale Biologie Cellulaire
	LEVEQUE Maude	Parasitologie et mycologie
	MAKINSON Alain	Maladies infectieuses, Maladies tropicales Maîtres
	MARIA Alexandre	Médecine interne ; gériatrie et biologie du vieillissement ; addictologie
	PANTEL Alix	Bactérologie-virologie ; hygiène hospitalière
	PERS Yves-Marie	Thérapeutique; addictologie
	BERTRAND Martin	Anatomie
	ROUBILLE Camille	Médecine interne ; gériatrie et biologie du vieillissement ; addictologie
	BOUDOUSQ Vincent	Biophysique et médecine nucléaire
	SZABLEWSKY	Anatomie et cytologie pathologiques
	BRET Caroline	Hématologie biologique
	BROUILLET Sophie	Biologie et médecine du développement et de la reproduction ; gynécologie médicale Maitres de Conférences des Universités
	COSSEE Mireille	Génétique
	Maîtres de Conférences hors classe GIRARDET-BESSIS Biochimie et biologie moléculaire Anne BERNEX Florence Physiologie
	HERRERO Astrid	Chirurgie viscérale et digestive
	CHAZAL Nathalie	Biologie cellulaire
	LAVIGNE Géraldine	Hématologie ; transfusion
	LESAGE François-Xavier Médecine et Santé au Travail
	Maîtres de Conférences de classe normale
	MATHIEU Olivier	Pharmacologie fondamentale ; pharmacologie clinique ; addictologie
	BECAMEL Carine	Neurosciences
	MOUZAT Kévin	Biochimie et biologie moléculaire

de Conférences des Universités -Médecine Générale MCU-MG de 1 re classe

	MINET Mathilde BENNYS Karim	COROIAN Flavia-Oana	HEDON Christophe	PERRIGAULT Pierre François	VACHIERY-LAHAYE Florence
	PAVAGEAU Sylvain BERNARD Nathalie	COUDRAY Sarah	HENRY Vincent	PEYRON Pierre-Antoine	VERNES Eric
	REBOUL Marie-Catherine BERTCHANSKY Ivan	CRANSAC Fréderic REMERCIEMENTS JAMMET Patrick	PICARD Eric	VIALA Maurice
	SERAYET Philippe BIBOULET Philippe A mes maîtres et membres du jury : CUNTZ Danielle	JEDRYKA François	PICOT Marie Christine	VINCENT Laure
			Praticiens Hospitaliers Universitaires
	BIRON-ANDREANI Christine DARDALHON Brigitte	JREIGE Riad	PIERONI Laurence	WAGNER Laurent
	CAZAUBON Yoann	Pharmacologie fondamentale ; pharmacologie clinique ; addictologie
	DAGNEAUX Louis BLANC Brigitte A Monsieur le Professeur Samir Jaber, Je vous remercie de l'immense honneur que vous me DAVID Aurore KINNE Mélanie POQUET Hélène WALTHER LOUVIER Ulrike Chirurgie orthopédique et traumatologique BLANCHARD Sylvie DE BOUTRAY Marie LABARIAS Coralie PUJOL Sarah-Lise ZERKOWSKI Laetitia faîtes en acceptant de présider ce jury de thèse. Votre parcours et vos travaux exemplaires dans
	DUFLOS Claire notre belle spécialité qu'est l'Anesthésie-Réanimation sont un modèle pour chacun d'entre nous. Biostatistiques, informatique médicale et technologies de la communication
	Médecine interne ; gériatrie et biologie du vieillissement ; addictologie DE LA TRIBONNIÈRE Xav LABORDE Caroline PUPIER Florence Bien que l'évolution de mon parcours ne m'ait pas permis de venir me former à vos côtés, je vous BLANCHET Catherine GOULABCHAND Radjiv BLATIERE Véronique DEBIEN Blaise LACAMBRE Mathieu QUANTIN Xavier assure de l'admiration et du profond respect que je voue à votre travail. Veuillez trouver ici
	MIOT Stéphanie l'expression de ma grande reconnaissance. Médecine interne ; gériatrie et biologie du vieillissement ; addictologie
	BOBBIA Xavier	DELPONT Marion	LANG Philippe	RAFFARD Laurence
	ROCH Benoît	Pneumologie, addictologie
	BOGE Gudrun	DENIS Hélène		LAZERGES Cyril	RAPIDO Francesca
	SARRABAY Guillaume	Génétique
	BOURRAIN Jean Luc	DEVILLE de PERIERE Gil LE GUILLOU Cédric	RIBRAULT Alice
	SOUCHE François-Régis	Chirurgie viscérale et digestive
	BOUYABRINE Hassan	DI CASTRI Alberto	PH chargés d'enseignements LEGLISE Marie Suzanne RICHAUD-MOREL Brigitte
	ABOUKRAT Patrick	BRINGER-DEUTSCH Sop DJANIKIAN Flora	LE MOINE DONY Marie-Christine	RIDOLFO Jérôme
	AGUILHON Sylvain	BRINGUIER BRANCHERE DONNADIEU-RIGOLE Hélène	LETERTRE Simon	RIPART Sylvie
	AKKARI Mohamed	BRISOT Dominique	FAIDHERBE Jacques	LOPEZ Régis	RONGIERES Michel
	ALRIC Jérôme	BRONER Jonathan	FATTON Brigitte	LUQUIENS Amandine	ROULET Agnès
	AMEDRO Pascal	CADE Stéphane	FAUCHERRE Vincent	MANZANERA Cyril	RUBENOVITCH Josh
	AMOUROUX Cyril	CAIMMI Davide Paolo	FAURE Elsa	MARGUERITTE Emmanuel	SANTONI Fannie
	ANTOINE Valéry	CARR Julie		FILLERON Anne	MARTIN Lucille	SASSO Milène
	ARQUIZAN Caroline	CARTIER César	FILLOLS Mélanie	MATTATIA Laurent	SCHULDINER Sophie
	COSTA David ATTALIN Vincent	CASPER Thierry	FITENI Frédéric	MEROUEH Fadi	SEGURET Fabienne
	OUDE ENGBERINK Agnès AYRIGNAC Xavier	CASSINOTTO Christophe FOURNIER Philippe	MEYER Pierre	SENESSE Pierre
	BADR Maliha	CATHALA Philippe	GAILLARD Nicolas	MICHEL Moïse	SERRE Jean-Emmanuel
	MCU-MG de 2 éme classe BAIS Céline CAZABAN Michel	GALMICHE Sophie	MILESI Christophe	SKALLI El Medhi
	FOLCO-LOGNOS Béatrice BARBAR Saber Davide	CHARBIT Jonathan	GENY Christian	MORAU Estelle	SOLA Christelle
	CARBONNEL François BASSET Didier	CHEVALLIER Thierry	GERONIMI Laetitia	MORQUIN David	SOULLIER Camille
	BATIFOL Dominique	CHEVALLIER-MICHAUD J GINIES Patrick	MOSER Camille	SOUKSI MEDIONI Isabelle
	BATTISTELLA Pascal	COLIN Olivier	Maîtres de Conférences associés -Médecine Générale GRECO Frédéric MOUSTY Eve	STOEBNER DELBARRE Anne
	CAMPAGNAC Jérôme BAUCHET Luc	CONEJERO Ismael	GUEDJ Anne Marie	MOUTERDE Gaël	TEOT Luc
	LOPEZ Antonio BELL Ariane	CONSEIL Mathieu	GROSSIN Delphine	PANSARD Nicole	THIRION Marina
	MILLION Elodie BENEZECH Jean-Pierre	CORBEAU Catherine	GUYON Gaël	PERNIN Vincent	TUNEZ Virginie

A Monsieur

le Professeur Laurent Muller, Je

  vous remercie pour votre présence dans ce jury, c'est un grand honneur que de soumettre ce travail à votre jugement. Je vous remercie également pour votre dévouement et votre passion à enseigner grâce auxquels j'ai beaucoup appris tout au long de mon internat. Soyez assuré de toute ma gratitude et de ma grande estime.

A Madame

la Professeure Claire Roger, c

  avoir guidée et soutenue depuis le début de ce long chemin. Merci Maman de m'avoir montré qu'il vaut mieux avancer à petit pas pour gravir la montagne et de m'avoir donné toute ta force, à chaque étape. Merci Papa d'avoir su dédramatiser tant de situations et d'avoir cru en moi. Merci de m'avoir expliqué tout ce que tu as compris de la vie, et de m'avoir montré qu'il existe toujours plusieurs points de vue dans chaque situation. Merci pour les blagues et les charades, et merci à Maman de trouver toujours si brillamment les réponses. Merci à vous deux pour la bulle de bienveillance et d'amour que vous avez créé autour de nous 3 et qui nous accompagne chaque jour. Merci d'être toujours présents et d'être ce refuge quand tout va mal. Merci pour votre support sans failles. Je vous aime.Merci à toi Manon, ma petite soeur préférée, pour cette relation si proche et enrichissante. Merci d'être tellement toi, un petit bonhomme qui marche très vite, rayonnante, et de réussir autant que Maman aux charades de Papa (pas cher la maison 4 pièces). Merci d'être la plus créative d'entre nous, tu relèves le niveau. J'ai hâte de lire les aventures des Mamy cool et de recouvrir mes murs de tes peintures. Si tu n'existais pas il faudrait t'inventer. Je t'aime.A ma deuxième famille : Merci à toi Théo d'avoir croisé ma route et de ne plus l'avoir quittée. Difficile d'imaginer que l'on irait si loin alors que tu portais des espadrilles à notre premier date et que ma technique d'approche était basée sur un don de stylo… Comme quoi la vie est pleine de surprise. J'ai découvert avec toi le bonheur de la vie à 2, la simplicité et l'évidence d'une relation saine. Tu es mon meilleur ami et mon meilleur allié (et en plus t'es trop trop rigolo). Hâte d'aller explorer le monde à tes côtés. Je t'aime mille. Bisous à notre bébé Pêche. merci de m'avoir accueillie parmi vous, on ne rencontre pas des familles de bolo tous les jours ! C'est toujours un immense plaisir de partager du temps avec vous, et de vous découvrir un peu plus à chaque fois. Merci d'avoir créé l'être presque parfait qui m'accompagne au quotidien. Bisous à Jospin. Nous avons partagé toutes nos premières expériences (dès les premiers jours de P2 chez Jérem'), tu as été une alliée et un point de repère dans la tornade de l'intégration et des premières années. Grâce à toi j'ai découvert les voyages, la Thaïlande reste un souvenir incroyable (j'ai adoré dormir dans le train), sans ta motivation et ton énergie nous n'aurions jamais osé rêver un voyage aussi grand et plein de découvertes. Merci pour ces souvenirs et c'est toujours un grand plaisir de te revoir aujourd'hui.A Manon, mon acolyte, mon p'tit bouchon. Tellement de moments forts et joyeux vécus ensemble, tellement de rigolades, de fiestas, de voyages, de weekend, de déménagements, de discussions, de pleurs (oui t'es une chialeuse aussi), de blagues, de sport. Merci d'avoir été ma coloc a plusieurs reprises, merci de m'aimer toujours en connaissant mon côté sombre, merci d'être une tornade d'énergie et de twerker en poirier, je crois que c'est vraiment ma partie préférée de toi. Merci d'être toujours trop occupée (Manon 1er ministre), merci d'être premier degré (Manon premier degré), merci d'être dermato pour toutes ces crèmes que je n'ai plus besoin d'acheter, merci d'être toujours partante, toujours de bonne humeur, toujours motivée, et d'avoir toujours autant d'histoires à raconter. Tu es mon pilier.A Audrey, la plus drôle et la plus énergique de toutes mes copines. Grâce à toi j'ai appris à ne plus être susceptible (merci pour tous les clash), à faire la chandelle, à dire que « je l'apprécie ». Merci à toi pour les moments de folie à m'en mettre un slip sur la tête, à rigoler à m'en faire pipi dessus, à danser toute la nuit. Merci d'être ma meilleure copine de bloc aussi (on l'aura dit à tout le monde hihi), même si tu as refusé d'être référente avec moi. Un jour je m'en remettrais. Merci pour les rires, les pleurs, les rigolades, les accès de panique, les potins, les potins et encore les potins. Et un bisou à Ruru. Montpellier je sais que je peux compter sur toi (pour les best brunchs de la région notamment). Je sais que nos racines catalanes nous permettront de nous rejoindre encore longtemps. Bisous à Moustique.Mallo et Richard, vivre 6 mois à vos côtés m'a permi de découvrir beaucoup (trop) de nouveautés culinaires, merci pour toutes ces sorties en famille (avec Môôman) et la plongée à Banyuls. 6 mois de rigolades, déguisements en tout genre, râlage à gogo et beaucoup beaucoup d'amour (hein Richard, j'espère que t'as apprécié nous voir tous débarquer dans ta chambre). un confinement avec vous c'est inoubliable, merci de m'avoir partagé votre folie d'un soir (tous les soirs), votre enthousiasme à toute épreuve et vos idées toujours plus folles.

	A ma promo d'anesth-réa, tous futurs PU en devenir, ce fut un plaisir de partager ces 4 années
	avec vous !
	Anne Maud,
	A tous mes copains :

'est un honneur d'avoir travaillé avec toi sur ce projet. Je te remercie de m'avoir guidé tout au long de ce travail, ta bienveillance et tes conseils avisés ont été précieux. Ton parcours et ton investissement forcent le respect, tu es un modèle et un mentor. Je t'exprime toute ma gratitude et ma plus profonde reconnaissance.

A Madame le Docteur Stéphanie Bulyez, quel plaisir de travailler avec toi depuis plus de deux ans sur ce projet. Je te remercie pour ta disponibilité, tes relectures, le lien que tu as formé avec l'équipe Nîmoise. Tu m'as connue à mes premiers pas en tant qu'interne, aujourd'hui tu m'accompagnes jusqu'à l'aboutissement de mes études. C'est un honneur et par ces quelques mots je t'exprime ma profonde reconnaissance, ma gratitude et toute mon amitié.

A ma famille :

Merci à mes parents de m'

A Florence, Alain, Paul et Laura,

A mes amies :

A Clara, notre amitié s'est construite sur la base de tous nos déménagements et de la distance et malgré ça nous avons réussi à construire une relation très proche. Merci de m'avoir accompagnée de ta bienveillance tout au long de notre relation, de ton regard éclairé et pour ton partage. C'est désormais une habitude que de te retrouver à Vence, nos repas ou nos balades sont toujours un grand plaisir. Je souhaite qu'un jour on se rapproche enfin pour profiter et partager plus de moments ensemble ! A Alexia, notre rencontre au même moment compliqué de nos vies a forgé un beau socle pour notre amitié. Merci pour ces soirées déjantées (on ne donne pas son numéro à des inconnus en boite je te rappelle), pour tous ces verres et ces moments partagés, tu m'as été d'un grand soutien durant ces études. Je te souhaite que du bonheur, quelle hâte d'assister à votre mariage avec Arthur, vous êtes radieux ensembles. Bisous à Onyx et Newt'.

A ma coloc' d'amour Léa, sans toi l'année de la D4 aurait été bien plus difficile. Nos lundi soir titi, la découverte de la neige à Cimiez, notre si charmante voisine, tous ces moments resteront gravés dans ma mémoire. Et un final en beauté avec notre voyage à l'autre bout du monde, que de nouvelles expériences… pour nos corps surtout, si tu vois ce que je veux dire (je crois que Manon dans le désert voit bien ce que je veux dire), que de rencontres (Luis, les Italiens, la végé extrémiste, notre guide dans le désert et tous ces chauffeurs de taxi), que de paysages superbes comme le plancton phosphorescent dans la nuit… Merci d'être toi. Même si les kilomètres nous séparent aujourd'hui je sais et je sens que notre lien reste fort. Bisous à Maurice.

A Marie, notre rencontre et notre amitié née dès les premiers jours de ces études de médecine.

A Manon, toi que j'ai réussi à convaincre de venir vivre à Montpellier, merci pour tous les moments de rigolades, les petits verres chez toi et chez moi, pour toutes les bonnes adresses grâce à Henraille (vous êtes mes références pour les sorties héhé), pour les balades à la plage, dans les étangs, et toutes ces anecdotes de galère au boulot comme dans la vie qui me font mourir de rire à chaque fois. Merci pour les conseils vinted et tes vide placards qui me donnent l'impression d'avoir plein de cadeaux. J'espère que nos chemins vont rester proches encore longtemps. Bisous à Moka.

A Laura, ma première copine après ce grand bond dans l'inconnu de l'internat. Merci d'être tout pareil que moi, t'as été mon repère et mon binôme dès le début de cette aventure. Merci d'avoir l'air super jeune tout comme moi, d'aimer les gouters tout comme moi, et tout autant aller boire des verres et manger des sushis et aller danser toute la nuit. Tout pareil je te dis ! On devrait plus souvent rallier Montpellier Nîmes pour se voir. Bisous à Billy.

A Marion, ce semestre à Perpi nous en aura fait vivre des aventures ! J'ai découvert là-bas une personne au grand coeur, pleine de vie et pilier de bar incontournable (lol). Tu as été d'un grand soutien lors de ce semestre loin du monde et même si on est toujours trop occupées à Cypus, Pierre, Loic, Ornella, Margot, Océane, Christian, Capucine, Marion, Valentin, vous égayez les soirées montpelliéraines de votre folie et c'est toujours un plaisir de vous retrouver pour toujours plus de folies, des pistes de ski comme à la piste de danse ! Manon, Agathe, Sophie,

Julie, Romane, Yasmine, Laure et toute l'équipe des Doudou, un

  semestre avec vous plein de souvenirs aussi, vous resterez une famille de coeur après s'être tous retrouvés fraichement débarqués de nos campagnes ! On remet la féria quand vous voulez.La meute, pensée pour vous aussi car je crois qu'on risqué d'être amené à se revoir pour un moment… Hâte d'assister à tous les anniversaires des trentenaires, vous avez placé la barre haut ! Aux team de co internes :De réa chir, d'abord, vous avez été les premiers vous occuperez toujours une place spéciale.

Laulau, Arthur, Yasmina, Mathias, Jacques, vous m'avez appris le travail de grande et montré la solidarité qui unit la famille des réanimateurs.

A Luke et Alex, les Aréanimateurs, ce fut un plaisir d'Aréanimer avec vous dans la joie et la bonne humeur. Le rythme palpitant de cette réanimation nous aura permi de vibrer ensemble pendant 3 mois. Merci pour ce que vous faites.

A la team Perpivie, Perpichill, vous avez égayé ces 6 mois d'exil loin de la vie Montpelliéraine. Je lève un verre à tous ces cafés bus sur la terrasse. De Raph en lunettes de soleil à 6h du matin à Marion en coccinelle à la fin du semestre, en passant par Romain scotché au brancard, Cécilou presque bloquée dans l'ascenseur, Dorian au barbeuc' et un petit tour d'hélico, on en aura vu de toutes les couleurs. J'espère que nos retrouvailles à Montpellier perdureront longtemps.

STUDY DESIGN, POPULATION, AND DATA COLLECTION 28 2.2 ETHICS AND CONSENT 29 2.3 STATISTICAL ANALYSES 29 RESULTS 30 3.1 PATIENT CHARACTERISTICS 30 3.2 FACTORS ASSOCIATED WITH VITAL STATUS AT DAY 28 31 3.3 FOCUS ON TPE 35 DISCUSSION 37 CONCLUSION 41 ANNEX 42 ACKNOWLEDGMENTS 43 BIBLIOGRAPHY 44

  l'équipe du DAR D, merci pour votre accueil chaleureux dans l'équipe et l'intégration de notre groupe parmi vous. Merci pour le partage de cette spécialité si pointue, et merci de nous laisser prendre de l'autonomie au bloc et en réanimation en toute sécurité. Il n'est pas si facile de laisser la main aux plus jeunes, et c'est là tout le défi qui m'attend en tant que future sénior.

	ABREVIATIONS
	AP: Acute Pancreatitis
	ARDS: Acute Respiratory Distress Syndrome
	BMI: Body Mass Index
	CRRT: Continuous Renal Replacement Therapy
	DFPP: Double Filtration Plasmapheresis INTRODUCTION	26
	Et merci à tous les chefs, I.A.D.E, internes, équipes médicales et paramédicales que j'ai eu l'occasion de côtoyer et qui ont participé de près ou de loin à ma formation. E.g: for example MATERIALS AND METHODS 28
	2.1

HTG: Hypertriglyceridemia HTG-AP: Hypertriglyceridemia induced acute pancreatitis ICU: Intensive Care Unit LOS: Length Of Stay SAP: Severe Acute Pancreatitis SIRS: Systemic Inflammatory Response Syndrome SOFA: Sequential Organ Failure Assessment TPE: Therapeutic Plasma Exchange VAP: Ventilation Associated Pneumoniae

  patients' gender, BMI, habitus, potential pancreatitis inductor treatment and comorbidities, except for age (p=0.0074) and history of cirrhosis (p=0.0108)

		Alive at Day 28 (n=82)	Dead at Day 28 (n=13)	Total (n=95)	p-value
	Male gender n, %	60 (72.3%)	11 (73.3%)	71 (72.4%)	1.0000
	Age mean, SD	42.1 (12.3)	53.9 (16.3)	43.9 (13.6)	0.0074
	BMI mean, SD

Table 1 : Patient characteristics at baseline, according to survival status.

 1

	)	0.7050

Table 2 : Univariate regression to identify factors associated with survival status at day 28.

 2

	The results of the multivariate analysis are presented in TABLE 3. RANSON score
	(OR=2.545, IQ[1.284-5.044], p=0.0074) and SOFA score (OR=1.313, IQ[1.028-1.677],
	p=0.029) were statistically associated with mortality at day 28 (FIGURE 1).
		OR	IC95 -	IC95 +	p
	RANSON score	2.545	1.284	5.044	0.0074
	SOFA score	1.313	1.028	1.677	0.029
	Age	1.041	0.963	1.126	0.3133
	Necrosis (yes/no)	13.4	0.924	194.291	0.0571
	TG plasma level (g/L) at admission	1.011	0.973	1.05	0.5785

TABLE 3 : Independent risk factors associated with 28-day mortality.

 3

Table 3 :

 3 TPE characteristics according to survival status

Merci à toi Thibaut, AH Thibaut, mon tout petit frère préféré, d'être la personne la plus raisonnée de cette famille. Merci d'avoir supporté tous ces avis de grande soeur sans devenir fou. Merci de nous partager toutes tes aventures, de nous faire rêver, d'être aussi idéaliste, le monde a besoin de personnes comme toi. Je t'aime.Merci à mon Papi de m'avoir appris la rigueur et de ne jamais abandonner. Merci de guider cette famille et de nous montrer l'exemple, on rêve tous d'être capable de jouer au golf tous les jours à 83 ans. Merci pour ton partage de l'histoire familiale, la tienne et celle de tes parents. Il est bon de savoir d'où l'on vient. Merci pour ces 6 mois de coloc', c'est un temps précieux que nous avons partagé.Merci à ma Mamie chérie de prendre soin de moi depuis toujours. Merci pour ton oreille et ton épaule toujours disponible, d'être toujours là pour des réflexions sur les grandes questions de la vie. Merci pour tes éclats de rire qui réjouissent nos conversations et merci pour ton amour si réconfortant. Merci d'être le lien qui nous unit tous.Merci à Phiphi, Séra, Claire, Rémi et Bertrand pour votre folie de Primot', votre vie à mille à l'heure et vos projets toujours plus grands. Le temps à vos côtés est toujours joyeux et rempli de surprises. Avec vos idées toujours plus étonnantes, vous nous montrez que rien n'est impossible. J'ai adoré grandir avec vous.Merci à Pierre et Sandy d'avoir créé les petites cousines les plus mignonnes et joyeuses que j'ai rencontré. Roxanne et Jeanne, quelle chance de vous voir grandir et évoluer. J'espère continuer longtemps à partager des moments avec vous.Merci à ma Mamie Anne Marie d'avoir toujours vu la bonne étoile au-dessus de moi. Tes histoires du passé toujours racontées avec passion dans tes grands yeux bleus qui brillent, sont précieuses.

ACKNOWLEDGMENTS

Author contributions: Pr Roger and Dr Bulyez have full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Roger, Bulyez, Bourdin, Mezzaroba. Acquisition, analysis, or interpretation of data: Roger, Bulyez, Bourdin, Mezzaroba, Paris (Bichat-Beaujon-St Antoine), Lyon Sud, Lille, Montpellier, Poitiers, Besancon, Nancy, Nice and Perpignan) Drafting of the manuscript: Roger, Bulyez, Bourdin, Mezzaroba. Critical revision of the manuscript for important intellectual content: All authors Statistical analysis: Mezzaroba

ETHICS AND CONSENT

Ethical approval was obtained by the local Institutional Research Board (IRB 21.10.01).

This study conforms to French law concerning retrospectives studies "MR 004" of CNIL 2018. The protocol has been published on clinicaltrials.gov (NCT05096455, October 27, 2021).

An information letter has been sent to each participant. Consent is obtained if nonrefusal is manifested. The authors attested to the accuracy and completeness of the data and analyses.

STATISTICAL ANALYSES

Data analysis

The statistical analysis of the data was performed using SAS software version 9.4 (SAS Institute Inc).

First analysis was performed to describe the population. Results are presented as mean, standard deviation (SD) and median, interquartile (IQ) for quantitative variables, and as number, percentage (%) for qualitative variables. Mortality at day 28 was analysed with a logistic regression model. In a univariate analysis, Student's t-test or Mann-Whitney-Wilcoxon test were used for continuous variable, and Chi2 or Fisher's exact test were used for qualitative variables. P<0.05 are considered to be statistically significant, all p values are two tailed.

Factors associated with 28 day's mortality were included in a multivariate analysis if p<0,02. Collinearity, temporality, and potential "colliders" bias were tested for robustness. Survival was analysed using a Kaplan-Meier curve. Data were censored at discharge from ICU, hospital, and day 28, which occurs first.

DISCUSSION

In this large multicentre cohort study of HTG-AP patients, the main determinants for 28-day mortality were the Ranson and the SOFA scores at admission. One third of the cohort received TPE as part of AP management but no benefit on survival was identified.

Recent observational studies show that the prevalence of HTG-AP has increased, currently representing 10-20% of AP [START_REF] Carr | Systematic review of hypertriglyceridemia-induced acute pancreatitis: A more virulent etiology? Pancreatol Off[END_REF][START_REF] Zhu | A Study on the Etiology, Severity, and Mortality of 3260 Patients With Acute Pancreatitis According to the Revised Atlanta Classification in Jiangxi, China Over an 8-Year Period[END_REF][START_REF] Zheng | A multicenter study on etiology of acute pancreatitis in Beijing during 5 years[END_REF][START_REF] Jin | A 16-year trend of etiology in acute pancreatitis: The increasing proportion of hypertriglyceridemia-associated acute pancreatitis and its adverse effect on prognosis[END_REF][START_REF] Fan | Epidemiology and Etiology of Acute Pancreatitis in Urban and Suburban Areas in Shanghai: A Retrospective Study[END_REF]. The 15% hospital mortality rate observed in our cohort is higher than those previously reported by Lu et al. and Pascual et al. (9% and 6.7%, respectively) [START_REF] Pascual | Association of elevated serum triglyceride levels with a more severe course of acute pancreatitis: Cohort analysis of 1457 patients[END_REF][START_REF] Lu | Elevated triglycerides on admission positively correlate with the severity of hypertriglyceridaemic pancreatitis[END_REF]; This may be explained by the small numbers of patients requiring ICU admission in those studies. Nawaz et al. showed that severe TG plasma levels (TG > 20g/L) were independently correlated to mortality [START_REF] Nawaz | Elevated serum triglycerides are independently associated with persistent organ failure in acute pancreatitis[END_REF]. In the present study, organ failure and AP severity score were the main determinants of 28-day mortality but not the severity of HTG. The mortality observed in our cohort was close to the mortality reported in Click's review that included patients with organ failure (19.2%) [START_REF] Click | The role of apheresis in hypertriglyceridemia-induced acute pancreatitis: A systematic review[END_REF]. The lack of correlation between TG plasma level at admission and patient prognosis was unexpected. Indeed, previous studies identified TG plasma level as an independent factor for HTG-AP prognosis with different cut-off of TG. Although 10g/L seems the most admitted cut off to induce AP, several values of TG varying from 7.5 to 26 g/L have been proposed as risk factors for organ dysfunction. [START_REF] Pascual | Association of elevated serum triglyceride levels with a more severe course of acute pancreatitis: Cohort analysis of 1457 patients[END_REF][START_REF] Nawaz | Elevated serum triglycerides are independently associated with persistent organ failure in acute pancreatitis[END_REF][START_REF] Kiss | The effect of serum triglyceride concentration on the outcome of acute pancreatitis: systematic review and metaanalysis[END_REF][START_REF] Wang | Relationship between Plasma Triglyceride Level and Severity of Hypertriglyceridemic Pancreatitis[END_REF].

Our findings demonstrate that the clinical course of HTG-AP patients admitted to ICU is determined by different factors. Non survival group data show more necrosis and liver dysfunction at admission. It is understood that those elements play a more important role on survival [START_REF] Kiss | The effect of serum triglyceride concentration on the outcome of acute pancreatitis: systematic review and metaanalysis[END_REF][START_REF] Wang | Relationship between Plasma Triglyceride Level and Severity of Hypertriglyceridemic Pancreatitis[END_REF][START_REF] Swaroop | Severe acute pancreatitis[END_REF].

Guidelines evolved along this period and improvement in standard of care impacts mortality [START_REF] Adiamah | A systematic review of the epidemiology, pathophysiology and current management of hyperlipidaemic pancreatitis[END_REF][START_REF] Leppäniemi | WSES guidelines for the management of severe acute pancreatitis[END_REF][START_REF] Jabaudon | Thoracic Epidural Analgesia and Mortality in Acute Pancreatitis: A Multicenter Propensity Analysis[END_REF].

The use of TPE can be limited by clinicians' beliefs and the availability of the technique.

Despite those limits, this is the first cohort in the literature of severe HTG-AP hospitalized in ICU. The low incidence explains our small cohort, but the frequency is increasing.

Conflict of interest disclosures: All authors disclosed no potentional conflict of interest.

RESUME

Contexte : Les pancréatites aigues d'origine hypertriglycéridémique (HTG-PA) sont une cause sévère d'hospitalisation en réanimation, associée à un taux de mortalité important. Les données récentes montrent que la plasmaphérèse pourrait avoir un impact positif sur l'évolution de cette pathologie. Objectifs : Décrire cette pathologie en réanimation et identifier des facteurs pronostics. Méthode: Cette étude rétrospective, observationnelle, multicentrique a été menée dans 12 centres en France de 2010 à 2020. Les données ont été récoltées à partir des dossiers médicaux de chaque patient. Nous avons analysé les facteurs influençant la survie à 28 jours (J28) grâce à un modèle de régression logistique multivarié. Résultats: 95 patients hospitalisés en réanimation pour HTG-PA ont été inclus. Le taux de mortalité à J28 était de 13.3%. La mortalité à J28 est associée à un SOFA score plus élevé (Odds Ratio (OR)=2.545, IQ[1.284-5.044], p=0.0074) ainsi qu'un score de RANSON plus élevé (OR=1.313, IQ[1.028-1.677], p=0.029à l'admission. La durée médiane d'hospitalisation en réanimation était de 7 (1-96) jours dans le groupe survivant versus 2 (1-97) jours dans le groupe décès à J28 (p=0.1009). Le taux de triglycérides à l'admission n'était pas associé à la mortalité en analyse uni et multivariée (p=0.2283). Seulement 37% des patients ont été traité par plasmaphérèse, sans impact significatif sur la mortalité (OR=1.011, IQ(0.973-1.05), p=0.1227). Conclusion: Dans cette première cohorte française de pancréatite aiguës d'origine hypertriglycéridémique en réanimation, le taux de triglycérides à l'admission et la plasmaphérèse ne sont pas associés à la mortalité.

Mots-clés: Pancréatite aiguë sévère; hypertriglycéridémie; mortalité; réanimation.

Context: Hypertriglyceridemia induced acute pancreatitis (HTG-AP) is a severe condition seen in Intensive Care Unit (ICU), associating with high mortality. Recent clinical data suggest that therapeutic plasma exchanges (TPE) might improve HTG-AP's course. Objective: To describe this emergent pathology in ICUs and to find HTG-AP's prognosis factors. Methods: This retrospective, observational cohort study was conducted among 12 different ICUs in France from 2010 to 2020. Data were recorded from medical files for each patient. We evaluated factors influencing survival status at day 28 using a multivariable logistic regression analysis. Results: 95 adult patients with an HTG-AP diagnosis were enrolled in the study. Mortality rate was 13.3% at day 28. Death at day 28 was associated with worse SOFA (Odds Ratio (OR)=2.545, IQ[1.284-5.044], p=0.0074) and RANSON score (OR=1.313, IQ[1.028-1.677], p=0.029) at admission. Median ICU length-of-stay was 7 (1-96) days in the survival group versus 2 (1-97) days in the non-survival group (p=0.1009). The triglyceride (TG) level was not associated with mortality in our univariate and multivariate analysis (p=0.2283). Only 37% of patients were treated by TPE in this study, without significant impact on mortality (OR=1.011, IQ(0.973-1.05), p=0.1227).

Conclusion:

In this first French cohort of HTG-AP patients in ICU, TG level at admission and TPE are not associated with mortality.

Keys words: Severe acute pancreatitis; hypertriglyceridemia; mortality; ICU.


Zhaobo Zhu
email: zb.zhu@szu.edu.cn

Hang Lin

Min Chen

Peiwen Han

The Spillover Effect of Economic Policy Uncertainty: Evidence from Analyst Behaviors in Hong Kong 

Keywords: Economic Policy Uncertainty, Spillover Effect, Analysts' Earnings Forecast Accuracy, Forecast Dispersion, Analyst Coverage, Recommendations

This paper examines the spillover effect of economic policy uncertainty on the financial market by comparing how local and external policy uncertainties affect the behaviors of analysts in an international financial center. Unlike findings in the United States and the United Kingdom, high local policy uncertainty does not significantly decrease analysts' earnings forecast accuracy or exacerbate forecast dispersion in Hong Kong. In contrast, high external policy uncertainty from Mainland China, the U.S., Europe, and across the globe significantly decrease analysts' forecast accuracy in Hong Kong, although these external policy uncertainties have also no significant effect on forecast dispersion. In addition, both local and external policy uncertainties have significant impact on analyst coverage and recommendations. These results provide strong evidence on the cross-country spillover effect of economic policy uncertainty on a developed and international financial market.

1

Introduction

Political or policy uncertainty is a key channel through which various factors affect financial markets including asset pricing and corporate activities (e.g. [START_REF] Kelly | The price of political uncertainty: Theory and evidence from the option market[END_REF]Veronesi, 2012, 2013;[START_REF] Brogaard | The Asset-Pricing Implications of Government Economic Policy Uncertainty[END_REF][START_REF] Baker | Measuring economic policy uncertainty[END_REF][START_REF] Kelly | The price of political uncertainty: Theory and evidence from the option market[END_REF]Brogaard, Dai, Ngo, and Zhang, 2020). Existing studies show that local political and policy uncertainty have significant impact on analyst behaviors, especially in the U.S. and U.K. (e.g., [START_REF] Baloria | Policy uncertainty and analyst performance[END_REF][START_REF] Chen | Economic policy uncertainty and analyst behaviours: Evidence from the United Kingdom[END_REF][START_REF] Chourou | Economic policy uncertainty and analysts' forecast characteristics[END_REF][START_REF] Chen | Economic policy uncertainty and analyst behaviours: Evidence from the United Kingdom[END_REF].

However, no study has explicitly compared how local and external policy uncertainty affect analyst behaviors. It is necessary to investigate the impact of external policy uncertainty on local analyst behaviors, helping us better understand the factors influencing analyst behaviors.

With increasing globalization, economies have become dynamically interrelated around the world. Recent studies show that political and policy uncertainty in the U.S. would have significant impact on the financial markets in other countries. [START_REF] Brusa | One central bank to rule them all[END_REF] and Brogaard et al. (2020) show that the monetary and political policy of the U.S. Federal Bank has a significant impact on global financial markets. Therefore, we expect that external policy uncertainty has a spillover effect on local analyst behaviors.

In this paper, we contribute to the literature by focusing on the spillover effect of economic policy uncertainty (EPU) on global financial markets via an important information intermediary (i.e., financial analysts). Specifically, we compare how local and external economic policy uncertainty affect the behaviors of analysts in an international financial center (i.e., Hong Kong).

As information intermediaries, financial analysts play an important role in interpreting and transmitting valuable firm-level information on investment and financing decisions to external investors, thereby influencing the aggregate capital market.

Hong Kong (HK) is an ideal empirical setting because Hong Kong, as a developed international financial center, confronts economic policy uncertainty from different countries.

Many firms listed in the Hong Kong exchange are headquartered elsewhere. These nonlocal public firms are expected to be affected by policy uncertainty in home countries. For example, many firms in Mainland China are listed on the Hong Kong exchange. Therefore, we expect that these Chinese public firms listed in the Hong Kong exchange would be affected by policy uncertainty in Mainland China. At the same time, policy uncertainty in HK should have significant impact on analyst behaviors in HK. Therefore, Hong Kong is a natural setting in which we can identify the different impacts of local and global policy uncertainty.

We examine analysts' behavior from the aspects of earnings forecast accuracy, the forecast dispersion, analyst coverage, the number of upward stock recommendations, and the number of downward recommendations. We expect a negative relation between the forecast accuracy and the Hong Kong EPU because the forecasting environment is likely to be more challenging when EPU is high, and a negative relation between the forecast dispersion and the EPU because of analysts' herding behavior in times of more challenging tasks (e.g., Lin 2020). We also predict negative relations between analyst coverage and the EPU because analysts are unlikely to follow new firms when existing tasks become more challenging. Further, the numbers of upward and downward recommendation revisions are expected to be negatively related to the EPU because analysts are concerned over unforeseeable prospects.

We measure economic policy uncertainty with the EPU index developed by [START_REF] Baker | Measuring economic policy uncertainty[END_REF]. Interestingly, we find that HK EPU does not have significant impact on analysts' earnings forecast accuracy and dispersion. In contrast, external EPUs such as EPU in Mainland China, U.S., Europe, and across the globe have significant impact on analysts' forecast accuracy in HK, suggesting that external EPUs has stronger impact than local HK EPU on analysts' forecast accuracy in HK. In addition, unlike the findings in existing studies, neither local HK nor external EPU has significant impact on analyst forecast dispersion in HK, suggesting analysts in HK tend to keep pace with each other during high uncertainty periods.

Although local and external EPUs have different impact on earnings forecast accuracy, they have same impact on analyst coverage and recommendations. Analysts tend to decrease their firm coverage and are reluctant to change both upgrade and downgrade recommendations.

Overall, these results suggest that analysts tend to be more conservative when confronting both local and external increasing policy uncertainty.

Data and Methodology

Data and Sample

We obtain analyst data and firms' financial data from CSMAR. We start with public firms on the Hong Kong exchange and keep the latest one-year-ahead individual analysts' earnings forecasts and stock recommendations. We then delete any observation with missing data on analyst behavior and control variables. The final sample covers the period from 2000 to 2018 and comprises with 1,700 firm-year observations. Table 1 presents descriptive statistics for all variables. Panel A reports that the mean (median) analyst earnings forecasts accuracy is -0.034 (-0.017); the mean (median) dispersion of earnings forecasts is 0.00021 (0.0001); and the mean (median) log of analyst following for a firm in a certain year is 2.297 (2.485), equivalent to a mean (median) of 13 (11) analyst following a firm. The mean log of the number of analyst upward recommendation revisions is 0.127, equivalent to 0.494 upward recommendation revisions. The mean log of the number of analyst downward recommendation revisions is 0.121, equivalent to 0.745 downward recommendation revisions. The medians of the log of downward recommendation revisions as well as upward revisions are both 0.000, equivalent to 0 downward and upward recommendation revisions. In addition, the sample firms have a mean (median) ROA of 0.057 (0.044); a mean (median) leverage of 0.519 (0.527); and a mean (median) growth of 0.010 (0.001). The mean (median) log of market capitalization is 2.401 (2.404). The mean (median) of market volatility in Hong Kong is 0.012 (0.010).

An unreported Pearson correlation shows that the HK EPU is positively correlated with forecast accuracy, but negatively related with analyst coverage, recommendation upgrades, and recommendation downgrades. This suggests that local EPU complicates analysts' forecast tasks, and analysts are reluctant to follow new firms or make recommendation revisions. In addition, EPU in Mainland China, HK, Europe, U.S., and global EPU are positively related with each other.

2.2Methodology

To examine the relationship between analyst behavior and macro uncertainty, we use the following model:

Analyst Behavior i,t = α EPU i,t + β Controls i,t + Ɛ i,t
where EPU is measured with the Hong Kong EPU index. This index is a weighted-average of [START_REF] Baker | Measuring economic policy uncertainty[END_REF] economic political uncertainty index in the most recent two months.1 Analyst performance is measured with earnings forecast accuracy, earnings forecast dispersion, analyst coverage, stock recommendation upgrades, and stock recommendation downgrades. Forecast accuracy (accuracy) is calculated as -1 times the absolute difference between the mean analyst earnings forecast per share over a year and firms' actual EPS scaled by the price per share.

Forecast dispersion (dispersion) is the standard deviation of all individual analysts' earnings forecasts issued for a firm over a year. Analyst coverage (logfollow) is calculated as the natural logarithm of the summation of one and the number of analysts following a firm. Stock recommendation upgrades (lognumrecup) is the natural logarithm of the summation of one and the number of recommendations that have been revised upward, whereas recommendation downgrades (lognumrecdown) is the natural logarithm of the summation of one and the number of recommendations that have been revised downward.

We control for market volatility which influences analysts' behavior at the macro level to isolate the effects of EPU on analyst behavior. It is measured by the standard deviation of the returns generated with the Hong Kong Hang Seng index over the past twelve months. We also control firm-level characteristics, such as return on assets, leverage, growth, and firm age, because prior research documents a correlation between analyst behavior and these firm characteristics. In addition, we include industry-fixed effects in the regressions. Appendix 1 presents the variable descriptions in detail. All dependent variables and control variables are winsorized at 1% and 99% levels.

Empirical Results and Discussions

Local EPU and Analyst Behaviors

Table 2 reports the results of the relationships between HK EPU and analyst behaviors after controlling for other macro-level variables and firm-level variables. Column 1, which tabulates the results on analyst forecast accuracy, shows an insignificant coefficient of -0.001 on HK EPU, after controlling for other variables. This indicates no significant influence of local HK EPU over analyst earnings forecast accuracy, although the sign is expected. This differs from the finding of [START_REF] Chourou | Economic policy uncertainty and analysts' forecast characteristics[END_REF] that in U.S. that analyst forecasts are less accurate as U.S. EPU increases, suggesting the uniqueness of HK market as the international finance center. This finding suggests that analysts in HK seem to devote more to forecasting when local policy uncertainty is high.

Column 2, which shows the results on analyst forecast dispersion, tabulates an insignificant coefficient of -0.001 on the HK EPU. This insignificant relation demonstrates no change in volatility of analysts' earnings forecasts during times of economic uncertainty. This differs again from Chourou et al. ( 2021)'s findings in U.S. that analyst forecast dispersion are significantly related to the U.S. EPU. This finding suggests that analysts in HK tend to keep pace with each other when local uncertainty is high.

Column 3 tabulates the results on analyst forecast following and shows a significant coefficient of -0.341 on HK EPU. This implies reduced supply of analyst coverage in times of greater uncertainty due to the more challenging forecasting tasks. Columns 4 and 5 report results on recommendation upgrades and downgrades. The coefficient on HK EPU for the number of upgrades is -0.062 whereas the coefficient on HK EPU for the number of downgrades is -0.087. This indicates that analysts are reluctant to revise recommendations during times of uncertainty due to concerns over unforeseeable firms' prospects. Overall, these results show that local EPU has no significant impact on analysts' forecast accuracy and dispersion in HK, but local EPU still has significant impact on analyst coverage and recommendations.

External Policy Uncertainty and Analyst Behaviors

With increasing globalization, economies have become dynamically interrelated around the world. We explore whether globalization applies to economic policy uncertainty. That is, does economic policy uncertainty in some regions of the world influence other regions? Hong Kong provides a natural setting for this question because it confronts economic policy uncertainty from different countries as a developed international financial center. We investigate the impact of EPU in Mainland China, the U.S., and Europe, and Global EPU on Hong Kong analysts' behaviors.

Table 3 reports the results of EPU of Mainland China and analysts' behaviors in Hong Kong. Column 1 shows a statistically significant coefficient of -0.005 on the Mainland China's EPU. This suggests that economic policy uncertainty in Mainland China complicates the forecast tasks and decreases analyst forecast accuracy in Hong Kong. Column 2 reports a negative but insignificant coefficient on Mainland China's EPU. This shows no relationship between Mainland China's EPU and Hong Kong analysts' forecast dispersion. Column 3 shows that the coefficient on analyst coverage is statistically significant of -0.245, indicating that the analyst following of firms in Hong Kong tend to decrease when Mainland China's EPU is high.

Columns 4 and 5 show significant coefficients of -0.065 and -0.058 on Mainland China's EPU.

This suggests that analysts in Hong Kong are reluctant to revise recommendations when Mainland China's EPU is high. While the results on analyst coverage and stock recommendations are similar to those in the main analysis in Table 2, the findings on analyst forecast accuracy are different when we examine the impact of the EPU of Mainland China and the impact of the local HK EPU. This difference demonstrates the spill-over effect of Mainland China's economic policy uncertainty over the HK financial market.

Table 4 presents the effect of the European EPU on analyst behaviors in Hong Kong. The results are similar to those in Table 3. Column 1 shows a significant coefficient of -0.006 on the European EPU for analyst forecast accuracy. Column 2 reports an insignificant coefficient of -0.001 on the European EPU for analyst forecast dispersion. Column 3 tabulates a significant coefficient of -0.559 on the European EPU for analyst coverage. Columns 4 and 5 show significant coefficients of -0.140 and -0.135 on the European EPU for upgrade and downgrade recommendation revisions. The result on analyst forecast accuracy is different from those presented in Table 2 which shows no influence from local HK EPU. This provides evidence of the spill-over effect of European economic policy uncertainty over Hong Kong's financial market.

Table 5 reports the results for the impact of U.S. EPU on Hong Kong analyst behaviors.

The results are consistent with those in the previous analyses. Column 1 presents the results of the analyst forecast accuracy. The coefficient -0.016 on the U.S. EPU is significant. Column 2 tabulates that the effect of U.S. EPU on analyst earnings forecast dispersion in Hong Kong is insignificant. Column 3 shows a statistically significant coefficient of -0.398 on the global EPU for analyst coverage. Columns 4 and 5 which report regression results of recommendation upgrade and downgrade revisions show statistically significant coefficients of -0.107 and -0.051 on the U.S. EPU. These findings demonstrate that policy uncertainty in the U.S. impacts analyst behaviors in HK.

Table 6 reports the results for the impact of Global EPU on analyst behaviors in Hong

Kong. Column 1 presents the results of the analyst forecast accuracy. The coefficient on the global EPU is -0.009 and is statistically significant. Column 2 tabulates that the effect of global EPU on analyst earnings forecast dispersion in Hong Kong is insignificant. Column 3 shows a significantly negative coefficient of -0.444 on the global EPU for analyst coverage. Columns 4 and 5 report significant coefficients of -0.116 and -0.100 on the global EPU for recommendation upgrade and downgrade revisions. The finding on analyst forecast accuracy again is different from that presented in Table 2. This demonstrates that policy uncertainty around the world has a significant impact on analyst behaviors in HK.

Potential Endogeneity Concern

To address potential endogeneity issue, we employ an instrument variable of partisan polarization that represents the level of political polarization in the US Congress. This variable has been used widely in the literature as an instrument for policy uncertainty (e.g. [START_REF] Gulen | Policy uncertainty and corporate investment[END_REF][START_REF] Nguyen | Policy uncertainty and mergers and acquisitions[END_REF]. This instrument variable carries a significant relationship with EPU in HK, but it is not apparently related to analysts in HK.

Following [START_REF] Gulen | Policy uncertainty and corporate investment[END_REF], we use the first dimension of the DW-NOMINATE scores of McCarty, Poole, and Rosenthal (1997) to represent partisan polarization. We perform two-stage least square estimations with Polarization as the instrument variable. An unreported table shows that the coefficients on the predicted HK EPU are significantly related to analyst coverage and recommendation upgrade and downgrade, but are insignificantly related to forecast accuracy and dispersion. These results are consistent with our findings in the main analyses.

Conclusions

This paper documents that local policy uncertainty has no significant impact on analyst forecast accuracy and dispersion in HK. In contrast, external policy uncertainty from other main countries such as China and USA and global and Europe could significantly and negatively affect forecast accuracy in HK, although the external policy uncertainty still has no significant impact on forecast dispersion in HK. In addition, both local and external policy uncertainties have significant impacts on analyst coverage and recommendations in HK. These findings emphasize the spillover effect of economic policy uncertainty on global financial markets.

There are some limitations due to the limited space. In particular, it is meaningful to explore in more detail why local and external economic policy uncertainties have significantly different impact on analysts' earnings forecast accuracy, which is one of the most variables in the literature on analysts. In addition, it is also interesting to explore why local and external policy uncertainties have different impact on different aspects of analysts' behaviors. These research questions are left for the future research.

Table 2 :

 2 Hong Kong Economic Policy Uncertainty and Analyst BehaviorsThis table presents the average estimated coefficients from regressions of measures of analyst behaviors on economic policy uncertainty (EPU) index in Hong Kong. All variables are defined in Appendix 1. *, **, and *** indicate significance at the 10%, 5%, and 1% levels (two-tailed), respectively. T-statistics are in parentheses.

	HK EPU	1,700	5.162	0.518	4.455	4.792	5.124	5.655	5.788
	US EPU	1,700	4.759	0.244	4.441	4.643	4.784	4.930	5.019
	European EPU	1,700	5.096	0.406	4.358	4.931	5.073	5.402	5.579
	Global EPU	1,700	4.898	0.428	4.278	4.676	4.863	5.068	5.513
	LogMarketCap	1,700	2.401	1.416	0.742	1.396	2.404	3.310	4.260
	ROA	1,700	0.057	0.055	0.003	0.019	0.044	0.086	0.135
	Leverage	1,700	0.519	0.228	0.205	0.340	0.527	0.699	0.808
	Growth	1,700	0.010	0.019	0.000	0.000	0.001	0.012	0.029
	MKT Volatility-Hong Kong	1,700	0.012	0.006	0.006	0.008	0.010	0.018	0.018

Table 3 :

 3 Mainland China Economic Policy Uncertainty and Analyst Behaviors in Hong KongThis table presents the average estimated coefficients from regressions of measures of analyst behaviors on the China mainland's economic policy uncertainty (EPU) index in Hong Kong. All variables are defined in Appendix 1. *, **, and *** indicate significance at the 10%, 5%, and 1% levels (two-tailed), respectively. T-statistics are in parentheses.

		Accuracy	Dispersion	Coverage	Upgrade	Downgrade
	Intercept	-0.027***	0.001	2.502***	0.348***	0.379***
		(-3.23)	(0.45)	(18.3)	(6.42)	(6.87)
	China Mainland EPU	-0.005***	-0.001	-0.245***	-0.065***	-0.058***
		(-3.73)	(-0.41)	(-10.2)	(-6.73)	(-5.90)
	LogMarketCap	0.008***	0.001***	0.420***	0.054***	0.034***
		(10.6)	(5.89)	(32.3)	(10.5)	(6.61)
	ROA	0.264***	-0.001	-1.049***	-0.099	0.194
		(12.5)	(-1.33)	(-2.96)	(-0.72)	(1.38)
	Leverage	-0.009*	0.001***	0.075	-0.042	-0.011
		(-1.79)	(5.01)	(0.91)	(-1.30)	(-0.33)
	Growth	-0.025	0.002***	-2.740***	-1.015***	-1.047***
		(-0.45)	(4.39)	(-2.93)	(-2.72)	(-2.76)
	MKT Volatility	-0.810***	0.006***	0.956	0.710	-2.707**
		(-5.05)	(5.77)	(0.36)	(0.67)	(-2.52)
	Firm age	0.001	0.001**	0.009**	0.002	0.001
		(0.16)	(2.08)	(2.44)	(1.56)	(0.29)
	Industry Fixed Effects	Yes	Yes	Yes	Yes	Yes
	N	1484	1533	1608	1687	1687
	R 2	0.2361	0.0869	0.4488	0.0966	0.0573

Table 4 :

 4 European Economic Policy Uncertainty and Analyst Behaviors in Hong KongThis table presents the average estimated coefficients from regressions of measures of analyst behaviors on the European economic policy uncertainty (EPU) index in Hong Kong. All variables are defined in Appendix 1. *, **, and *** indicate significance at the 10%, 5%, and 1% levels (two-tailed), respectively. Tstatistics are in parentheses.

		Accuracy	Dispersion	Coverage	Upgrade	Downgrade
	Intercept	-0.022*	0.001	3.993***	0.708***	0.746***
		(-1.65)	(0.72)	(17.8)	(7.85)	(8.14)
	European EPU	-0.006**	-0.001	-0.559***	-0.140***	-0.135***
		(-2.36)	(-1.47)	(-12.6)	(-7.82)	(-7.40)
	LogMarketCap	0.008***	0.001***	0.428***	0.056***	0.036***
		(10.5)	(6.00)	(33.3)	(10.9)	(6.97)
	ROA	0.259***	-0.001	-1.308***	-0.169	0.131
		(12.2)	(-1.39)	(-3.75)	(-1.23)	(0.93)
	Leverage	-0.009*	0.001***	0.084	-0.042	-0.010
		(-1.88)	(5.07)	(1.04)	(-1.30)	(-0.30)
	Growth	-0.046	0.002***	-2.403***	-0.966***	-0.959**
		(-0.82)	(4.64)	(-2.62)	(-2.61)	(-2.55)
	MKT Volatility	-0.753***	0.006***	1.429	0.867	-2.634**
		(-4.72)	(5.71)	(0.54)	(0.83)	(-2.48)
	Firm age	0.001	0.001**	0.013***	0.003*	0.001
		(-0.14)	(2.41)	(3.51)	(1.96)	(0.80)
	Industry Fixed Effects	Yes	Yes	Yes	Yes	Yes
	N	1484	1533	1668	1687	1687
	R 2	0.2317	0.0881	0.4660	0.1049	0.0682

Table 5 :

 5 U.S. Economic Policy Uncertainty and Analyst Behaviors in Hong KongThis table presents the average estimated coefficients from regressions of measures of analyst behaviors on economic policy uncertainty (EPU) index in the US in the Hong Kong sample. All variables are defined in Appendix 1. *, **, and *** indicate significance at the 10%, 5%, and 1% levels (two-tailed), respectively. T-statistics are in parentheses.

		Accuracy	Dispersion	Coverage	Upgrade	Downgrade
	Intercept	0.022	-0.001**	3.131***	0.526***	0.335**
		(1.12)	(-2.00)	(9.50)	(4.02)	(2.51)
	U.S. EPU	-0.016***	0.001	-0.398***	-0.107***	-0.051*
		(-3.93)	(1.57)	(-5.63)	(-3.82)	(-1.78)
	LogMarketCap	0.008***	0.001***	0.415***	0.053***	0.033***
		(10.5)	(5.80)	(31.3)	(10.2)	(6.28)
	ROA	0.260***	-0.001	-1.220***	-0.157	0.145
		(12.3)	(-1.32)	(-3.37)	(-1.13)	(1.03)
	Leverage	-0.009*	0.001***	0.054	-0.049	-0.019
		(-1.79)	(4.91)	(0.64)	(-1.50)	(-0.58)
	Growth	-0.057	0.002***	-4.571***	-1.497***	-1.525***
		(-1.04)	(4.27)	(-4.90)	(-4.08)	(-4.08)
	MKT Volatility	-0.620***	0.006***	7.678***	2.379**	-1.444
		(-3.89)	(5.66)	(2.81)	(2.25)	(-1.34)
	Firm age	-0.001	0.001*	0.003	0.001	-0.002
		(-0.20)	(1.73)	(0.66)	(0.30)	(-1.10)
	Industry Fixed Effects	Yes	Yes	Yes	Yes	Yes
	N	1484	1533	1608	1687	1687
	R 2	0.2368	0.0883	0.4244	0.0802	0.0396

Table 6 :

 6 Global Economic Policy Uncertainty and Analyst Behaviors in Hong KongThis table presents the average estimated coefficients from regressions of measures of analyst behaviors on the global economic policy uncertainty (EPU) index. All variables are defined in Appendix 1. *, **, and *** indicate significance at the 10%, 5%, and 1% levels (two-tailed), respectively. T-statistics are in parentheses.

		Accuracy	Dispersion	Coverage	Upgrade	Downgrade
	Intercept	-0.010	-0.001	3.363***	0.572***	0.560***
		(-0.83)	(-0.06)	(16.3)	(6.93)	(6.65)
	Global EPU	-0.009***	-0.001	-0.444***	-0.116***	-0.100***
		(-3.65)	(-0.72)	(-10.6)	(-6.89)	(-5.79)
	LogMarketCap	0.008***	0.001***	0.421***	0.054***	0.035***
		(10.6)	(5.92)	(32.4)	(10.5)	(6.61)
	ROA	0.262***	-0.001	-1.177***	-0.135	0.161
		(12.3)	(-1.35)	(-3.33)	(-0.98)	(1.15)
	Leverage	-0.009*	0.001***	0.075	-0.044	-0.013
		(-1.81)	(5.03)	(0.91)	(-1.35)	(-0.38)
	Growth	-0.028	0.002***	-2.714***	-1.021***	-1.073***
		(-0.49)	(4.47)	(-2.91)	(-2.74)	(-2.83)
	MKT Volatility	-0.783***	0.006***	1.927	0.963	-2.450**
		(-4.91)	(5.79)	(0.72)	(0.92)	(-2.30)
	Firm Age	0.001	0.001**	0.010***	0.002	0.001
		(0.17)	(2.17)	(2.65)	(1.61)	(0.27)
	Industry Fixed Effects	Yes	Yes	Yes	Yes	Yes
	N	1484	1533	1608	1687	1687
	R 2	0.2357	0.0871	0.4513	0.0978	0.0567

We derive similar results from using different estimates of the policy uncertainty index in the formation period.

University and San Francisco State University for their helpful comments. This work is supported by Shenzhen Humanities & Social Sciences Key Research Bases. Zhu acknowledges that this study was partially funded by Audencia Foundation.