A Sokal

A Sauvanet

B Fantin

Victoire De Lastours
email: lastours@aphp.fr

Angiocholites : diagnostic et prise en charge Acute cholangitis : diagnosis and management

Keywords: angiocholite, étiologie, épidémiologie, prise en charge acute cholangitis, etiology, epidemiology, management

Key points -Acute cholangitis diagnosis is primarily clinical, and confirmed by biological and radiological data. -While it has multiple etiologies, lithiasic and neoplastic obstacles are the two main causes. -The most frequently found germs are Escherichia coli and Klebsiella spp. -Treatment associates antimicrobial therapy targeting Enterobacteriaceae and adapted to the environment (particularly in cases involving biliary prosthesis or bilio-digestive anastomosis) associated with endoscopic draining of the biliary ducts Résumé : L'angiocholite est une infection de la bile et des voies biliaires, secondaire dans la majorité des cas à une obstruction des voies biliaires. Les étiologies en sont multiples, dominées par la maladie lithiasique et les néoplasies. Le diagnostic clinique repose sur la triade de Charcot (douleur, fièvre, ictère) mais sa sensibilité insuffisante a mené à son remplacement par un score plus complexe, ajoutant des données biologiques et radiologiques, validé par les Tokyo Guidelines depuis 2007. En cas de suspicion diagnostique, l'échographie abdominale permet une exploration rapide des voies biliaires mais ses performances diagnostiques sont médiocres, surtout en cas d'obstacle non lithiasique, contrairement à l'IRM pancréato-biliaire et l'écho-endoscopie dont les performances diagnostiques sont excellentes. Le scanner abdomino-pelvien reste néanmoins le plus disponible, avec des performances diagnostiques intermédiaires. La réalisation de prélèvements microbiologiques tels que les hémocultures (positives dans 40% des cas) et les cultures biliaires est indispensable. En cas d'angiocholite « communautaire », les 2 pathogènes les plus fréquents sont Escherichia coli et Klebsiella spp., justifiant une antibiothérapie probabiliste par céphalosporine de 3 ème génération. L'intérêt d'une couverture systématique des entérocoques et des anaérobies est encore débattu, habituellement recommandée en cas d'angiocholite associée aux soins, en présence de critères de gravité pour l'entérocoque, et en présence d'une anastomose bilio-digestive pour les anaérobies. L'existence d'une prothèse biliaire est le seul facteur de risque identifié d'infection à bactérie multirésistante. A l'antibiothérapie doit s'ajouter un drainage des voies biliaires endoscopique ou radiologique. Malgré les progrès dans la prise en charge, la mortalité des angiocholites reste d'environ 5%.

biological and radiological data. In case of clinical suspicion, abdominal ultrasound quickly explores the biliary tract, but its diagnostic capacities are poor, especially in case of non-gallstone obstruction, as opposed to magnetic resonance cholangiopancreatography and endoscopic ultrasound, of which the diagnostic capacities are excellent. CT scan is more widely available, with intermediate diagnostic capacities. Bacteriological sampling through blood cultures (positive in 40% of cases) and bile cultures is essential. In cases involving a wide variety of bacteria, the main pathogens having been found are Escherichia coli and Klebsiella spp., justifying first-line antimicrobial therapy by a thirdgeneration cephalosporin. Systematic coverage of Enterococcus spp. and anaerobic infections remains debated, and is usually recommended only in case of health-care associated cholangitis, elevated Enterococcus severity levels, or anaerobic bilio-digestive anastomosis for anaerobes.

Presence of a biliary stent is the only identified risk-factor associated with infections by multidrugresistant pathogens. Along with antimicrobial therapy, endoscopic or radiological biliary drainage is a crucial management component. Despite improved management, mortality in cases of acute cholangitis remains approximately 5%.

Introduction :

Acute cholangitis or angiocholitis (from the Greek angeion: vessels and kholé: bile) is a potentially severe bile and biliary duct infection. Its first known description was given in 1877 by Jean Martin Charcot (1825Charcot ( -1893) ) in his "Lesson on diseases of the liver, biliary tract and kidneys" at the Paris faculty of medicine [START_REF] Charcot | Leçons sur les maladies du foie, des voies biliaires et des reins[END_REF]. In the 18th lesson "Of symptomatic hepatic fever -Comparison with urosepsis fever", he described an association of intermittent hepatic fever with icterus and biliary colic, which was to become the well-known eponymous triad: pain-fever-jaundice. In our times, this triad remains essential to clinical diagnosis, and is confirmed more often than not, by biological, microbiological and radiological data. In this review, we shall discuss the respective role of each of these, while bearing in mind that according to the Tokyo Guidelines, the gold standard for diagnosis of acute cholangitis consists in: observation of purulent bile; clinical remission following bile duct drainage; remission achieved by antimicrobial therapy alone, in patients in whom the only site of infection was the biliary tree [START_REF] Kiriyama | TG13 guidelines for diagnosis and severity grading of acute cholangitis (with videos)[END_REF][START_REF] Kiriyama | New diagnostic criteria and severity assessment of acute cholangitis in revised Tokyo Guidelines[END_REF].

In addition to diagnosis, treatment of acute cholangitis remains a major medical issue. Points of interest include management of patients with comorbidities, severity assessment, evolution of the implicated pathogens influencing the choice of probabilistic antimicrobial therapy (degree of coverage against multidrug-resistant bacteria [MRB], anaerobic infections, enterococci...), duration of antibiotic treatment and timing of bile duct drainage. The cruciality of bile duct treatment and management bears mentioning; while endoscopic procedures have yielded undeniable improvement, the respective roles of endoscope ultrasound and interventional radiology have yet to be clearly defined.

Since 2007, a group of experts from throughout the world has been working together in view of proposing recommendations for diagnosis and treatment of acute cholangitis: the Tokyo Guidelines, which were updated in 2013 and most recently in 2018 [START_REF] Kiriyama | Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos)[END_REF]. This article proposes a review of recent developments incorporating the main points of interest stemming from the Tokyo Guidelines.

1-Pathophysiology and etiologies of acute cholangitis

Two central phenomena explain the pathophysiology of acute cholangitis. The first is obstruction of the biliary tract by an obstacle, leading to stoppage of enterohepatic circulation of bile and increased intraductal pressure, which is responsible for altered biliary secretion and brings about bilio-venous and bilio-lymphatic reflux [START_REF] Scott-Conner | The Pathophysiology of Biliary Obstruction and Its Effect on Phagocytic and Immune Function[END_REF][START_REF] Kimura | Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines[END_REF]. The second consists in bacterial proliferation in bile, which is normally sterile, even though some colonization has been observed in persons without biliary tract infection. There are two possible sources of contamination: ascendant (duodenal flora) or hematogenous (portal venous blood) [START_REF] Sung | Defense system in the biliary tract against bacterial infection[END_REF]. Heightened intraductal pressure subsequently leads to bilio-venous bacterial translocation. It bears mentioning that by definition, reflux cholangitis is the exception inasmuch as it is secondary not to biliary tract obstruction, but rather to food debris reflux, a source of transitory obstruction that is considerably more difficult to highlight (Figure 1).

The multiple etiologies of acute cholangitis are presented as exhaustively as possible in des Table 1, which supplements the table put forward by Mosler [START_REF] Mosler | Diagnosis and Management of Acute Cholangitis[END_REF] and Carpenter [START_REF] Mukai | Indications and techniques of biliary drainage for acute cholangitis in updated Tokyo Guidelines 2018[END_REF] and schematized in Figure 2 (according to [START_REF] Mukai | Indications and techniques of biliary drainage for acute cholangitis in updated Tokyo Guidelines 2018[END_REF], [START_REF] Carpenter | Bacterial and Parasitic Cholangitis[END_REF]). Given for information purposes only, the reported frequencies of occurrence should be interpreted cautiously insofar as they may vary considerably from one center to another according to patient recruitment and series duration. While the most recent and robust multicenter epidemiological data (more than 6000 acute cholangitis episodes) date from 2017, they originated in Japanese and Taiwanese centers [START_REF] Gomi | Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis[END_REF]. And while lithiasis of the common bile duct represents the main etiology of acute cholangitis, other causes are tending to become more and more frequent; they include neoplasia (especially in patients over 50 years of age, possibly becoming the predominant etiology) [START_REF] Singh | Diagnostic Accuracy of MRCP as Compared to Ultrasound/CT in Patients with Obstructive Jaundice[END_REF], primary sclerosing cholangitis and ascending cholangitis following instrumentation of the biliary duct (0.5 to 2.4% of endoscopic retrograde cholangiopancreatography cases [ERCP]) [START_REF] Ong | Complications of endoscopic retrograde cholangiography in the post-MRCP era: A tertiary center experience[END_REF]. Lastly, in patients with a biliary prosthesis, occlusion of the latter occurs in half of cases with a plastic prosthesis and in a quarter of cases in patients with self-expandable metal prostheses, putting them at high risk of cholangitis [START_REF] Sawas | Self-expandable metal stents versus plastic stents for malignant biliary obstruction: a meta-analysis[END_REF].

Asymptomatic gallstones (vesicular lithiasis) is frequent (around 10% of the population in Europe [START_REF] Payen | Lithiase biliaire[END_REF]), but cholangitis occurrence seems exceptional in asymptomatic patients and has relatively seldom been studied. As regards the few publications concerning patients with initially asymptomatic gallstones, not a single cholangitis episode was reported in three large-scale cohorts (at least 100 patients having been monitored for at least 10 years) [START_REF] Ransohoff | The Natural History of Silent Gallstones[END_REF][START_REF] Attili | The natural history of gallstones: The GREPCO experience[END_REF][START_REF] Shabanzadeh | A Prediction Rule for Risk Stratification of Incidentally Discovered Gallstones: Results From a Large Cohort Study[END_REF]. In two other cohort studies, only one cholangitis episode was reported among 739 and 135 patients respectively [START_REF] Halldestam | Development of symptoms and complications in individuals with asymptomatic gallstones[END_REF][START_REF] Mcsherry | The natural history of diagnosed gallstone disease in symptomatic and asymptomatic patients[END_REF], while in a third study four cases involving cholangitis were reported among 123 patients monitored for 20 years, but they went by different names ("angiocholitis" and "obstructive icterus") [START_REF] Friedman | Prognosis of gallstones with mild or no symptoms: 25 years of follow-up in a health maintenance organization[END_REF]. On the basis of other, less recent data, the authors of the Tokyo Guidelines (TG) 2013 found an incidence of 0.3% to 1.6% of acute cholangitis in biliary lithiasis patients [START_REF] Kiriyama | TG13 guidelines for diagnosis and severity grading of acute cholangitis (with videos)[END_REF].

One particular case is reflux cholangitis, which complicates approximately 10% of bilio-digestive anastomoses whatever the indication: bile duct stones [START_REF] Panis | Long term results of choledochoduodenostomy versus choledochojejunostomy for choledocholithiasis. The French Association for Surgical Research[END_REF], postoperative stenosis repair [START_REF] Barbier | Long-term consequences of bile duct injury after cholecystectomy[END_REF] or cephalic duodenopancreatectomy [START_REF] Ueda | Refractory Long-Term Cholangitis After Pancreaticoduodenectomy: A Retrospective Study[END_REF]. Reflux is likely to consist in food debris and may possibly be objectified by imaging (one example: contrast radiography of the upper gastrointestinal transit in choledocoduodenal anastomosis) or scintigraphy (one example: biliary scintigraphy after cephalic duodenopancreatectomy). In this context, repeated cholangitis episodes should instigate search for a contributing factor such as anastomotic stenosis or an impediment to digestion beneath the anastomosis [START_REF] Barbier | Long-term consequences of bile duct injury after cholecystectomy[END_REF][START_REF] Ueda | Refractory Long-Term Cholangitis After Pancreaticoduodenectomy: A Retrospective Study[END_REF].

2-Acute cholangitis diagnosis

Clinical diagnosis of acute cholangitis is classically based in the Charcot triad (pain, fever, jaundice). However, its excellent specificity (96%) is counteracted by its poor sensitivity (26%) [START_REF] Kimura | Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines[END_REF]. In fact, association of the three symptoms may be present in only 22% of cholangitis patients [START_REF] Csendes | Risk factors and classification of acute suppurative cholangitis[END_REF]. While the most frequent symptoms are fever and abdominal pain (up to 80% of patients), abdominal pain may be absent in half of elderly subjects [START_REF] Agarwal | Endoscopic management of acute cholangitis in elderly patients[END_REF], and jaundice is present in 60 to 70% of patients.

In 2007, a multidisciplinary meeting of international experts took place in Tokyo and published their initial recommendations (Tokyo Guidelines=TG), which were subsequently updated in 2013 and 2018. In TG 2007, a new diagnostic score introducing biological and radiological data was proposed and yielded improved but still insufficient sensitivity and specificity scores (83% and 80% respectively) [START_REF] Kiriyama | New diagnostic criteria and severity assessment of acute cholangitis in revised Tokyo Guidelines[END_REF]. The score was revised in 2013 and maintained in 2018 [START_REF] Yokoe | Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with videos)[END_REF], it is presented in Table 2. In diagnosis of acute cholangitis, it presents sensitivity and specificity scores of 92% and 78% respectively. The revised score no longer includes abdominal pain, which is not sufficiently specific.

3-Severity criteria

In view of predicting the severity of an episode of acute cholangitis, in 2013 the TG experts drew up a scoring system, presented in Table 3, which was not modified in 2018. Three groups are classified according to severity; the illness is categorized as grade 1, non-severe, if none of the following serious symptoms are present : fever >39°C, age >75 years, hyperleukocytosis >12G/L, bilirubinemia >85µmol/L or hypoalbuminemia < 0.7 x the lower limit of the normal range. Grade 3 is reached in the event of organ failure, while a patient is considered as grade 2 or intermediate when at least two of the above-mentioned serious symptoms are present, but no organ failure has occurred. The three degrees of severity are associated with increasing mortality, from 1.2% for grade 1 to 2.6% for grade 2 and more than 5% for grade 3 [START_REF] Kiriyama | TG13 guidelines for diagnosis and severity grading of acute cholangitis (with videos)[END_REF][START_REF] Kiriyama | Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos)[END_REF][START_REF] Kiriyama | Clinical application and verification of the TG13 diagnostic and severity grading criteria for acute cholangitis: an international multicenter observational study[END_REF]. It should nonetheless be noted that correlation between severity as measured by the score is less than perfect, particularly in patients suffering from cholangitis secondary to neoplasia, biliary prosthesis obstruction, or intrahepatic obstruction [START_REF] Kiriyama | Clinical application and verification of the TG13 diagnostic and severity grading criteria for acute cholangitis: an international multicenter observational study[END_REF][START_REF] Sun | Comparison of two editions of Tokyo guidelines for the management of acute cholangitis[END_REF]; moreover, the score often tends to underestimate severity. Procalcitonin could constitute an interesting marker for severity (sensitivity at 97% and specificity at 73% for diagnosis of severe acute cholangitis) [START_REF] Umefune | Procalcitonin is a useful biomarker to predict severe acute cholangitis: a single-center prospective study[END_REF].

4-Imagery

Highlighting biliary tract dilatation or an obstacle in the biliary tract is a key diagnostic element.

Several imagery modalities may be envisioned: abdominal ultrasound, abdominal CT, MRI and echoendoscopy (EE), coupled or not with ERCP. Ultrasound is often the first-line diagnostic test, as it facilitates search for biliary tract dilatation, buy while the results are relatively simple to visualize, they may be inadequate in the event of acute obstruction. Moreover, according to a Cochrane metaanalysis (to be interpreted with caution insofar as it is based on non-recent series, with pronouncedly variable results), ultrasound manifests low sensitivity (73%) in detection of common bile duct stone [START_REF] Gurusamy | Ultrasound versus liver function tests for diagnosis of common bile duct stones[END_REF]. And as regards obstacles other than choledocholithiasis, its performances have been even less impressive. To sum up, abdominal ultrasound does not function as differential diagnosis, and other examinations must be proposed.

Abdominal and pelvic CT with and without injection presents several advantages; it is more sensitive and specific than ultrasound (a score proposed in 2012 presents sensitivity >83% and specificity approximating 83% in acute cholangitis diagnosis, whatever the cause) [START_REF] Kim | Diagnostic performance of multidetector CT for acute cholangitis: evaluation of a CT scoring method[END_REF]; moreover, it facilitates search for complications (hepatic abscess, portal thrombosis…) and excludes alternative etiologies of abdominal pain. Bilio-pancreatic MRI represents the non-invasive modality with the best diagnostic yield when seeking out the origin of an obstacle, whatever the etiology, particularly with regard to malignant causes (sensitivity 96 %, specificity 100%) and bile duct stenoses [START_REF] Singh | Diagnostic Accuracy of MRCP as Compared to Ultrasound/CT in Patients with Obstructive Jaundice[END_REF]. Lastly, EE and ERCP, which can be carried out if necessary during the same anesthetic procedure, have evinced similarly excellent performances in detection of calculi; in addition, ERCP allows for therapeutic action [START_REF] Park | Endoscopic ultrasound-guided biliary drainage of hilar biliary obstruction[END_REF].

That much said, a recent meta-analysis showed that MRI and EE performed as well as one another in detection of common bile duct stones [START_REF] Giljaca | Endoscopic ultrasound versus magnetic resonance cholangiopancreatography for common bile duct stones[END_REF]. While the literature often evokes the supposedly excellent diagnostic value of EE in cases of biliary neoplasia, there presently exists no study assessing with sufficient clarity its diagnostic performances.

In clinical practice :

-Hepatic ultrasound and abdominal MRI are non-invasive and non-irradiating, but restricted availability of the latter limits its utilization in emergencies, notwithstanding its excellent diagnostic performances.

-Non-invasive but irradiant, abdominal and pelvic CT is of interest due to its widespread availability, and diagnostic performances generally superior to ultrasound but inferior to MRI. .

-While EE and ERCP are second-line invasive examinations, their diagnostic performances are excellent; ERCP is irradiant but allows for therapeutic action.

4-Microbiology

The two key microbiological tests in case of acute cholangitis are hemoculture and bile culture.

Hemocultures were positive in 40% of the episodes reported in a recent retrospective multicenter series and even more positive in the event of biliary stent obstruction [START_REF] Gomi | Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis[END_REF][START_REF] Rerknimitr | Microbiology of bile in patients with cholangitis or cholestasis with and without plastic biliary endoprosthesis[END_REF]. In 20% of cases, hemocultures may be polymicrobial [START_REF] Tagashira | Impact of inadequate initial antimicrobial therapy on mortality in patients with bacteraemic cholangitis: a retrospective cohort study[END_REF]. Bile cultures are even more cost-efficient (positive in 83% of cases according to the same multicenter study [START_REF] Gomi | Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis[END_REF], but frequently more in other series) and objectify polymicrobial infection in at least 50% of cases [START_REF] Rerknimitr | Microbiology of bile in patients with cholangitis or cholestasis with and without plastic biliary endoprosthesis[END_REF][START_REF] Park | How to interpret the bile culture results of patients with biliary tract infections[END_REF][START_REF] Reuken | Risk Factors for Multi-Drug Resistant Pathogens and Failure of Empiric First-Line Therapy in Acute Cholangitis[END_REF]. A 2014 retrospective study showed total agreement of 31% between bile cultures and hemocultures, a finding raising the questions about the pathogenicity of the germs present in polymicrobial bile cultures, but over 70% of the tests were carried out more than 24h after installation of a biliary drain [START_REF] Park | How to interpret the bile culture results of patients with biliary tract infections[END_REF]. The main isolated germs are presented in Table 4, adapted from TG 2018 [START_REF] Gomi | Tokyo Guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis[END_REF]: Escherichia coli and Klebsiella spp. are the two main germs responsible for acute cholangitis.

As regards antibiotic resistance of the germs responsible for acute cholangitis, more particularly the occurrence of episodes implicating enterobacteria producing extended spectrum β-lactamases (ESBLs), data vary widely from one country to another; in Europe, a retrospective study on the positive bile test results from 83 patients in a German tertiary center identified 29% of multidrugresistant (MDR) bacteria, including 54% of ESBL [START_REF] Reuken | Risk Factors for Multi-Drug Resistant Pathogens and Failure of Empiric First-Line Therapy in Acute Cholangitis[END_REF]. In Korea, E. coli ESBLs are the first microorganisms responsible for acute cholangitis, including community-acquired cholangitis, all in all representing 30.4% of cases [START_REF] Kwon | Changes in causative pathogens of acute cholangitis and their antimicrobial susceptibility over a period of 6 years[END_REF]. Biliary stenting is the one MDR-independent risk factor identified in two retrospective studies, with relative risk of 3.6 to 4 times [START_REF] Reuken | Risk Factors for Multi-Drug Resistant Pathogens and Failure of Empiric First-Line Therapy in Acute Cholangitis[END_REF][START_REF] Schneider | Risk factors for increased antimicrobial resistance: a retrospective analysis of 309 acute cholangitis episodes[END_REF]. Presence of a biliary endoprosthesis is also a risk factor for cholangitis with enterococci (particularly E. faecium), Pseudomonas aeruginosa and Stenotrophomonas maltophila [START_REF] Weber | Spectrum of pathogens in acute cholangitis in patients with and without biliary endoprosthesis[END_REF]. Finally, even though colonization stents by fungal microorganisms is a frequent occurrence, fungal cholangitis remains exceptional [START_REF] Lübbert | Epidemiology and Resistance Patterns of Bacterial and Fungal Colonization of Biliary Plastic Stents: A Prospective Cohort Study[END_REF].

5-Treatment of acute cholangitis

Treatment of acute cholangitis is a response to an emergency built around two fundamental procedures: antimicrobial therapy, and biliary tract drainage (Figure 1).

a-Antimicrobial therapy

The severity of acute cholangitis necessitates immediate antimicrobial therapy in emergency care, which is most often chosen probabilistically. Antibiotic treatment must cover the germs described above according to local ecology, without neglecting to take into consideration the relevant characteristics of the patient (renal and hepatic functions, allergies, known MRB colonization…) and of the antibiotic, as well as the severity of the specific case of acute cholangitis.

Generally speaking, as regards community-acquired forms without severity grade, the schema is based on 3rd-generation cephalosporin (cefotaxime or ceftriaxone), associated with an anaerobic agent in cases involving biliary-enteric anastomosis. In initially severe, nosocomial or care-associated forms (including prostheses), preferred anti-microbial treatments include broad-spectrum cephalosporin (cefepime) or an association piperacillin + tazobactam, both of them associated with vancomycin and an anti-anaerobic in cases involving biliary-enteric anastomosis [START_REF] Gomi | Tokyo Guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis[END_REF][START_REF] Solomkin | Diagnosis and management of complicated intraabdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America[END_REF][START_REF]Société française d'anesthésie et. Antibiothérapie probabiliste des états septiques graves[END_REF]. These schemas require adaptation to local ecology and to patients' past history of infection and colonization (ESBL, vancomycin-resistant enterococcus (VRE), etc.). A synthesis of the different therapeutic schemas is proposed in Table 5. Given high rates of resistance, even in cases of community-acquired infections and, more broadly, the development of resistances, fluoroquinolones are not a recommended probabilistic antibiotic therapy. In any event, in order to reduce the risk of emergent multi-resistant organisms, antimicrobial therapy must be secondarily adapted to bacteriological test results.

In fact, the rationale for these associations revolves around a few fundamental issues. The first of these concerns the need to take anaerobes into account in probabilistic treatment, even though, due presumably to their low prevalence, the lnfectious Diseases Society of America (IDSA) and the TG 2018 did so only in the case of biliary-enteric anastomosis [START_REF] Gomi | Tokyo Guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis[END_REF][START_REF] Solomkin | Diagnosis and management of complicated intraabdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America[END_REF]. The second issue involves the debated pathogenicity of enterococci, which is supposed to be taken into account in empirical treatment only in the event of severe infection, a nosocomial context or immunosuppression [START_REF] Solomkin | Diagnosis and management of complicated intraabdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America[END_REF].

These recommendations should be compared to the results of a recent retrospective study on 573 episodes of acute bacterial cholangitis in two Japanese tertiary centers, where it was found that lack of coverage for enterococci and anaerobes was responsible for 30 and 8% respectively of the 133 cases in which anti-microbial therapy was inappropriate. However, more than 60% of acute cholangitis cases were care-associated or nosocomial, and a substantial proportion of them were serious episodes; 43% were grade III [START_REF] Tagashira | Impact of inadequate initial antimicrobial therapy on mortality in patients with bacteraemic cholangitis: a retrospective cohort study[END_REF]. At an individual level, the risk-benefit ratio of the addition of metronidazole, a molecule with few side effects when utilized for a short time period, remains under discussion with regard to non-severe community-acquired forms. Lastly, effective coverage of Pseudomonas aeruginosa, of which the prevalence is highly variable, seems indispensable in patients fulfilling severity criteria.

Biliary diffusion of antibiotics could represent a selection criterion in anti-microbial therapy; and justify preference of ceftriaxone to cefotaxime, notably in non-severe forms due to its bilio-digestive excretion. However, studies conducted since 1976 on different antibiotics have shown that bile duct obstruction drastically reduced the biliary diffusion of antibiotics. Even biliary excretion molecules are well below minimal inhibitory concentrations (MIC) in bile in cases involving bile duct obstruction [START_REF] Dhalluin-Venier | Effects of biliary obstruction on the penetration of ciprofloxacin and cefotaxime[END_REF][START_REF] Keighley | Antibiotics in biliary disease: the relative importance of antibiotic concentrations in the bile and serum[END_REF][START_REF] Leung | Antibiotics, biliary sepsis, and bile duct stones[END_REF]. These considerations open debate on the usefulness of choosing an antibiotic with satisfactory biliary diffusion and underline the crucial importance of bile duct drainage.

In the final analysis, it is the duration of antimicrobial therapy that is most debatable. The 2018 Tokyo Guidelines suggested 4 to 7 days after identification of the source of infection, except with regard to enterococci and streptococci, for which the recommended duration, due to a risk of endocarditis, is 2 weeks [START_REF] Gomi | Tokyo Guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis[END_REF]. However, the French Infectious Disease Society (SPILF) has proposed a reduction of anti-microbial therapy duration to 3 days, including in cases of bacteremia (with the notable exceptions of primary sclerosing cholangitis and liver transplant recipients) [START_REF] Wintenberger | Proposal for shorter antibiotic therapies[END_REF]. The above recommendations are based on two studies. The first, conducted by Kogure et al., was a singlecenter prospective study testing cessation of anti-microbial therapy once body temperature has been lower than 37°C for 24h after bile duct drainage; as regards the 18 patients included, among whom 17 presented with cholangiolithiasis, the median duration of anti-microbial therapy was 3 days without relapse over the following 4 weeks [START_REF] Kogure | Fever-based antibiotic therapy for acute cholangitis following successful endoscopic biliary drainage[END_REF]. The second was a single-center retrospective study of 80 patients comparing acute cholangitis relapse rates according to duration of anti-microbial therapy. The 41 patients having received anti-microbial therapy <3 days did not relapse more often after median 71-day follow-up compared to those having received 4-5 days or >5 days of treatment [START_REF] Van Lent | Duration of antibiotic therapy for cholangitis after successful endoscopic drainage of the biliary tract[END_REF].

To sum up, probabilistic anti-microbial therapy must be initiated immediately after hemoculture testing and consists in a beta-lactam antibiotic covering entero-bacteria, while anaerobic bacteria should probably be targeted only in cases involving biliary-enteric anastomosis, and enterococci only in contexts of nosocomial context, high severity, or immunodepression. Duration of 5 days following drainage appears sufficient.

b-Bile duct obstruction treatment

In cases of acute cholangitis, effective treatment of bile duct obstruction is of paramount importance. Post-surgical reflux cholangitis is an exception insofar as it generally does not necessitate drainage due to the fact that for all practical purposes, the bile has already been drained out [START_REF] Miura | Tokyo Guidelines 2018: initial management of acute biliary infection and flowchart for acute cholangitis[END_REF]. In all other cases, drainage is an essential means of avoiding septic shock, death and complications such as hepatic abscesses; it also optimizes the action of antibiotics. Several modalities may be envisioned: surgical treatment (nowadays exceptional due to its high morbi-mortality compared to endoscopic treatment) [START_REF] Lai | Endoscopic Biliary Drainage for Severe Acute Cholangitis[END_REF], endoscopic drainage during ERCP or EE through installation of a metallic or plastic prosthesis or a naso-biliary drain or, finally, percutaneous transhepatic biliary drainage.

As regards the general principles of biliary (bile duct) drainage, the current reference method is transpapillary biliary drainage during ERCP, either by placing a stent in the bile ducts, or by means of naso-biliary drainage; according to a meta-analysis carried out in TG 2018, efficacy of the two modalities is similar in terms of endoscopic and clinical success, adverse effects, and risk of "redo" operation [START_REF] Mukai | Indications and techniques of biliary drainage for acute cholangitis in updated Tokyo Guidelines 2018[END_REF]. Association with ERCP endoscopic sphincterotomy aimed at reducing occurrence of post-ERCP acute pancreatitis should not be systematic insofar as its benefits remain debatable ; moreover, sphincterotomy is a complicated procedure with severe hemorrhaging in 4 to 8% of relevant cases [START_REF] Hui | Does the Addition of Endoscopic Sphincterotomy to Stent Insertion Improve Drainage of the Bile Duct in Acute Suppurative Cholangitis?[END_REF][START_REF] Sugiyama | The benefits of endoscopic nasobiliary drainage without sphincterotomy for acute cholangitis[END_REF].

In the event of failure, percutaneous transhepatic or echo-endoscopic drainage (EE) is generally proposed. A recent meta-analysis (9 studies and 483 patients) showed better performances with EE (higher success rate and fewer complications), but these positive results should be readjusted due to probable bias in favor of EE [START_REF] Sharaiha | Efficacy and safety of EUS-guided biliary drainage in comparison with percutaneous biliary drainage when ERCP fails: a systematic review and metaanalysis[END_REF].

In clinical practice:

-In non-severe or moderate cholangiolithiasis, biliary drainage is not systematically called for. In fact, stone removal is recommended subsequent to endoscopic sphincterotomy, or else following balloon dilatation (in the event of hemostatic disorders or small-scale lithiasis); when associated with extraction maneuvers, these procedure often suffices to effectively eliminate the obstacle. In the event of failure and persistent lithiasis in the common bile duct, biliary drainage becomes necessary.

The naso-biliary drain is more frequently used in Asia than in Europe, where biliary endoprosthesis tends to be preferred on account of its relative simplicity.

-In cases of a large or multiple lithiases, and particularly in the event of vesicular lithiasis, treatment is two-stepped. First, biliary drainage is carried out according to the modalities described above; second, lithiasis extraction is performed after dilatation with a larger balloon (with or without sphincterotomy) during a second ERCP. Cholecystectomy is subsequently carried out [START_REF] Mukai | Indications and techniques of biliary drainage for acute cholangitis in updated Tokyo Guidelines 2018[END_REF].

-Non-lithiasic cholangitis (especially when secondary to neoplasia) necessitates ERCP with insertion of an endo-biliary prosthesis or a naso-biliary drain; while they are similarly effective, the latter can cause patient discomfort. It should also be noted that in two retrospective studies involving 118 and 128 patients respectively, in cases of hilar (Klatskin) tumor, endoscopic drainage by naso-biliary drain was found to be superior to drainage by biliary prosthesis, insofar as it occasioned fewer complications and/or "redo" operations [START_REF] Kawakubo | Lower incidence of complications in endoscopic nasobiliary drainage for hilar cholangiocarcinoma[END_REF][START_REF] Kawakami | Endoscopic nasobiliary drainage is the most suitable preoperative biliary drainage method in the management of patients with hilar cholangiocarcinoma[END_REF].

-If ERCP drainage fails, two options may be: (1) percutaneous drainage, possibly completed secondarily by endoscopic stent placement using the "rendezvous" procedure, which permits removal of external drainage or (2) EE, but only in cases of non-lithiasic origin) [START_REF] Calvo | The rendezvous technique for the treatment of choledocholithiasis[END_REF].

Choosing the optimal moment for biliary drainage is another, incompletely elucidated question of interest, even if early drainage appears primordial [START_REF] Xu | Early ERCP for severe cholangitis? Of course![END_REF]. A retrospective study on a large-scale sample (77323 patients) highlighted longer hospital stays and higher costs in the event of ERCP >48h [START_REF] Parikh | Outcomes Associated With Timing of ERCP in Acute Cholangitis Secondary to Choledocholithiasis[END_REF].

Furthermore, two prospective studies involving 199 and 166 patients showed in multivariate analysis that mortality risk was 3.6 times higher when ERCP was carried out after 72 hours and that early biliary drainage performed within 24h was a predictive factor of survival at 30 days (OR 0.23, CI95 [0.05-0.95]; P = 0.04 ) [START_REF] Hou | Optimal Timing of Endoscopic Retrograde Cholangiopancreatography in Acute Cholangitis[END_REF][START_REF] Tan | Association between early ERCP and mortality in patients with acute cholangitis[END_REF].

According to TG 2018, endoscopic treatment delay should be stratified according to cholangitis severity (cf. Table 3): -for grade I, it is envisaged only in the event of failed anti-microbial treatment; for grade 2, it is recommended early; for grade 3, it is recommended as a matter of urgency, without any precise indication of time lapse (in general in the literature, emergency surgical drainage takes place during the first 12-24 hours, and early drainage during the first 48 hours). However, this stratification necessitates validation, especially insofar as an initial study did not find a correlation according to degree of severity (except for grade 2) between survival and time elapsed prior to drainage [START_REF] Kiriyama | Clinical application and verification of the TG13 diagnostic and severity grading criteria for acute cholangitis: an international multicenter observational study[END_REF]. It also bears mentioning that in a retrospective study, it was suggested that some patients classified in grade I were actually in need of endoscopic drainage, a finding apparently in agreement with the data detailed above [START_REF] Nishino | Clinical evaluation of the Tokyo Guidelines 2013 for severity assessment of acute cholangitis[END_REF].

c-Treatment in particular cases

In cases of liver abscess of biliary origin subsequently associated with bile duct obstruction, treatment consists in anti-microbial therapy and biliary duct drainage associated to a greater or lesser extent with abscess drainage. Anti-microbial therapy need be adapted to identified germs; when relevant documentation is incomplete, anti-microbial therapy similar to the treatment proposed above, and in Table 5, for acute cholangitis, may be recommended, taking the two following particularities into close account: (1) since anaerobia represents 35 to 45% of the germs under consideration, systematic coverage can be justified; (2) treatment duration is prolonged: 4 weeks when the abscess is small-scale or drained, and 6 weeks without drainage, if radio-clinic evolution is favorable. Biliary drainage is carried out as described above, and percutaneous drainage or puncture aspiration of the abscess must be performed when size exceeds 5 cm [START_REF] Rossi | Abcès hépatiques[END_REF].

For patients with stenosis following digestive surgery, TG 2018 recommended ERCP assisted by balloon enteroscopy provided that experienced endoscopic surgeons are available; its success rate is high. If it fails or is impossible, percutaneous trans-hepatic approach should be proposed.

In patients suffering from primary sclerosing cholangitis, ERCP drainage is also indicated with balloon dilation of stenosis, and stenting need not necessarily be systematic. What matters in these cases is to eliminate the cholangio-carcinoma responsible for the stenosis; with this priority in mind, the diagnostic performances of cholangioscopy are superior to those of blind sampling [START_REF] Lindor | ACG Clinical Guideline: Primary Sclerosing Cholangitis[END_REF].

As concerns prevention of recurrent reflux cholangitis, to our knowledge up until now no study has validated medical treatment.

A simplified algorithm of cholangitis treatment is proposed in Figure 1.

6-Complications and prognosis

Notwithstanding improved treatment and management, acute cholangitis remains a severe disease with mean mortality at 30 days ranging according to series and in correlation with initial severity, from 2.6% to 5% [START_REF] Gomi | Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis[END_REF][START_REF] Kiriyama | Clinical application and verification of the TG13 diagnostic and severity grading criteria for acute cholangitis: an international multicenter observational study[END_REF][START_REF] Sun | Comparison of two editions of Tokyo guidelines for the management of acute cholangitis[END_REF]. While some single-center studies have reported different rates, recruitment bias is likely to have occurred, with the mortality rate partially depending on obstruction etiology. For example, Kiriyama et al. reported a mortality rate of 7.2% in conjunction with underlying neoplasia. While different factors explaining poor prognoses have been identified, they vary from one study to the next, some examples being organ dysfunction, hypoalbuminemia, intrahepatic obstruction [START_REF] Sun | Comparison of two editions of Tokyo guidelines for the management of acute cholangitis[END_REF], a Charlson score > 3 (reflecting major comorbidities), bilirubin > 42.5µmol/L, neoplastic obstruction or unsuitable initial anti-microbial therapy [START_REF] Tagashira | Impact of inadequate initial antimicrobial therapy on mortality in patients with bacteraemic cholangitis: a retrospective cohort study[END_REF]. And finally, even though assay is difficult to carry out in routine testing, a study has suggested that a low level of interleukin 7 associated with a high level of procalcitonin (>0.5 ng/mL) may be a predictive factor for mortality [START_REF] Suwa | IL-7 and procalcitonin are useful biomarkers in the comprehensive evaluation of the severity of acute cholangitis[END_REF].

Few complications of acute cholangitis are regularly reported. The main ones are: associated acute pancreatitis (especially in the case of lithiasic etiology; around 7.6% of cases in the series by Gomi et al [START_REF] Gomi | Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis[END_REF], septic shock (at least 4% of cases) and hepatic abscesses (2% to 2,5%) [START_REF] Gomi | Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis[END_REF][START_REF] Sun | Comparison of two editions of Tokyo guidelines for the management of acute cholangitis[END_REF]. Other complications occur less often: portal vein thrombosis [START_REF] Plessier | Acute portal vein thrombosis unrelated to cirrhosis: A prospective multicenter follow-up study[END_REF], or infectious endocarditis (very rare: up to 0.26%) [START_REF] Gomi | Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis[END_REF]. Just one case of bacterial meningitis has been reported [START_REF] Yamamoto | Severe Acute Cholangitis with Complications of Bacterial Meningitis Associated with Hearing Loss[END_REF].

Conclusions

Acute cholangitis remains a severe disease necessitating emergency multidisciplinary treatment associating anti-microbial therapy and biliary tract drainage. From a microbiological as well as an etiological standpoint, its epidemiology is subject to change and calls for regular and rigorous reassessment. Notwithstanding the existence of recommendations (Tokyo Guidelines), treatment and prognosis are closely connected with a patient's particularities (MRB colonization, biliary prosthesis, digestive surgical assemblies…), subjacent etiology, and a given center's availability of imagery and drainage techniques. A multidisciplinary management approach appears essential.

The authors have no ties of interest to declare.

Etiologies

Table 1 : Etiologies of acute cholangitis.

 1

	Frequency	References

Table 2 : TG2013/2018 diagnostic criteria

 2

	-Escherichia coli	35-62	31-44
	-Klebsiella spp.	12-28	9-20
	-Pseudomonas spp.	4-14	0.5-19
	-Enterobacter spp.	2-7	5-9
	-Citrobacter spp.	2-6
	-Acinetobacter spp.	3
	Gram-positive cocci
	-Enterococcus spp.	10-23	3-34
	-Streptococcus spp.	6-9	2-10
	-Staphylococcus spp.	2	0
	Anaerobia	1	4-20
	Others	17

. CRP: C reactive protein, ASAT: aspartate aminotransferase, ALAT: alanine aminotransferase, ULN: Upper limit of normal

Table 4 : Micro-organisms responsible for acute cholangitis. Adapted from Tokyo Guidelines 2018 Recommendations Community-acquired Presence of bilio-digestive anastomosis Care-associated or nosocomial (including post-ERCP) Without severity criterion With gravity criterion SFAR (2004) [45]

 4

	-Amoxicillin /clavulanic + gentamicin or netilmicin	-Piperacillin/tazobactam
	-Ticarcillin /clavulanic acid	-Imipenem
	-Piperacillin + Metronidazole	-Ceftazidime + Metronidazole
	-Cefoxitin	-In association with amikacin
	-Cefotaxime or Ceftriaxone + Metronidazole
	-With serious symptoms: association of gentamicin or
	netilmicin.

In association with metronidazole and vancomycin TG 2018 [39] Severity TG grade 1 Severity TG grade 2 Severity TG grade 3

  According to local ecology (<20% resistance) § Only for patients allergic to beta-lactam antibiotics or following antibiogram IDSA: Infectious Diseases Society of America; SFAR: Société Française d'Anesthésie et de Réanimation; IDSA: TG2018: Tokyo Guidelines 2018, See Table 3 for severity criteria

	-Cefazolin* or Cefotiam* or	-Ceftriaxone or Cefotaxime	-Piperacillin/tazobactam	-Piperacillin/tazobactam
	Cefuroxime* or Ceftriaxone or	Or Cefepime		-Cefepime or Ceftazidime	-Cefepime or Ceftazidime or
	Cefotaxime	Or Cefozopran		or Cefozopran	Cefozopran
	metronidazole if bilio-digestive	Or Ceftazidime		(+metronidazole if bilio-	(+ metronidazole if bilio-
	anastomosis)	(+ Metronidazole if bilio-	digestive anastomosis)	digestive anastomosis)
	-Cefmetazole*,	digestive anastomosis)		-Imipenem/cilastatin	-Imipenem/cilastatin
	-Cefoxitin*	-Cefoperazone/sulbactam		-Meropenem	-Meropenem
	-Flomoxef*	-Ertapenem		-Doripenem	-Doripenem
	-Cefoperazone/sulbactam	-	Ciprofloxacin	or	-Ertapenem	-Ertapenem
	-Ertapenem	levofloxacin or pazufloxacin	-Aztreonam	(+	-Aztreonam (+ metronidazole if
	-Ciprofloxacin or levofloxacin or	or moxifloxacin		metronidazole if bilio-	bilio-digestive anastomosis)
	pazufloxacin or moxifloxacin	(+ metronidazole if bilio-	digestive anastomosis)	-In	association	with
	Metronidazole if bilio-digestive	digestive anastomosis) §		-In	association	with	vancomycin
	anastomosis) §				vancomycin

*

Table 5 : Probabilistic anti-microbial therapy for acute cholangitis, as proposed in different recommendations.

 5

Grade

Germ

Hemoculture (%) Biliary cultures (%) • Bilio-digestive anastomosis ?

Gram negative bacilli

• Biliary duct dilatation?

• Biliary obstacle?

Operation necessary 3 days

Biliary retention

Emergency biliary draining

To be pursued 3 days after biliary drainage Remote treatment Nothing (Explorations if recurrence)

Curative treatment of obstacle


Kathlyne Dupuis Maurin

Chloé Girod

M.D Julia Lou Consolini

PhD Raoul Belzeaux

PhD Bruno Etain

PhD Barbara Cochet

Marion Leboyer

Catherine Genty

Lucie Gamon

Marie Christine Picot

PhD Philippe Courtet

Ph.D Emilie Olié
email: e-olie@chu-montpellier.fr

Use of a serious game to strengthen medication adherence in euthymic patients with bipolar disorder following a psychoeducational programme: A randomized controlled trial

Keywords: Serious game, bipolar disorder, psychoeducation, BIPOLIFE ®, medication adherence, psychosocial intervention

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

Introduction

More than 50% of patients with bipolar disorder (BP) do not take their medications as prescribed [START_REF] Leclerc | Determinants of adherence to treatment in bipolar disorder: a comprehensive review[END_REF]. Poor medication adherence is associated with a higher risk of mood recurrence, cognitive impairment, depressive residual symptoms, and suicidal acts, as well as increased use of mental healthcare and poorer quality of life [START_REF] Altman | Predictors of relapse in bipolar disorder: A review[END_REF][START_REF] Gonzalez-Pinto | Suicidal risk in bipolar I disorder patients and adherence to longterm lithium treatment[END_REF][START_REF] Gianfrancesco | Antipsychotic treatment adherence and associated mental health care use among individuals with bipolar disorder[END_REF], Martinez-Aran et al., 2009[START_REF] Belzeaux | Depressive residual symptoms are associated with lower adherence to medication in bipolar patients without substance use disorder: results from the FACE-BD cohort[END_REF][START_REF] Sparding | Cognitive functioning in clinically stable patients with bipolar disorder I and II[END_REF]. Psychoeducational programmes have been developed to improve medication adherence. Their short-term (i.e., just after programme completion) efficacy has been demonstrated (D 'Souza et al., 2010[START_REF] Javadpour | The impact of a simple individual psycho-education program on quality of life, rate of relapse and medication adherence in bipolar disorder patients[END_REF], but their positive effects seem to decrease in the long term. For instance, [START_REF] Eker | Effectiveness of six-week psychoeducation program on adherence of patients with bipolar affective disorder[END_REF] reported that 13% of patients who completed a psychoeducational programme were nonadherent 6 weeks later. [START_REF] Colom | A randomized trial on the efficacy of group psychoeducation in the prophylaxis of recurrences in bipolar patients whose disease is in remission[END_REF] found higher lithium but not valproate and carbamazepine plasma levels in patients enrolled in a psychoeducation programme compared with controls (no programme) at the 2-year follow-up visit. Conversely, at the 5-year visit, treatment adherence (on the basis of the patients' clinical assessment, first-degree relatives' interviews, and plasmatic dosages of mood stabilizers) was not different between patients in the psychoeducation programme and controls [START_REF] Colom | Group psychoeducation for stabilised bipolar disorders: 5-year outcome of a randomised clinical trial[END_REF]. Therefore, additional innovative tools should be developed to consolidate the psychoeducation programme positive effect on medication adherence because most of these programmes do not include booster sessions for maintaining the effects.

One potential strategy could be serious games. These are "interactive computer applications, with or without a significant hardware component, that have a challenging goal, are fun to play with, incorporate some concept of scoring, and impart in the user a skill, knowledge or attitude which can be applied in the real world" [START_REF] Bergeron | Appendix A: glossary. Developing serious games[END_REF]. Some serious games have been developed for psychiatric patients. For example, SPARX is an interactive fantasy game designed to deliver cognitive behavioural therapy for depression. Its use efficiently reduced depressive symptoms at the 3-month follow-up in depressed adolescents compared with patients treated as usual [START_REF] Merry | The effectiveness of SPARX, a computerised self help intervention for adolescents seeking help for depression: randomised controlled non-inferiority trial[END_REF]. In BD, it has been shown that using new technologies to provide complementary mental care is feasible and acceptable. For instance, the use of a mobile application to monitor thymic status and early warning signs after a psychoeducation programme can improve depressive symptoms. Moreover, the compliance to this application is good [START_REF] Depp | Augmenting psychoeducation with a mobile intervention for bipolar disorder: a randomized controlled trial[END_REF]. SIMPLE, a smartphone-based psychoeducation programme [START_REF] Hidalgo-Mazzei | Psychoeducation in bipolar disorder with a SIMPLe smartphone application: Feasibility, acceptability and satisfaction[END_REF], is another satisfactory and acceptable add-on instrument for BD self-management. Finally, MoodSwings 2.0, an internet-based self-management programme that includes psychoeducation and cognitive behavioural therapy, efficiently improved depressive symptoms in patients with BD with a good acceptability [START_REF] Gliddon | A randomized controlled trial of MoodSwings 2.0: An internet-based self-management program for bipolar disorder[END_REF].

Recently, AstraZeneca Pharmaceutics, in collaboration with Ubisoft, developed BIPOLIFE ® , a serious game (or edutainment tool) for patients with BD. This interactive tool gives information about BD and its management, and the influence of routine daily behaviours on mood. BIPOLIFE ® wants to highlight the importance of: 1/ adherence to medication, 2/ healthy lifestyle (regular sleep, physical activity, social contacts, and avoidance of alcohol and illicit substances), and 3/ visit to a psychiatrist in case of relapse.

We hypothesized that BIPOLIFE ® could be used as an additional tool to strengthen the immediate benefits of a psychoeducational programme on therapeutic adherence. To this aim, we carried out a randomized controlled study to compare compliance rate up to 4 months after completion of psychoeducation in patients using or not BIPOLIFE ® . Our secondary objectives were to assess modifications in beliefs/attitudes towards medications and BIPOLIFE ® acceptability.

Methods

Study design

This study was a prospective, open, randomized controlled trial, registered at clinicaltrials.gov (Clinical Trial ID#NCT02936466). Eligible participants were randomly assigned with a 1:1 ratio to connect to BIPOLIFE ® for 4 weeks as an add-on tool to their treatment, or to follow their treatment as usual (TAU). The randomization sequence was centralized and computed in blocks of four for each level of stratification by the study statistician in an order unknown by the investigators.

Population

Participants were recruited from the Departments of Psychiatry in three French Academic Hospitals (Montpellier, Marseille, and Créteil). Inclusion criteria were: older than 18 years of age; diagnosis of BD according to the DSM-IV TR; being euthymic, defined by a total Montgomery and Asberg Depression Rating Scale (MADRS) score <12, and Young Mania Rating Scale (YMRS) score <8 during the last 3 months; having completed a psychoeducation programme within the week preceding their inclusion; having attended more than half of the psychoeducation sessions; having access to internet; and being able to speak, read and understand French.

The psychoeducational program preceding the intervention was led by two trained caregivers (nurse, psychologist and / or psychiatrist) of the center. It was consisting of 12 weekly sessions of 90 min and included up to 12 patients (adapted from [START_REF] Colom | A randomized trial on the efficacy of group psychoeducation in the prophylaxis of recurrences in bipolar patients whose disease is in remission[END_REF]).

The primary outcome was the adherence rate, defined by a Medication Adherence Rating Scale (MARS) total score >7 [START_REF] Thompson | Reliability and validity of a new Medication Adherence Rating Scale (MARS) for the psychoses[END_REF][START_REF] Rosa | Validity and reliability of the Functioning Assessment Short Test (FAST) in bipolar disorder[END_REF] at the 4-month follow-up visit. Secondary outcomes were the variation of MARS adherence score, attitude toward psychiatric medications assessed using the Drug Attitude Inventory (DAI-10) [START_REF] Hogan | Subjective response to neuroleptics and outcome in schizophrenia: a re-examination comparing two measures[END_REF], and healthcare use between the inclusion and the 1-and 4-month follow-up visits. Moreover, the serious game acceptability and satisfaction were also investigated in the intervention group.

The study was conducted in accordance with the CONSORT ethical guidelines. All participants signed a written informed consent form. The study was approved by the Montpellier University Hospital (CPP Sud Mediterranée IV) ethics committee.

Treatment conditions and procedures

Serious game BIPOLIFE®

BIPOLIFE® is a gaming experience centred on an avatar who has BD and acts in a variety of everyday life situations. The objective is to learn how to regulate the avatar's mood and energy levels by making daily life choices. The player must balance mood and energy levels to reach a situation of euthymia.

First, patients choose a personalized avatar (gender, name, physical appearance). Then, during a tutorial, they discover the rooms of the house where the avatar lives and the possible interactions with the environment (Figure 1). The rooms represent the main domains of the patient's life. The living room stands for social life, the kitchen stands for personal health practices, the office stands for business/work, the bedroom stands for sleep, and the bathroom stands for hygiene/self-care. A clock helps to identify the time of actions during the day.

During the tutorial, the avatar gradually shows more manic symptoms, leading to hospitalization. Patients receive information on the characteristics of the manic and depressive phases, and advice on how to manage them by watching the psychiatrist and the avatar. Then, the serious game starts.

Patients have to drive their avatar through daily actions: eating, sleeping, taking medications, having fun, learning about BD, calling the psychiatrist or friends, avoiding alcohol/illicit substances, and practicing sports. Patients receive feedbacks ("bonus" or "malus" points) related to the consequences of their decisions on the avatar's mood and energy levels. The game is over when the patient manages to maintain the mood/energy balance for 3 consecutive virtual days. In addition to "bonus" or "malus" points, the computer provides messages to promote appropriate actions he/she could do. For example when the avatar is standing in the kitchen at a given period of the day, a message "you could have breakfast" may appear. In addition, the patient is invited to read short messages to learn about the consequences of given actions during the game. For example, the patient may have explanations about why practicing sport may be associated with bonus points during euthymia (i.e. to promote physical health) or malus points when the level of energy is high (i.e. symptom of mania).

Patients were asked to play how often and how long they wanted during the month following their inclusion. The frequency and mean duration of connection were rated by patients during the follow-up visits.

Treatment as usual (TAU)

TAU consisted of visits to the referral psychiatrist and the prescription of at least one mood stabilizer. The frequency of visits to the psychiatrist was not standardized; it was defined by the referral psychiatrist who was not systematically involved in the study. Patients could receive any additional pharmacological treatments or could follow any additional psychotherapeutic programs.

Assessments

Clinical assessments were carried out by trained psychologists or psychiatrists who remained blind to the group allocation. Participants were instructed not to communicate their group assignment. Three visits were planned: pre-intervention (inclusion) within the week following the completion of the psychoeducation programme, at 1 month after inclusion (at the end of the period of BIPOLIFE® use for the intervention group), and at 4 months after inclusion. Sociodemographic (sex, marital status, level of study, occupational status) and lifetime axis I diagnoses according to the DSM-IV using the MINI 5.00 [START_REF] Sheehan | The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10[END_REF] were recorded at inclusion. At inclusion and at each follow-up visit, clinicians assessed depressive and manic symptomatology using the MADRS [START_REF] Montgomery | A new depression scale designed to be sensitive to change[END_REF] and the YMRS questionnaires [START_REF] Young | A rating scale for mania: reliability, validity and sensitivity[END_REF], and global functioning using the Functioning Assessment Short Test (FAST) [START_REF] Rosa | Validity and reliability of the Functioning Assessment Short Test (FAST) in bipolar disorder[END_REF]. They also recorded the number of visits to a psychiatrist (scheduled/emergency/attended) and to the emergency department, and the number of hospitalizations for psychiatric reasons since the last visit, based on the patient's declarations.

Patients assessed their medication adherence using the MARS [START_REF] Thompson | Reliability and validity of a new Medication Adherence Rating Scale (MARS) for the psychoses[END_REF] and their beliefs on pharmacological treatments using the DAI-10 ( [START_REF] Hogan | Subjective response to neuroleptics and outcome in schizophrenia: a re-examination comparing two measures[END_REF].

Patients in the intervention group were asked to rate their satisfaction about the BIPOLIFE® game at the 1-month follow-up visit.

Statistical analysis

Baseline characteristics were described for each group using means and standard deviations (SD) or median and inter-quartile ranges (IQR) for continuous variables, and frequencies and proportions for categorical variables. The primary analysis was performed according to the intention to treat principle, and involved all patients for whom data on the primary outcome (MARS score) at inclusion and at the 1and 4-month follow-up visits were available (full analysis set).

Categorical data (primary and secondary outcomes) were compared using the chi-square test.

Continuous variables (total MARS, YMRS, FAST, DAI scores and their absolute variation between inclusion and follow-up visits) were compared between groups using the Student's ttest (in the case of normal distribution) or the Mann Whitney test. The bilateral significance threshold was set at 5%. The effect size was estimated with the Cohen's d. All analyses were performed with Statistical Analysis Software (SAS Institute, Cary, North Carolina).

Results

Participant flow

The participant flow is shown in Figure 2 : 43 patients signed the consent form; one patient had a manic relapse before randomization, and one patient withdrew the consent.

Therefore, 41 patients were randomized at inclusion.

In the BIPOLIFE ® group (n=20), one participant was lost to follow-up during the first month, and one between the 1-and 4-month follow-up visits. Another participant had a depressive relapse during the study period. Fifteen patients (75%) connected to BIPOLIFE during the first month (and five continued to connect afterwards). Ten participants (50%) completed the BIPOLIFE® game during the first month (i.e., maintained the avatar's mood/energy balance for 3 virtual days).

In the control group (TAU; n=21), only one participant was lost to follow-up between the 1-and 4-month follow-up visits.

In total, data were available for 41 participants at inclusion (after the psychoeducation programme), for 40 patients (98%) at the 1-month visit (end of the intervention), and for 37 patients (90%) at the 4-month visit.

Baseline characteristics (Table 1)

At inclusion, sex, marital status, education level, occupational status, BP type, current psychiatric comorbidities, BP duration, and number of hospitalizations for mental health reasons were not significantly different between groups. Antidepressant intake was more frequent in BIPOLIFE® than in TAU group.

Mood and global functioning during the study period (Table 2)

All patients (but one) remained euthymic during the study period. Depressive (MADRS score) and manic symptomatology (YMRS score) and global functioning (FAST score) were comparable between groups. The patients were euthymic according to MADRS and YMRS scores, with a mildly to moderately impaired global functioning according to FAST score.

Adherence and attitudes towards treatment (Table 3)

At inclusion, the percentage of patients with MARS score >7 was higher in the TAU than in the BIPOLIFE® group (90% vs. 40%, p= 0.02). The difference was no longer significant at the 1-month (68% vs 81%; p=0.36) and 4-months visits (80% vs. 53%; p=0.07).

Moreover, the absolute variation of the MARS and DAI scores was higher in the BIPOLIFE® than in the TAU group at the 1-month visit (p=0.03 and p=0.002, respectively) but not at the 4-month visit (p=0.22 and p=0.07, respectively).

The number of consultations with a psychiatrist (scheduled or in emergency) during the study period was not significantly different between groups (data not shown).

These results remained unchanged when considering per protocol analyses, i.e. only patients having declared at least one connection to BIPOLIFE ® during the first month vs. TAU group (data not shown).

Acceptability and satisfaction with BIPOLIFE® (Table 4)

For the BIPOLIFE ® group (N=19), the median frequency of connexion to BIPOLIFE® was once per week (min-max : 0-5) for a median duration of 60 minutes (minmax : 0-180) par week. Four participants declared no connexion to BIPOLIFE®. When considering only patients declaring a connexion to BIPOLIFE ® during the first month (N=15), the median number of connexion was 1.5 times (min-max : 0.5 -5) per week with a mean weekly duration of 90 minutes (min-max : 20 -180). Most participants said to be satisfied with BIPOLIFE®: 82% of participants found that the serious game content was informative and would be relevant to others, and 76% of participants thought that the information provided by the game was useful.

Discussion

Our study is the first to investigate the efficiency and acceptability of a serious game as an add-on psychoeducational tool in euthymic patients with BD. Our results suggest that the use of BIPOLIFE® after completing a psychoeducation programme improves medication adherence and attitudes towards medication at the 1-month, but not at the 4-month follow-up visit. Our results could be underestimated because three participants in the intervention group never connected to BIPOLIFE®. The serious game BIPOLIFE® may be an additional tool to propose to patients who have not reached adequate adherence after a conventional psychoeducational programme. While playing, the patient gradually learns to identify harmful actions that worsen mood and energy level, and also behaviours that promote mood balance.

Our results on medication adherence are not explained by different access/use of psychiatric care between groups during the follow-up. Interestingly, the attitude towards medications, which is positively associated with medication adherence [START_REF] Sharifi | The pattern of adherence in patients with bipolar I disorder; an eight weeks study[END_REF][START_REF] Levin | Medication Adherence in Patients with Bipolar Disorder: A Comprehensive Review[END_REF], was improved after the 1-month BIPOLIFE® intervention. Enhancing positive beliefs and attitudes towards treatment by playing BIPOLIFE® could contribute to strengthen medication adherence.

In our study, half of participants in the intervention group completed the BIPOLIFE® game (i.e. maintained the avatar's balance mood and energy for 3 consecutive virtual days). [START_REF] Lauder | A randomized head to head trial of MoodSwings.net.au: an Internet based self-help program for bipolar disorder[END_REF] found a similar rate of completion for online psychoeducation modules in patients with BD. This low completion may be explained by the age of our intervention group (46.58 ± 14.01 years) because older age decreases the odds of using internet [START_REF] Bauer | Internet use by patients with bipolar disorder: Results from an international multisite survey[END_REF]. It would be interesting to assess completion rate in younger patients with BD who are more at risk of poor compliance [START_REF] Baldessarini | Factors associated with treatment nonadherence among US bipolar disorder patients[END_REF][START_REF] Proudfoot | Effects of adjunctive peer support on perceptions of illness control and understanding in an online psychoeducation program for bipolar disorder: a randomised controlled trial[END_REF]. For example, [START_REF] Merry | The effectiveness of SPARX, a computerised self help intervention for adolescents seeking help for depression: randomised controlled non-inferiority trial[END_REF] found good adherence rates to SPARX ®, a serious game for depressed adolescents: 60% of participants completed the game.

Patients declared that BIPOLIFE ® was a satisfactory instrument to provide and consolidate psychoeducational messages. We previously conducted a pilot study to assess acceptability and feasibility of BIPOLIFE ® in euthymic BD patients with encouraging results [START_REF] Quintilla | Etude d'acceptabilité de Bipolife, serious game à l'attention de patients souffrant de trouble bipolaire[END_REF]. Among 63 consecutive bipolar patients, only 11% could not be enrolled in the study because of computer's defection or absence of access to internet. Moreover, all of patients reported to well understand information delivered by BIPOLIFE®.

The game may improve adherence through psychoeducational messages but also through the observation of the consequences of actions of avatar on mood and energy. Some patients reported that if helped them to realize how quality of lifestyle and treatment adherence are important to manage bipolar disorder. Other patients reported that it was important to test actions on avatar in order to observe what the consequences were. By contrast, patients criticized the limited number of possible actions leading the game be repetitive. Finally, some patients pointed out that BIPOLIFE ® did not seem appropriate to be a psychoeducational tool for relatives.

Previous studies showed that patients consider useful the availability of psycho-education programs for BD on internet [START_REF] Simon | An online recovery plan program: can peer coaching increase participation?[END_REF][START_REF] Proudfoot | Effects of adjunctive peer support on perceptions of illness control and understanding in an online psychoeducation program for bipolar disorder: a randomised controlled trial[END_REF][START_REF] Todd | A web-based self-management intervention for Bipolar Disorder 'living with bipolar': a feasibility randomised controlled trial[END_REF][START_REF] Barnes | A web-based preventive intervention program for bipolar disorder: outcome of a 12-months randomized controlled trial[END_REF][START_REF] Gliddon | A randomized controlled trial of MoodSwings 2.0: An internet-based self-management program for bipolar disorder[END_REF]. It could be interesting to develop a BIPOLIFE® version for tablets and smartphones because they are more frequently used than computers for serious games in mental health [START_REF] Lau | Serious Games for Mental Health: Are They Accessible, Feasible, and Effective? A Systematic Review and Metaanalysis[END_REF]. Moreover, the application format may help to increase BIPOLIFE® use over time. For instance, SIMPLE, a smartphone-based psychoeducational programme for BD, was still used by 74% of participants after 3 months [START_REF] Hidalgo-Mazzei | Psychoeducation in bipolar disorder with a SIMPLe smartphone application: Feasibility, acceptability and satisfaction[END_REF].

This study has some limitations. First, the sample size was small and may lack power to demonstrate an effect at 4 months. Second, BIPOLIFE® use was only declarative and not measured based on connexion data (e.g., frequency, duration). Participants declared to play BIPOLIFE ® on average once a week, with a connexion lasting for one hour, during the month following their inclusion. Patients declared to drastically reduce their rate of connexion during the follow up (5 patients connected to BIPOLIFE ® after the first month).It would be of great interest to define the minimal frequency or duration of connexion to have an improvement and to define a targeted population benefiting from such interventions.

Third, the limited and repetitive daily actions of the avatar may impair the motivation to regularly play to BIPOLIFE ®. To add other actions such as working, or having social contacts would make the game more playful and enhance patient's engagement [START_REF] Shah | Developing Digital Intervention Games for Mental Disorders: A Review[END_REF].

Fourth, medication adherence was only evaluated according to a self-report measure, which may overestimates medication adherence compared to objective measures [START_REF] Jonsdottir | Medication adherence in outpatients with severe mental disorders: relation between self-reports and serum level[END_REF]. WHO recommends to combine both subjective and objective measures (i.e. plasma levels or pill counts) [START_REF] Sabate | Adherence to long-term therapies: evidence for action[END_REF]. Fifth, our results are not fully generalizable because the study was only proposed to patients having completed more than 50% of the psychoeducation sessions.

Nevertheless, our results may encourage developing the use of add-on serious games to strengthen or maintain the effects of psychoeducation programmes.

Highlights

-Additional tools may help to maintain medication adherence after psychoeducational programmes -BIPOLIFE® a serious game centred on an avatar teaches how to regulate mood and energy in everyday life -BIPOLIFE® improves attitudes towards medications during the first month after a psychoeducation programme

Table 1

 1 Comparability of demographic and clinical variables between the two groups at inclusion

	BIPOLIFE ® (n=20) TAU (n=21)
	n (%)	n (%)

Table 2

 2 Mood state and Functioning during the study

		Post intervention (1 month)		Follow up (4 months)
		Bipolife®	TAU		Bipolife®	TAU
		mean (SD)	mean (SD)	p value*	mean (SD)	mean (SD)	p value*
	MADRS	4.42 (4.18)	5.71 (8.21)	0.87	5.18 (7.33)	6.05 (5.25)	0.24
	YMRS	2.00 (3)	1.33 (2.22)	0.63	1 (1.46)	2.4 (5.05)	0.91
	FAST	19.26 (7.87) 20.43 (9.89) 0.77	16.41 (9.8)	20.9 (8.94)	0.15
	*between group comparisons at each visit
	MADRS : Montgomery and Asberg Depression Rating Scale ; YMRS : Young Mania Rating Scale; FAST :
	Functioning Assessment Short Test

Table 2

 2 Mood state and Functioning during the studyFigure 1: Image showing a screen shot of the BIPOLIFE® serious game

		Post intervention (1 month)			Follow up (4 months)
		Bipolife®	TAU			Bipolife®		TAU
		mean (SD)	mean (SD)	p value*	mean (SD)	mean (SD)	p value*
	MADRS	4.42 (4.18)	5.71 (8.21)	0.87	5.18 (7.33)	6.05 (5.25)	0.24
	YMRS	2.00 (3)	1.33 (2.22)	0.63	1 (1.46)		2.4 (5.05)	0.91
	FAST	19.26 (7.87) 20.43 (9.89) 0.77	16.41 (9.8)	20.9 (8.94)	0.15
	*between group comparisons at each visit
	MADRS : Montgomery and Asberg Depression Rating Scale ; YMRS : Young Mania Rating Scale; FAST :
	Functioning Assessment Short Test
	Table 3
	Adherence and attitudes towards
	treatment
			Pre-			Post-			Post-
			intervention		intervention (1		intervention (4
			(inclusion)		month)			months)
			BIPOL	TAU		BIPOL	TAU		BIPOL	TAU
			IFE ®			IFE ®			IFE ®
			mean	mean	p	mean	mean	p	mean	mean	p
			(SD)	(SD)	valu	(SD)	(SD)	valu	(SD)	(SD)	valu
					e *			e *		e *
	Adherent	patients	11	19	0.02 13	17	0.36 9	16	0.07
	(MARS total score >7),	(60%)	(90%		(68%)	(80%		(53%)	(80%)

Acknowledgements

We thank Elisabetta Andermarcher for careful reading of the manuscript.

Astra Zeneca funded psychologists and clinical research associates. They did not intervene in the study design and data interpretation. This study has been funded by Astra Zeneca. All authors approved the final version of the manuscript.


Mario Serouart

MAIZE ARCHITECTURAL ADAPTATION IN INTRASPECIFIC COMPETITION

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Relative Distances Plasticity Index

Ranking species according to their plasticity

PLASTICITY«

  The ability of an organism to change its phenotype in response to different environments. » ] [ plasticity ] Wies G, Mantese AI, Casal JJ, Maddonni GÁ. Phytochrome B enhances plant growth, biomass and grain yield in field-grown maize. Ann Bot. 2019;123(6):1079-1088. doi:10.1093/aob/mcz015 Monzon JP, Tenorio FA, et al. Climate and agronomy, not genetics, underpin recent maize yield gains in favorable environments. Proceedings of the National Academy of Sciences of the United States of America. 2022 Jan;119(4). DOI: 10 .1073/pnas.2113629119. PMID: 35042796; PMCID: PMC8795556 Environments VG, VE, VGxE Chevin LM, Lande R, Mace GM . Adaptation, plasticity, and extinction in a changing environment: towards a predictive theory. Liu, Frédéric Baret, Mariem Abichou, Loïc Manceau, Bruno Andrieu, et al.. Importance of the description of light interception in crop growth models. Plant Physiology, American Society of Plant Biologists, 2021, 186 (2), pp.977-997. ff10.1093/plphys/kiab113ff. ffhal-03222455 Azimuth Angle R. Lopez-Lozano, Frédéric Baret, Michaël Chelle, N. Rochdi, M. España. Sensitivity of gap fraction to maize architectural characteristics based on 4D model simulations. Agricultural and Forest Meteorology, Elsevier Masson, 2007, 143 (3-4), pp.217-229. ⟨10. 1016/j.agrformet.2006.12. 005⟩. ⟨hal-01192023⟩ Etienne David. The challenge of robust trait estimates with Deep Learning on high resolution RGB images. Agronomy. Avignon Université, 2021. English. ⟨tel-03431192⟩ Atlin, Gary N.; Cairns, Jill E.; Das, Biswanath (2017). Rapid breeding and varietal replacement are critical to adaptation of cropping systems in the developing world a given level of the environment treatment • i' another given environment different from i.

  Valladares F, Sanchez-Gomez D, Zavala M a. (2006) Quantitative estimation of phenotypic plasticity: Bridging the gap between the evolutionary concept and its ecological applications. J Ecol 94 :1103-1116 . doi: 10.1111/j.1365-2745.2006.01176.x VERTICALITY GEODESIC EUCLIDEAN

PERSPECTIVES