 Introduction

The "Virulence Bactérienne et maladies Infectieuses" (Bacterial virulence and infectious diseases) unit is an INSERM unit (U 1047) affiliated to the University of Montpellier 1. This unit reunifies three entities with distinct research topics or themes, two of which being interested in fundamental microbiology (Brucella and Burkholderia), and one related to clinically-oriented research (diabetic foot ulcers). The AERES visit on site has been organized on January 30 th , 2014. The scientific program included an overall presentation of the unit by the unit director, describing its history and achievements as well as the past and future organization. This presentation was followed by 3 scientific presentations of the past activity and projects of the three main topics developed in the unit. The director of the unit presented the work of the Brucella group and the work on diabetic foot ulcers, while the work on the Burkholderia group was presented by the principal investigator in charge of this thematic. Additional meetings with (i) researchers with permanent positions (ii) PhD students and post-doctoral fellows, (iii) engineers, technicians and administrative staff and (iv) representatives of the Montpellier University and INSERM administrations were also organized.

History and geographical location of the unit

The U 1047 was created in its current form in 2011. The unit is attached to the Université Montpellier 1, and is located in the Nimes campus of the Faculté de Médecine and Nimes University Hospital.

Management team

The U 1047 unit is headed by Mr David O'CALLAGHAN, each research theme (or subgroup) being directed by a permanent researcher. The unit has no laboratory council per se but all the members of the unit participate to a weekly laboratory meeting in which information on the life of the unit are shared and discussed. 2  Assessment of the unit

Global assessment of the unit

The U 1047 unit is a small-size INSERM unit, associated with the Montpellier University and closely associated with the Nîmes hospital, a number of permanent researchers of the unit being PH (Practicien Hospitalier, Medical Doctor). The research is divided in three distinct themes: two fundamental research themes closely related (mechanisms involved in the virulence of Brucella and Burkholderia) combined with a clinically-oriented theme dedicated to Diabetic Foot Ulcers and Staphylococcus. There are a number of connections between the fundamental and clinical research but these connections might be strengthened by additional collaborative projects.

Although the general output of the unit in terms of publication and presentations at international meetings is good, there is clear imbalance between the three research themes. The fundamental research groups are well represented at international meetings and are well-known but the level of publication (both in terms of number of published articles and of impact) is low. By contrast, the clinical research group is publishing at a higher level but is less present at international meetings (apparently there is a focus on national meetings). In general, the atmosphere in the unit appears to be excellent. The unit has access to specialized equipment for developing their studies (biosafety L3 for work with the bacterial pathogens, fish tanks for the zebrafish model, access to clinical samples through the strong involvement of the clinicians at the hospital).

Strengths and Opportunities

The unit gathers a number of renowned scientists and medical doctors. Within the three themes, the research focusses on both the bacterial and the host side, which is a strength and helps to better understand the relationships and cross-talks during infection. Clinicians have direct access to samples from the hospital and the unit is well equipped with BS3 facility and fish tanks. A number of internal and external collaborations are already in place. Although the clinical theme seems a bit disconnected from the two other groups (which might be a weakness, see below), it is also a strength to have such a strong connection with the hospital (which may support the wish to keep the research on site rather than joining existing units in Montpellier) and to have complementary expertise.

The unit director has an excellent scientific network and is internationally well-known. One example of this is the fact that several members of the unit have been recently asked to write review papers and book chapters, which clearly indicates the acknowledged expertise by the scientific community. The expertise of the Director on Brucella has promoted the unit to host the reference center for Brucella and brucellosis (Centre National de Reference).

Weaknesses and Threats

The link between fundamental and clinical researches is not clear or insufficient. Although there is "Zebraclub" meeting, the relationships with other units in the Montpellier/Nîmes area are limited.

One threat is the lack of funding for the next couple of years as most public financing and industrial contracts have already come to an end. Although there is substantial funding from the INSERM and the University of Montpellier, external funding is unsecure.

The restriction from the French system (ANR, HDR, limited number of PhD students) is also an external threat and therefore the members should recruit abroad. As a consequence, only 3 PhD theses have been defended during the previous period and 4 are ongoing -which is not overwhelming. It is worthy to note that none of the unit members are part of the doctoral school council or participate in the selection committee for PhD fellowships. There is a clear need to be better connected with the University of Montpellier.

The number and impact of the publication is limited, especially for the two fundamental groups. For example, two of the PhD students who defended during the previous period published a single article (1 FEBS Open Bio as 1st author in 2012 for the first, 1 publication in J Infect Dis in 2012 as 3rd author for the second), while the third one did not get yet publication. A similar situation is found for the INSERM researcher in the Brucella group, who published one article since her arrival in the unit (last author in Microbes infect). Regarding visibility and attractivity, the clinical group (and to a lesser extent the Burkholderia group) should increase their international visibility.

Regarding the project proposed, there is clearly a lot of ideas but the focus is missing. This is particularly obvious for the Brucella group for which the future developments are simply unrealistic compared to the available manpower.

Recommendations

The committee recommends that a global and more integrated strategy is defined for the evolution of the unit in the coming years. This is particularly important to strengthen the links between the fundamental and clinical researchers, not only by increasing the discussions between members (it is clear that this already happens) but by developing collaborative projects.

The younger theme leaders should improve their visibility by participating to international conferences. Notably, the members of the Burkholderia theme should participate to more general meetings on cell biology to acquire expertise in this field and to improve their visibility and attractivity. Members of the clinical group are recommended to participate more actively to international meetings rather than being limited in the French or French-speaking area.

The productivity of the unit should be also improved by dedicating the available manpower to focussed lines of research. Raising funds to develop the team is also an important goal to achieve. The theme leaders are however aware of this and already postulated to financing agencies, but there is a critical need to be more aggressive on this, not only at the national level but also at European agencies.. The committee also encourages the unit to host more PhD students. This can be achieved by developing more connection with the University of Montpellier (higher involvement in the teaching activities, access to the Doctoral School council).

The projects are dedicated to understand the molecular basis underlying microbial infections, and therefore deal with both the bacterial and eukaryotic host sides. The unit should consider reinforcing the expertise on cell biology/immunology by attracting or recruiting talented young scientists. If this has already been done with the arrival of a PI, the committee encourages the unit to pursue this path to have equilibrated microbiology/cell microbiology/clinical experts.

 Detailed assessments Assessment of scientific quality and outputs

During the period under review the scientific output has been of good standard but no real breakthrough has been made (such as that deserving publication in high ranked general journals). This could be expected based on the relevance of the studied models and on the quality of the researchers gathered in this unit.

Taken together, the overall publication level of the unit could be considered as satisfactory. However, the heterogeneity is rather high. Clinical research produces a prominent part of the unit's publications. The publication level is situated between 5 and 10 publications per year (which represents an average of 1 publication per permanent researcher) and with impact factors situated, in average, between 2 and 6 (J Infect Dis, PLOS Pathogens, Blood, FEBS Lett, PLOS ONE, Clin Microbiol Inf, Diabetes Care, BMC Med, Infect Immun, J Bacteriol, Antimicrob Agent Chemother,…).

During the previous period, there was a good ability to raise funds (grants from ANR, FRM and VLM and funds from private companies). The European FP7 program was not a major funding source, although the unit director should consider this possibility based on his international recognition. The clinical research is not well funded by public agencies and does not seem to be overwhelmingly funded by the industry either. Although the overall funding was good, the future funding situation is unsecure as all the grants already finished.

Assessment of the unit's academic reputation and appeal

The unit director has an excellent networking and participates to a significant number of conferences. The international recognition is also indicated by the invitation to write reviews and book chapters (including as guest editor for an issue in Curr. Opin. Microbiol.). The leader of the Burkholderia team is well known in the field of secretion systems and starts to be recognized in the Burkholderia field (e.g., participation to the International Burkholderia cepacia Working Group) which is significant compared to the relatively limited number of years working on the topic. There is a need to participate to more general conferences related to bacterial pathogenesis to have a broader recognition. On the other hand, clinical scientists are much more often participating to national meetings and efforts should be made to increase the involvement of the members of this team at the international level.

Regarding academic attractivity, a relatively low number of theses have been defended during the past period, and a limited number of PhD students are currently working in the unit (with the exception of the Burkholderia team, see below). However, although this number seems limited, discussion with the representative of the doctoral school showed that the unit is doing well and that the number of PhD students is above average compared to other units belonging to the University of Montpellier. The attractivity for external PhDs or post-doctoral fellows is very low (except visitors involved in collaborative projects) and one may expect to see more foreign young researchers joining the unit with an increased participation to international meetings and with an increased publication rate.

The committee however recommends to develop more links with researchers in the Montpellier' area. It appears that a few connections already exist (such as the Zebrafish journal club) but these need to be strengthened. The unit has also connections with the Maison-Alfort veterinary institute.

Assessment of the unit's interaction with the social, economic and cultural environment

The unit has a strong link with the hospital of Nîmes, thanks to the clinical research, and has good interactions with private companies due to the health problems engendered by the bacterial models. A number of unit's members participate as experts for funding agencies or serve in Scientific Advisory Board of biotechnology companies. The unit hosts the National Reference Center for Brucellosis since 2012.

Assesment of the unit's organisation and life

The life and organization of the unit is excellent, and seems very democratic even though there is no laboratory council. Organizational, hygiene and safety, and strategic discussions are brought during the weekly seminar. All the questioned members of the unit felt that the organization is excellent and are very enthusiastic about working in this environment. Due to the isolation of the unit on the Nîmes campus in the Montpellier area, the interactions with other research units in Montpellier are rather limited. Maybe the unit should organize more regularly seminar series with invited speakers. A secretary position has been recently filled in by the INSERM. This was obviously an important requirement as the researchers of the unit were burden with administrative work. The unit is also supported by the Montpellier University, as shown by the recent obtainment of a permanent engineer position.

Assessment of the unit's involvement in training through research

The number of PhD students in the unit is rather limited. This is however partly due to the French system which limits the number of students (PhD per HDR, no PhD contract with ANR funding, lack of fund to pay trainees,…). As detailed above, it seems however that the number of PhD is above average compared to other units.

Although the members of the unit perform a significant level of teaching and/or are involved in several councils at the university, the unit is not strongly involved in leading licence or master degrees (with the exception of one PI). The committee recommends to the members of the unit to participate to the activities of the doctoral school (ED 168 Sciences Chimiques et Biologiques pour la Santé), such as being elected to the doctoral school council.

During the last years, the unit has been quite involved in training undergraduates (third year of Licence or ERASMUS), but this has been limited by the recent French laws regarding training periods.

Assessment of the five-year plan and strategy

The overall strategy is considered as good. Each theme will develop interesting studies but one may recommend to consolidate the links between fundamental and clinical researches. If the strategic goal of the unit is to foster translational research, one would expect more horizontal interactions between members of each team.

The projects are considered as good, although specific criticisms and recommendations will be developed below (prioritizing projects for the Brucella team, developing state-of-the-art techniques for the diabetic foot ulcer team).

Because of the recent developments toward the zebrafish model, there is a clear need to increase the overall cell biology expertise of the unit. The unit should therefore consider attracting or recruiting skilled young researchers with expertise in cell biology/immunology. This team develops projects on the Brucella genus. Among the current and future prospects, particular attention is paid on the Type IV secretion system (T4SS) and potential effectors delivered by this machinery, the analysis of Brucella genome sequences, the identification and function of small regulatory RNAs on the bacterial side, and the role of host proteins, such as CD98 or the v-ATPase, which are parasitized during Brucella infection, or the identification of host factors using large-scale RNA interference screens.

 Theme-by-theme analysis

Conclusion

 Summary:

The team, and more specifically the theme leader, is internationally recognized and highly respected in the Brucella field. The group has a long experience with this bacterium and the theme leader is extremely efficient in networking at both the national and international levels. The visibility of this subgroup is therefore high on the international scene, at least in the fields of Brucella, bacterial secretion systems and bacterial pathogenesis.

By contrast, the number of peer-reviewed publications during the previous period is rather low, considering the international visibility of the subgroup. Based on the scientific quality of the members of the subgroup, it is expected to publish more studies, and in higher impact journals.

Regarding the projects, the committee noticed that too many projects are developed. Although this reflects the fact that the leader has tons of ideas and that many areas on Brucella research need to be covered, the size of the team is currently not appropriate to follow all these projects efficiently. It would be probably better to focus on specific projects to ensure efficient publication rate rather than diluting the manpower and the efforts. As it stands, the feasibility of all these projects seems unrealistic and the manpower is not sufficient to be competitive on all these subjects. However, it is interesting that the second permanent scientist in the group, has the possibility to lead her own line of research.

 Strengths and Opportunities:

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The subgroup has excellent networking.

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The subgroup has a strong international recognition and expertise on Brucella. The recruitment of two permanent scientists (INSERM researcher and Engineer) has been achieved during the previous period.

-There is a complementary expertise between the subgroup members.

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The subgroup has developed up-to-date technologies.

 Weaknesses and threats :

-There is a limited number of publications.

-There are too many projects developed without sufficient manpower.

-There is a limited number of PhD students.

 Recommendations :

-The excellent networking of the theme leader should be actively pursued.

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The number of projects on the theme should be restricted to a limited line of studies. This diversity of projects is unsustainable, and the subgroup needs to focus much more. They must identify a selected number of topics and focus on these topics to ensure that they gain and maintain a niche and an international identity in the field. Importantly, this subgroup must focalize its activities to ensure it does not become outcompeted by other groups in the world. May be focusing on the relationship between T4SS and outer membrane vesicles, and on the host side (host specificity determinants, CD98) will be better, without putting too much effort (right now) on the OMIC and high-throughput (small RNA screen, RNAseq/proteome screens,…) approaches or on the T4SS effectors which is clearly a competitive field in absence of additional manpower.

-Strategies to secure future funding should be developed.

Theme 2 :

Burkholderia cepacia complex infections

Manager's name:

 Detailed assessments

This team is focused on the virulence of Burkholderia cenocepacia, an organism associated with diverse pathologies including cystic fibrosis. During the previous period, the activity of this group has been centered on the development of technological tools, such as the zebrafish model (transgenic reporter fishes, RNA interference and morpholinos, in situ and immune labeling) and the genetic engineering of Burkholderia.

 Summary :

The focus has been on the development of new tools. These recent technological developments have been very successful and although the publication and funding outputs are limited, the team has gained international recognition in the Burkholderia field as shown by the participation of group members to the meetings of the International Burkholderia cepacia Working Group (in fact the theme leader is organising the next meeting of this Working Group in Nimes in April 2014). Although the output is not yet very high, it is clear that these developments will lead to an increased activity in the near future and that the subgroup will benefit of these technologies to ask specific questions related to Burkholderia pathogenesis, both on the bacterial and host sides.

The subgroup has also been very successful for the recruitment of PhD students and has already started collaboration projects with other internationally-recognized Burkholderia groups worldwide. The quality of research is very good and is expected to grow thanks to the tools available. The level of publication remained low during this intermediate period but the new technologies should lead to important contributions in the future. The zebrafish research needs to be valorized, for exemple by increasing the participation to zebrafish-specific meetings or to general cell biology meetings, or by writing a review on this virulence model. These will allow to increase the visibility and the attractivity of the subgroup and of the theme leader.

It is interesting for this subgroup to develop both its own research projects and collaborative works with other laboratories interested on the zebrafish as a virulence model. However, the theme leader should be careful to restrict the number of collaborations or to maintain a balance between proper projects/collaborations to prevent becoming a technical facility.

The committee members were very enthusiastic on the technological developments and very optimistic regarding the fate of this subgroup.

 Strengths and Opportunities:

-Highly valuable technological tools have been developed in the recent years.

-Important, straightforward and focused projects are currently developed.

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The effort to develop state-of-the-art methodologies is pursued (e.g., flow cytometry coupled to RNA sequencing).

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The subgroup has a visibility in the Burkholderia field.

-Participation to the highly competitive Marie Curie ITN program has to be noticed.

 Weaknesses and Threats:

-There is a low level of publication but the outcome is expected to increase.

-Funding needs to be extended to maintain the research flow and follow up on the data in preparation.

-It is not clear whether the group has all the necessary expertise to tackle questions related to host innate immunity.

 Recommendations:

-Strategies to secure future funding should be developed.

-There is a need to increase the visibility and attractivity, notably on the zebrafish expertise.

subgroup should carefully examine future developments, and keep a good balance between independent research and facility-like technical/collaborative works.

-

The subgroup should consider attracting and recruiting a young researcher (long-term post-doctoral fellow or permanent position) with expertise on cell biology/immunology to strengthen the studies on the host.

Theme 3 :

Bacterial virulence and multidrug resistant bacteria

Manager's name: This subgroup is dedicated to understand the bases of the development of diabetic foot ulcers by identifying pathogens that play a role during the infection process, the role of phages/prophages in the attenuation of Staphylococcus aureus and the host responses triggered by the pathogens. The subgroup is mainly composed of medical personnel.

Conclusion  Summary:

The questions and the three main lines of research are relevant to better understand the infection processes complicating diabetic foot ulcers. The subgroup has performed very well during the previous period, including numerous publications, participation in several meetings and in cooperation networks. Although the local and national visibility is excellent, the team members deserve to be internationally recognized and this could be improved by increasing the participation to international, english-speaking, meetings.

 Strengths and Opportunities :

-There is a good local and national visibility on diabetic foot ulcer.

-Very good level of publication has been reached.

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The subgroup proposes straightforward and feasible clinical research projects (metagenomic approaches, rosa-like phages, host responses) that might turn to be useful for diagnosis and therapy.

-There is a pending patent.

-The subgroup has strong connections with the hospital of Nîmes.

 Weaknesses and Threats:

-The subgroup has low or inexisting participation to international, non-french speaking, meetings.

-The technology used for several projects is outdated (e.g., DGGE).

-Funding is rather low.

 Recommendations:

-The subgroup should increase the participation to international conferences.

-The subgroup should use or develop state-of-the-art technologies (e.g., deep sequencing instead of DGGE).

-Raising fund from the European community, participating to the EU H2020 framework program have to be envisioned. Tel (33) 4 66 02 81 46,Fax (33) 4 66 02 81 48, e-mail : david.ocallaghan@univ-montp1.fr

Nimes, 2nd April 2014

We thank the AERES evaluation committee for their report and recommendations. We have carefully considered the comments made during the visit and in the report and have already initiated plans for implementation of their suggestions in our research and management strategies. We appreciate the positive comments about our overall output (publications and international meetings) and overall strategy, and we are extremely pleased to find that our new scientific focus adopted four years ago with the creation of our new unite, towards a more cellular microbiology and immunology approach is well appreciated. We regret however to see that the written report concentrates on constructive criticism that seems to be aimed at helping us further improve some of the points that we believe are our strengths. The, sometimes contradictory, statements, that we will discuss point by point below, give a very negative feel to the report. The scientific quality and our exciting and innovative results that were presented in both the written report and during the visit are not mentioned in the report.

Specific points 1. Visibility

We are convinced that one of our strengths is our networking and national and international visibility. This is highlighted by the attraction of many (including foreign) PhD students, visitors and scientists from all over the world (at present we have almost 50% non-French lab members from 6 different nationalities), multiple invitations to speak at international meetings and workshops, organization of international meetings, participation in a European network and COST action etc. We therefore find it unfortunate that the report mentions at many occasions that we should improve our visibility, either in Montpellier, or at the international level. Although we do appreciate that differences exist between the three subgroups, and we will follow recommendations made by the committee to join more general meetings to enhance visibility at a more general level when possible, some of the comments seem in contradiction with the above average level of PhD students compared to groups in Montpellier (see below), the high numbers of visitors and foreign students, invitations at meetings etc. Interaction with groups and visibility in Montpellier. The report mentions that "due to the isolation of the unit on the Nîmes campus in the Montpellier area, the interactions with other research units in Montpellier are rather limited."

Although we are geographically separated from the main Montpellier campus, this has never been an obstacle for our local interactions. In fact, we have several scientific projects with groups in the Languedoc-Roussillon and Provence-Alpes-Côte-d'azur regions (Montpellier, Marseille, Marcoule and Nice), which may not have come out well during the visit, but are well-described in our report. This includes several shared PhD students financed by the foundation Méditerranée Infection on both fundamental and clinical projects. The clinical group works in close collaboration with clinicians and the microbiology laboratory at the CHU in Montpellier, as well as with other hospitals in the region and several projects in collaboration with URMITE in Marseille. They also have a very productive long standing collaboration with chemists at the Université Montpellier 2 which has been funded by ANR and EU FEDER grants. The fundamental groups have regular meetings, discussions and share tools with the groups in Montpellier working on intracellular pathogens (Brucella, Coxiella, Salmonella, Mycobacteria) and zebrafish (including, but not restricted to the Club Zebra) However our projects are often distinct and direct collaboration is not warranted. It is more logical and productive for us to establish collaborations with other groups throughout the world that offer expertise that is complementary to ours such as structural biologists in Lyon or proteome experts in Marcoule. In the past few years, we have applied for several joint projects with a group at the CPBS and two different groups at the IRD in Montpellier and with the CEA in Marcoule, unfortunately without positive outcome, and we are now applying for another joint PhD student project. Further, the laboratory leader is part of the animation committee of the 'Interactions Host Microorganism' network that assembles groups in the Languedoc-Roussillon region working on different aspects of interaction from infectious disease to symbiosis in humans, animals, invertebrates and plants. This network organizes an annual meeting giving a platform for scientists and students in the region to present their work to a diverse audience. We were also members of the 'Montpellier Infectious Disease' network and gave presentations at several of its meetings. Our invitations and participation in other networks, including the G-RREMI (Groupe Régional de Recherche en Microbiologie des Interactions in Lyon/Grenoble), and the 'Groupe de Recherche Pseudomonas', also shows visibility at the National level. The evaluation report suggested that 'maybe the unit should organize more regularly seminar series with invited speakers'. We have been organizing seminars for several years; they are either held in Nîmes (an example is a recent seminar series of renowned Montpellier scientists at the midterm meeting of our MC training network) as well as seminars from several scientists from the USA, or co-hosted with a group in Montpellier. As the committee recommends, we will continue with this programme, and try to increase the number of seminars. Finally one member of our unit is the co-leader of the Infectious Diseases group of the 'Pôle Rabelais', the new network that coordinates the teaching and research in Biology and Health in our University.

International

The report mentions that the international visibility of the clinical and to a lesser extent the Burkholderia research group should be improved, and we will follow the specific recommendations when possible (depending on financial and time constraints). While it is true that the majority of the presentations of the clinical team have been in French meetings, we would like to add that over the last 5 years they have presented data at 9 international meetings over Europe. The clinical team also has a strong international network of collaborators throughout Europe and the USA and hosts visiting scientists and PhD students. The leader of the group was one of the members of a short list which recently created the ESCMID study group on Staphylococci (ESGS). This clearly demonstrates the visibility of the group. The Burkholderia group is very active at the international level, and the lead scientist is well known in the type IV secretion field, the Brucella field, and Burkholderia community (in April 2014, we are hosting the 'International Burkholderia cepacia Working Group' meeting in Nîmes). Activity in the zebrafish disease field (participant in an ongoing European MC training network, and presentations by lab members at the annual international zebrafish disease model workshop), as well as an invitation to participate in a EU funded COST action leading to nomination as member of the Management Committee for France (as suppléant) in 2012, based on the development of the zebrafish model, show the international visibility also in this research area. The research group is indeed not strong in immunology, and recommendations made by the committee will be taken to heart.

Scientific project.

We are happy to see that the committee had no negative comments concerning the scientific quality of our projects. We do, however, agree with their comments that the Brucella project was unreasonably ambitious and does not have enough critical mass to be competitive on all of the aspects of the proposed project. Since our discussions on the day of the evaluation, we have taken their comments to heart and have redefined our priorities; we feel that this will allow us to be more productive. As suggested by the committee, we will re-focus on the areas for which we have the skills and the manpower, ie cellular microbiology of Brucella, with a focus on eukaryotic proteins involved and role of OMV. Also, the PI in this group, who has been developing their own research lines without any help since their arrival in the unit, is now in charge of a PhD student who's project will be developed in collaboration with a group in Marseille (Worldwide known for their expertise in Brucella cellular microbiology). This will strengthen the group of cell biology and will undoubtly lead to more publications in this field. The committee's report suggests that "The technology used for several projects is outdated (e.g., DGGE)" is a weakness for the clinical project. We think that there has been a misunderstanding; although we presented data using DGGE, in our project we are developing the use of new technologies such as next generation sequencing in our metagenomic studies as well as culturomics and metabolomics. This will be done in collaboration with the platforms in Marseille (URMITE).

Publications

Although fundamental projects usually require much more experimental time, and thus in general are "less productive" in terms of numbers of publications than clinical research, the committee correctly pointed out the misbalance between the number of publications of the fundamental and clinical aspects of the project. The fundamental projects are only now starting to harvest the fruits of the new projects developed over the past years. Since the project was submitted to the university in September, the fundamental teams have 3 more papers published, have submitted a further three and are working on several others The clinical team have submitted a further 14 manuscripts (3 accepted, 3 in revision) and are working on several others for submission in the next few months.

PhD students

At several points throughout the report it is repeated that the number of PhD students is too low, giving a negative impression of our ability to attract students. We find these comments confusingly contradictory:

Although the report acknowledges that this is partly described to be due to the French system "The number of PhD students in the unit is rather limited. This is however partly due to the French system which limits the number of students", the report also implies that this is related to limited visibility, and low involvement in the graduate school in Montpellier. "The committee also encourages the unit to host more PhD students. This can be achieved by developing more connection with the University of Montpellier (higher involvement in the teaching activities, access to the Doctoral School council". The number of PhD students in our research unit is above average compared to other labs in Montpellier: This was actually acknowledged by the committee 'However, although this number seems limited, discussion with the representative of the doctoral school showed that the unit is doing well and that the number of PhD students is above average compared to other units belonging to the University of Montpellier'. This clearly indicates that we are competitive with other research groups in Montpellier and also visible for the students that chose their projects based on a list of research topics. We agree with the committee that involvement in the ED is important. That is why, in contrast to what is mentioned in the report ("It is worthy to note that none of the unit members are part of the doctoral school council or participate in the selection committee for PhD fellowships"), two members of the laboratory were members (one as subcommittee president) of the ED Doctoral Concours in 2011, and will continue to do so in the next years. However, this being said, this would not improve our chances of more PhD students through the ED, since the students chose their topic. As additional information, in 2011 our laboratory obtained two of the total 14 PhD grants for the whole of the ED.

Limitations of the French system in number of PhD students, and the mode of acquisition of PhD students may indeed be low compared to other research laboratories abroad, and we appreciate the suggestions to attract foreign PhD students, which would help us to be more competitive at the international level. We do not agree with the comment that we are not attractive for such students because of low international visibility ("The attractivity for external PhDs or post-doctoral fellows is very low (except visitors involved in collaborative projects) and one may expect to see more foreign young researchers joining the unit with an increased participation to international meetings and with an increased publication rate."). The many international visitors including PhD students, for periods between 3-18 months in the different groups, are proof of our international visibility. A small correction concerning the number of PhD students in 2015; one PhD student for the Burkholderia project, one for the Brucella project and 2 for the clinical project. At present we have 5 PhD students registered at UM1 and a student from Portugal on a long term visit. The committee commented that three PhDs defended in recent years was 'not overwhelming'. It should be remembered that two of the scientists in the group have only recently obtained their HDR.

The report also suggested that we should improve our implication in the Masters Programme. Several members of the laboratory do participate in teaching of the Masters programme, and we also propose research projects for M1 students (we do not have funds to cover the Gratifications de Stage for M2 students). However, for safety reasons, we do not allow Masters students to work on Brucella. More importantly, one member of the Unite directs the BIOTIN specialty in the regional biology-health Masters programme and is also setting up an 'Innovation Week' for PhD students in the doctoral school in collaboration with INSERM-Transfert and the pole 'Entrepreneuriat-Emploie', and is contributing to different European Innovative training Networks. As a previous director of the Université de Nîmes, he is still the head of both the biology and biotechnology bachelor's degrees allowing the introduction of many students for training in the lab at an early stage of their education. It also opens the possibility of affecting an ATER position in the unit.

Funding

Our laboratory has a very strong record for its number of permanent scientists in attracting financial aid and participating in national and international programmes, including ANR, VLM, FRM, and European grants (Marie Curie ITN, Erasmus). The report pointed out the fact that our ANR funding has finished. Unfortunately the two ANR projects, and a Marie-Curie IIF grant we submitted recently were not successful. The reducing pool of ANR funds is a problem affecting the whole scientific community in France. We will continue with our requests. The report also suggested that we should pursue the EU as a funding source. We hope our participation in a European Marie Curie ITN that finances one PhD student, our implication in a European COST action (BM1003), and Erasmus programmes, will be in our advantage in our quest for financing in the Horizon 2020 programmes, depending on appropriate call topics being open. We will follow the advice of the committee to be more aggressive with this, including seeking financial support outside Europe. We are very surprised that the report suggests that the clinical work is poorly funded, as we discussed this point with the committee. Although there is little funding through public funding such sources such as the ANR, ALL of the research projects that were described in the written document and during the site visit are fully funded through clinical research projects from the CHU Nîmes (PHRC and AOI), which has a very active policy in funding research and through industrial contracts.

6 Assessment of the unit's interaction with the social, economic and cultural environment The report has under represented our interaction with the social, economic and cultural environment. Other than our strong interaction with the CHU, strong implication in teaching in the University of Nimes, in the Montpellier 1 university, at the Ecole de l'ADN (one member of the team has founded this school with its network of 12 schools in Europe and Canada, and he is still his president) and local lycees, we would also like to point out the implication in the Eurobiomed Pole de Competitivite. One of the members of the Unite is general secretary, member of the board and responsible for the 'Emploi/Formation' group of the pole acting to professionalize student of our universities. This is providing an easy access to 250 members including 170 companies located in the south east of France and reinforce links between academics and private companies. This will also permit us, via the local CHU and the Nîmes and Montpellier 1 universities, to become an active partner of the DigiHealth biodiagnostic platform (ex CR2i) obtained by Eurobiomed from "Grand Emprunt" sourcing and also dedicated to infectiology.

Interaction within the laboratory

The committee has recommended that we strengthen the links between the fundamental and clinical sub-groups. "The committee recommends that a global and more integrated strategy is defined for the evolution of the unit in the coming years. This is particularly important to strengthen the links between the fundamental and clinical researchers, not only by increasing the discussions between members (it is clear that this already happens) but by developing collaborative projects."

We agree with the committee that these interactions are one of the major strengths of our group. As pointed out by the committee, these connections do exist, as shown by several publications where scientists from different sub-groups are co-authors (Microbes Infect. 2013 ; PLoS One. 2012 ; Int Urogynecol J. 2011) with other publications in preparation. These interactions will be strengthened in future projects by more involvement of the fundamental scientists in the several aspects of the projects of the PhD students (Staphylococcus-cell interactions; effects of phage on S. aureus virulence and iron metabolism; effects of antibiotic resistance on virulence using zebrafish models). The clinical and fundamental scientist will also work together in several projects around the CNR Brucella.

  spent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) taken 3 Qualified research supervisors (with an HDR) or similar positions 5 5

  David O'Callaghan Ph.D Director INSERM U1047, Université Montpellier 1.

5 

 5 Conduct of the visit

	6
	Visit date:
	Start:	January 30 th 2014 at 9:00 am
	End:	January 30 th 2014 at 5:00 pm
	Visit site:	U 1047
	Institution:	UFR Médecine
	Address:	186 Chemin du Carreau de Lanes, 30908 Nîmes Cedex 2
	Conduct or programme of visit:
	AERES Scientific delegate: Ms Sophie de BENTZMANN
	Expert committee: Mr Eric CASCALES (Chair), Ms Marie-Cécile PLOY (INSERM CSS7), Mr Tom COENYE, Mr Jean-
	Jacques LETESSON, Mr Philippe MOREILLON, Ms Astrid van der SAR
	9:00-9:15 am	Presentation of AERES visit philosophy and of expert committee by the AERES scientific
		deputy
	9:15-10:15 am	Presentation of the unit, past activities
	10:15-11:00 am	Presentation of the unit, projects
	11:00-11:15 am	Break
	11:15-11:45 am	Meeting with technical staffs and non-permanents, and permanent researchers
	11:50-12:10 pm	Meeting with the director
	12:10-12:30 pm	Meeting with the supervising institutions and bodies
	12:30-1:45 pm	Lunch
	1:45-4:45 pm	Closed meeting of the committee
	5:00 pm	End of the visit

 Supervising bodies' general comments Dr David O'Callaghan, INSERM U1047, UFR Médecine, 186 Chemin du Carreau de Lanes, 30900 Nîmes, France.


 Introduction History and geographical location of the unit

The research group U 1061 was established in 2003 (E 361 then U 888) within La Colombière University Psychiatric Hospital thus facilitating collaboration between Inserm researchers, engineers and technicians with clinicians and academic staff from the university departments of Psychiatry, Neurology, Neuroradiology and Biochemistry in order to develop neuropsychiatric research in the Montpellier region. U 1061 is housed within a separate pavilion in the hospital grounds within easy access to all psychiatric departments and the nearby neurology hospital Gui de Chauliac, where the unit has a clinical suite for examinations carried out in the context of population studies.

Management team

The direction of the unit and its mode of functioning are determined by the director in collaboration with the unit Advisory Council, comprising the director and administrative assistant, leaders of each research theme, a representative of the technical/engineering staff, the health and hygiene officer, and a student representative. Following discussion by the unit's scientific Council, two associate directors will be appointed for the next five years; Dr Marie-Laure ANCELIN (DR2 Inserm) and Pr Sebastien GUILLAUME (PUPH, Department of Psychiatry). The unit, located in a hospital is composed of a single very productive team divided into 4 subthemes interacting in a very attractive mode. The combination of physicians trained in the unit and INSERM researchers give a lot of coherence to the project, as well as to the established connections with both psychiatric and neurological hospitals. The support from the university is obvious and very probably related to their outstanding and original scientifc production. The main themes (affective disorders, suicide, ageing cognitive disorders, sleep) are treated with a translational approach from cohorts to clinical trials. The research strategy is very original and give a unique national and international dimension to the unit.

AERES nomenclature

SVE1_LS5

Unit workforce

Unit workforce

Strengths and opportunities related to the context

The unit provides a multidisciplinary and synergistic approach to important neuropsychiatric health problems in an ageing society (i.e. depression, suicide, dementia, sleep disorders). Rather than just concentrating on descriptive and epidemiological methodology, the unit engages in truly translational research, providing the skills and knowledge to translate biological and epidemiological findings into improvements in health and social care. The unit impresses by its high international competitiveness and its academic excellence.

Weaknesses and threats related to the context

This ambitious program relies on a steady supply of data from long-term high quality cohorts. Retirement vacancies, if unfilled, may weaken the technical support of the unit in the near future.

The unit lacks engineers and research assistants.

Recommendation

Reinforce links with neuroimaging (post-processing of data) and biology (perhaps by creating a CRB in the hospital and university). Promote the emergence of new teams (ATIP or AVENIR) to anticipate retirement of researchers. Focus on main fields of expertise: late life depression, cognitive impairment and sleep disorders. This may require access to younger cohorts, as causes of late life ill-health may be found in early to mid-life.

 Detailed assessments

Assessment of scientific quality and outputs

The scientific production of the Inserm unit is outstanding with 737 papers published in the last 5 years, 38 of them in journals with impact factors above 10, and 154 above 5. The main findings of the unit are:

1) late onset depression and anxiety disorders constitute separate clinical sub-types;

2) adult suicidal behaviour is mediated by genetic vulnerability, childhood trauma exposure and impaired decision making;

3) risk factors for dementia are gender specific; 4) excessive daytime sleepiness and hypersomnia are related to high mental health risks.

The overall assessment of the unit programme is excellent in both quality and volume of production.

Assessment of the unit's academic reputation and appeal

The unit and several of its researchers have close interactions with the Royal College, the University of Melbourne or the University of Stanford. Researchers are members of the following advisory boards: Institut National de Veille Sanitaire, Haute Autorité de la Santé, MRC UK. 10 national and international conferences have been organised by researchers of the unit.

The unit director is a Member of the MRC steering committee on Biomedical Research and the MRC Lifelong Health unit (London UK), a Member of the Scientific Advisory Board of the Alzheimer's Research Trust, UK, as well as of the Institut de Veille Sanitaire One researcher is co-chair of the consortium EURECA (EUropean REsearch CArtel -Suicide) for genetic research on suicidal behaviour and the suicide network promoted by the European College of Neuropsychopharmacology (ECNP) Three researchers are members of the suicide task force of the World Federation of Societies of Biological Psychiatry.

One researcher is a Member of the national committee of Registries Inserm-Invs (2003-2013), a member of the scientific advisory board of the Institut National de Veille Sanitaire (Invs), president of the commission on Chronic Diseases of the High Council in Public Health (HCSP, Ministry of Health), and piloted the evaluation of a national health strategic plan.

A European Narcolepsy Network was also established in 2008. One researcher is a member of the board of EU-NN.

Since 2007, one researcher has been a member of the scientific board of the French Sleep Medicine and Research Society, a member of the European Sleep Research Society, International REM sleep behaviour study group, and of the American Academy of Sleep Medicine Several researchers are member of editorial boards of scientific journals.

Many post docs have been hosted by the unit and several researchers participated in FP 7 grants demonstrating their international impact.

Assessment of the unit's interaction with the social, economic and cultural environment Many members have participated in radio and TV programs, many articles have been written in French and international newspapers.

Many events have been organized with scientific societies and patient groups (la journée du sommeil, la semaine du cerveau, réunions de prévention du suicide).

Researchers participate in Alzheimer and rare disease plans. Researchers also advise the French drug agency (ANSM) on the risks of vaccination and the occurrence of narcolepsy.

All subtheme leaders have contracts with the pharmaceutical industry to test drugs in neurological and mental disorders. Some of the theme leaders are members of advisory boards of pharmaceutical groups. Projects are about "Sclerostin and DKK-1 on bone formation in anorexia nervosa" and "neuroanatomical bases of moral pain in depression and suicidal behaviour", about "Psycho-education in bipolar disorder" and about sleep research. Subtheme leader also participate to clinical trials with various pharmaceutical companies.

Assessment of the unit's organisation and life

The unit is based on strong interactions between epidemiological and clinical research with a transverse structure (biostatistical platform) to help interactions between groups and interface between university hospital medical staff and researchers. It also combines two major themes integrating psychiatric and neurological disorders (depression, suicidal behaviours, cognition, ageing, sleep). We noticed a strong collegiality between members regarding decisions but also intense scientific interactions when conducting projects. There are strong exchanges between the hospitals and the research unit and many professors running the clinical departments have being trained and work also in the unit as researchers.

The direction of the unit and its operating mode are determined by the director in collaboration with the unit advisory council, comprising the director and administrative assistant, leaders of each research theme, a representative of the technical/engineering staff, the health and hygiene officer and a student representative. Scientific or interpersonal difficulties experienced by individual members of the unit are discussed firstly with a member of the council and, if unresolved, are brought to the next council meeting (approximately every three months). Two-monthly unit meetings are followed by a scientific presentation, alternating regional, national and international speakers. All doctoral and post-doctoral students are required to present their work to the unit at least once before submission. The council requires all doctoral students and their supervisors to sign and adhere to a doctoral supervision agreement in order to assure an optimal environment for post-graduate study.

Assessment of the unit's involvement in training through research

The unit, which is mainly attached to the graduate school CBS2 n°168, organizes frequent seminars covering the different themes of the unit. The summer school helps training students in research methods in psychiatry. Researchers participate to teaching in the context of national diplomas (diplômes inter-universitaires). Members of the unit participate to training courses abroad (Switzerland, Australia).

Many physicans did their PhD in the unit and then becam professor of medicine will help significantly the transfert of training from the unit to the medical school.

Assessment of the strategy and the five-year plan

The project is clearly based on translational and synergistic approaches combining both epidemiological and clinical research. By using such a strategy, physiopathology is a relevant step to design new tests and interventional techniques, thereby improving health in depression, suicidal behaviours and neurological/cognitive disorders. The combination of genetic, biological and environmental risk factors to explain neuropsychiatric disorders opens very promising perspectives. Increasing the age range of the population and subjects studied is also a key element to interpret time or life experience components to explain risk factors. The relationship with sleep research will bring new insights in the role of sleep and sleep disorders in the occurrence of mental and neurological disorders. It is also worth noticing a strong involvement of both hospital and university in the setup of the research programmes. The present theme aims at better understanding the role of various contributing factors related to gene malfunctions primarily based on gene-gene or gene-environment interactions that are supposed to be play a major role in either deregulation of the hypothalamic-pituitary-adrenal axis (HPA axis) or disruption of neurogenesis, neuroprotection in affective disorders of the elderly patients. This topic is of great interest regarding the high prevalence of mood disorders in the general elderly population, who has been exposed to negative life events across their life span. Relationships with other potentially significant markers centred on sleep and brain morphological disturbances will also be explored. To date, this is the first time that the role of genetic and epigenetic determinants of affective disorders among a large population of aging patients is studied, including the putative link with certain physiological and anatomical impairments, by adopting a promising, innovative and integrative neuroscience approach. Also, there is a piece of translational research carried out in both human and laboratory animal models on the importance of stress-related inflammatory and neuroendocrine markers along with anatomical or functional modifications that are implied in the propensity to develop post-traumatic stress disorder (PTSD) and in the prediction of treatment responses and prognosis, thereby addressing relevant scientific questions, that are still relatively unanswered, although representing a crucial issue in the clinical context.

Researchers working on the present theme have been authors or co-authors of many articles (largely >100) whose 18 in journals with high impact factor ranging from 36 to 8, particularly including Nature Genetics, Lancet Neurology, Plos Medicine, the American Journal of Psychiatry, etc., while 84 others have been approved for publication in journal of impact factor comprising between 8 and 4. This is perfectly indicative of a sustained and intensive research productivity of very high scientific quality giving important new insights in the understanding of ageing-related pathologies.

Assessment of the theme's academic reputation and appeal

The present research team comprises internationally recognized experts in the field of dementia and affective disorders, who work on large cohorts of elderly patients, with an emphasis on the role of interactions between environmental and biological factors, as mechanisms of vulnerability. They are members of collaborative networks combining national and international research teams. They received numerous financial and institutional supports from ANR, PHRC or AOI, as well as prizes and distinctions, attesting to a leadership position beyond the national level. Finally, the internationally attractive status of the researchers working on the present theme is attested by foreign post-doctoral student (n=1) [financial support from: I) Foundation FondaMental, France (2010); II) the National Health and Medical Research Council (NHMRC), Australia (2011Australia ( -2015))] or academic colleagues (n=2) who have joined the group for a specified period of time.

Assessment of the theme's interaction with the social, economic and cultural environment

This research team is involved in the organization of symposia/conferences during the French "Semaine du cerveau" or the "Nuit des chercheurs". Researchers have been invited to participate in either television or radio interviews and to write several general articles that summarized major neuroscientific findings and printed in both French and international newspapers with high reader levels.

Assessment of the theme's organisation and life

Beyond the extended international collaborations mentioned previously (cf. overall unit assessment), strong partnerships exist with: I) theme 2 for the assessment of suicidal behaviours; II) theme 3 for the determination of structural brain abnormalities; III) theme 4 for the evaluation of sleep disturbances in the aging population; IV) the Academic Department of Adult Psychiatry in the "La Colombière" Psychiatric University Hospital for the recruitment of older patients, as target populations for the present theme; V) the Institute of Functional Genomics in Montpellier.

However, the incorporation of neuroimagers and geneticists within the unit, who would be familiar with the structural/functional neuroimaging and genetics in the specific field of psychiatric disorders respectively, could be of significant benefit by improving even more the projects' progress, data management and analysis.

Assessment of the theme's involvement in training through research

Among the two Ph.D. students who are actually hosted, one is an ophthalmologist occupying the current position of "Chef de Clinique-Assistant" at the interface academic hospital/Montpellier University. He is highly involved in a comprehensive eye examination for the detection of vision impairments in the selected research participants. The other one originating from China recently joined the research theme and participates in the scientific projects that are actually performed in ageing patients. Researchers affiliated to this research ensure a sustained supervision of their respective students during weekly regular meetings within the unit. Otherwise, they are implicated in several teaching programs that have been developed by the unit or organized in collaboration with international and institutional partners.

Assessment of the five-year plan and strategy

The scientific project related to theme 1 primarily aims at identifying genetic, epigenetic, physiological, neuroendocrine and structural markers that are supposed to substantially increase the risk for affective disorders in ageing patients on the basis of the stress-vulnerability model. Particular attention is paid to the genetic vulnerability with the determination of the candidate genes that could be strongly implicated in disturbances of the major stress response biological system HPA axis in elderly patients. Epigenetic mechanisms related to the methylation of the promoter regions of several genes involved in the glucocorticoid receptor expression, neurogenesis/neuroprotection are also studied. Relationships with either sleep disturbances or brain morphological abnormalities will also be examined. Also, another part of the present project is devoted to: I) the identification of biological markers of vulnerability for PTSD, course and treatment responses, which are associated with the peripheral metabolism, neuroinflammation or brain functioning; II) the impact of psychiatric conditions and associated treatments on the mortality and the physical activity in elderly patients.

Beyond the relevance of the topic, the quality of collaborative interactions is also one of the strongest points of the project with the participation of transnational research teams (including themes 2, 3 and 4 developed in the unit) that have complementary fields of expertise in perfect alignment with aims and methodological considerations. This is a critical issue that makes the project clearly feasible over the next 5-year contract.

Conclusion

 Overall opinion of the theme:

The research theme focused on the determination of clinical, genetic or biological factors implied in the pathophysiology of either late-onset mood disorders or post-traumatic stress disorder, which can be considered as putative markers predicting either the occurrence, relapse/recurrence or treatment responses. This research topic is overall interesting because such pathologies are well known to be highly prevalent in the general population, and therefore considered as serious public health problems. This project could thus increase our current knowledge about the biological substrates known to play a role in late-onset mood disorders or PTSD that might further become target for the development of novel therapeutic strategies in such pathological conditions.

 Strengths and opportunities:

-topic related to major depression in the elderly or post traumatic stress disorder, as major public health issues;

-methodological approach combining a wide range of experimental tools for the identification of genetic, biological and anatomic and functional markers of the vulnerability for these pathological conditions; -large cohorts with the recruitment of patients, which is enabled by the active collaboration with clinicians at the University Hospital in Montpellier; -active participation in large and international collaborative networks.

 Weaknesses and threats:

Absence of neuroimagers or geneticists familiar with the problematic of psychiatric disorders.

 Recommendations:

Attraction of neuroimagers or geneticists useful for the management and treatment of genetic or neuroimaging data.

Theme 2:

Suicidal behaviour Manager's name: The present research theme is focused on the cognitive, emotional and biological markers that are supposed to play a pivotal position in the determination of recurrent suicidal behaviours. This is an important issue in public health because of the high frequency of suicidal attempts that further increase the risk for death from suicide in the general population. This research could also contribute to substantially improve the nature of clinical interventions that could be adopted in order to reduce suicide attempts and therefore to prevent completed suicides. The methodological strategy combining genetic, epigenetic or molecular approaches intending to examine either several gene-gene or gene-environment interactions with the possible role of early life traumatic events is perfectly adapted to the objectives of the present project. Additionally, the use of functional neuroimaging techniques coupled with appropriate instrumental tasks is of particular relevance for assessing the importance of an impairment of decision making, emotional disturbances with the identification of brain regions of interest in suicidal behaviours. To our knowledge, this is the first time that the putative role of interactions genes-genes and gene-environment as well as cognitive and emotional factors are precisely examined with the attempt to better understand the pathophysiology of suicidal behaviours.

Researchers focusing their work on suicidal behaviours have several articles (n=6) in journals with high impact factor (ranging from 16 to 8), such as Plos Medicine, the American Journal of Psychiatry or Biological Psychiatry, as well as numerous articles (n=14) in international journals of lower impact factor (ranging from 8 to 4), while the remaining 76 have been accepted for publication in journal of impact factor below 4. It can therefore be considered that the ongoing research work is characterized by a high scientific quality providing significant new findings useful for improving our current knowledge about the pathophysiological determinants of suicidal behaviours. This is especially important given their high frequency in the general population.

Assessment of the theme's academic reputation and appeal

The clinical researchers who are working on this research topic are well recognized to be highly specialized in the clinical management of patients experiencing suicide attempts. They are widely considered as great experts in the identification of cognitive and genetic determinants for suicidal behaviours. They actively participate in: I) the consortium EURECA (EUropean REsearch CArtel -Suicide) for genetic research on suicidal behaviour and the suicide network promoted by the European College of NeuropsychoPharmacology (ECNP); II) the suicide task force of the World Federation of Societies of Biological Psychiatry.

They are financially supported by numerous institutional sources allowing conducting large clinical studies in this research field and are intimately linked to the FondaMental Foundation network along with numerous French clinical academic departments and research teams sharing high expertise levels in the field of suicide. They offer the opportunity to receive foreign post-doctoral students on scientific programs supported at least in part by the FondaMental Foundation grants, thereby illustrating the international reputation and attractiveness of the present research theme.

Assessment of the theme's interaction with the social, economic and cultural environment

There is an active contribution to develop monthly meetings for lay persons and patients' associations. This is paralleled by the participation in radio programs and the written of didactic articles in widely read newspapers on suicidal behaviours and prevention. Finally, there is substantial involvement in the organization of a relatively high frequented meeting every two years designed to inform the lay persons or associations about the ongoing research conducted on the present theme.

Assessment of the theme's organisation and life

Partnerships with: I) theme 1, with which studies of suicidal behaviours in the elderly are specifically conducted; II) the academic department of either Adult Psychiatry or neuroimaging at the University Hospital in Montpellier.

The possible weakness of the present theme might be primarily related to the absence of full researchers compared to that of clinical researchers, although clearly engaged in research activities for almost half time. However, this undoubtedly relies on the specific topic of the theme project with clinical research studies enrolling large psychiatric cohorts. The recruitment of neuroimagers familiarized with the anatomical and functional approaches in psychiatric diseases could make access to the neuroimaging equipment, acquisitions, data analysis even easier. Similar initiatives could be encouraged intending to facilitate the manipulation of genetic data beyond the existing interactions with the Institute of Functional Genomics located in Montpellier.

Assessment of the theme's involvement in training through research

Two Ph.D. students who are both psychiatrists are actually receiving training and participate in the ongoing research projects on the assessment of clinical, genetic and anatomic and functional markers of predisposition for suicidal behaviours. They benefit from an intensive supervision by the theme leader and collaborators during weekly regular or informal meetings at either the hospital or the unit. Otherwise, there are clinical researchers who are actively involved in significant teaching activities within: I) the university Diploma Introduction to cognitive-behavioural therapies (Université Montpellier I -UM1); II) the university Diploma Advanced cognitive-behavioural therapies (Université Montpellier I -UM1); III) university Diploma Management of Eating Disorders (Université Montpellier I -UM1, Université de Nantes, universities of Lille), etc.

Assessment of the five-year plan and strategy

The present project is expected to improve current knowledge about environmental, cognitive and biological factors that are assumed to be highly involved in the pathogenesis of suicidal behaviours by using various and appropriate experimental tools derived from genetic, neuropsychology and brain imaging. The 5-year plan and strategy adopted are both in accordance with the primary goals of this scientific project. The development of psychiatric cohorts will be helped by the active intervention of the theme leader within a large collaborative network specifically involved in the evaluation, treatment and prevention of suicide. Additionally, the academic department of Adult Psychiatry directed by the theme leader at Hospital is specialized in the clinical management of suicidal patients who will be easily recruited for the research programs defined in the scientific project. Among future strategies that might be considered, there are the attraction of neuroimagers and geneticists that could possibly be helpful for the collection and treatment of neuroimaging and genetic data, respectively.

Conclusion  Overall opinion of the theme:

The research theme centred on the identification of clinical, genetic and biological factors implied in the determination of vulnerability for suicidal behaviours is particularly relevant because of the high prevalence of suicidal attempts in the general population, thereby representing a serious public health problem. This project could also open new perspectives for the prevention of suicidal acts and recurrences in high-risk subjects.

 Strengths and opportunities:

-topic related to suicidal behaviours and related psychiatric disorders, as major public health issues; -methodological approach combining a wide range of experimental tools for the identification of genetic, biological and anatomic and functional markers of the vulnerability for suicidal behaviours; -large cohorts with the local recruitment of suicidal patients, which is facilitated by the active collaboration with the Academic Department of Adult Psychiatry at the University Hospital in Montpellier; -large international and national collaborative networks, particularly including Academic Departments of Psychiatry associated with the FondaMental Foundation.

 Weaknesses and threats:

-absence of neuroimagers or geneticists familiarized with the problematic of psychiatric disorders; -absence of full-time researchers.

 Recommendations:

-attraction of neuroimagers or geneticists useful for data collection, analyses.

Theme 3:

Ageing-related cognitive disorder Manager's name: This group aims to understand the determinants of the inter-individual variability in the ageing process through three different approaches: I) investigating the causal inference of modifiable risk factors on age-related health outcomes; II) identifying the MRI Brain morphological and functional biomarkers of cognitive decline and maintenance (cognitive reserve) ; III) assessing the clinical phenotypes and biomarkers of Alzheimer's disease.

For this purpose they have access to well-defined different cohorts of patients (3 cities, /ESPRIT, White Hall II, Gazel, E3N), CONSTANCES. Two ambitious projects (MORPHODEM,CRESCENDO) are described in the MRI approach which requires a strong collaboration with an imaging group expert in the field of post processing even if they have access to a platform which allows a good acquisition to the data. Some of these MRI biomarkers will be integrated with other imaging markers (PET amyloid tracers), clinical and biological markers into a better definition of clinical subtypes of the disease. This broad-based programme will contribute to a preventive approach through a better identification of risk factors and physiopathological aspects of the heterogeneity of the different phenotypes.

The project "modelling the impact of reversing risk factors for dementia" has shown that dementia incidence over the next decade may be reduced by a third with treatment and prevention of insulin resistance, depression, stroke and improvement of education and diet. This is excellent translational work of eminent practical impact. Similarly, the contribution to identify early biomarkers is of great clinical value, as reflected by multiple publications in highest impact refereed journals (such as Nature Genetics, JAMA, Mol Psych, NEJM). Equally, the participation in scientific networks and activities, the publicly financed institutional contracts, and the interactions with the social, economic and cultural environment are plentiful and of highest quality. Finally, the quantity of publications is excellent: we count 38 publications for theme 3 members in 2013 alone, three of these with impact factors >10 and a further 13 with impact factors >5.

Assessment of the theme's academic reputation and appeal

The theme co-leader is member of the national committee of registries INSERM-Invs, member of the scientific advisory board of the INVS, president of the commission of chronic diseases of the High Council of Public Health. (Ministry of Health). The other co-leader serves in different advisory boards of pharmaceutical companies. The group has obtained different prizes. They have national (Bordeaux, Villejuif, Paris, Toulouse, Grenoble, Lille) and international (Melbourne, Camberra, Sydney, University College London, Columbia University) collaborations.They organise or participate to national and international meetings (National Health registries, Clinical trials in Alzheimer disease).

Assessment of the theme's organisation and life

Partnership with theme 1 for the imaging project and theme 4 (alteration of sleep with aging as risk factor for cognitive decline). Participation to masters diploma, training of residents and students in public health, 2 post doctoral supervision/year.

Assessment of the theme's interaction with the social, economic and cultural environment Organisation of different events in relation to dementia and Alzheimer disease: regional "Science Bar", Workshops on Alzheimer disease prevention, (Association France Alzheimer), creation of an Alzheimer disease network in Languedoc-Roussillon, informations on Alzheimer disease and ageing through media.

Assessment of the theme's involvement in training through research

The theme caters for two to three masters diploma students and two doctoral students per year, trains three residents in public health and two neuropsychologists per year. These appear to be well supported within the theme.

Assessment of the five-year plan and strategy

The comittee was impressed by the width of approach to the theme of cognitive impairment. In particular the broad approach including 'resilience' and frequently allied conditions, such as depression in old age. If cognitive impairment in old age follows the paradigm of cardio-vascular disease (which appears likely), rather than that of Huntington's disease, a painstaking epidemiological strategy with careful evaluation of naturalistic studies, 'natural experiments' (as in the 'pieds noirs' study) and mass interventions (e.g. by change of diets) is indeed the way to go. Theme 3 will provide the sufficiently large critical mass of expertise to analyse such data

Conclusion

 Overall opinion of the theme:

This is an excellent theme group that is highly synergic with the overall unit's strategy and is likely to gain in importance in the near future. It is ideally placed in the retirement belt of France to make best use of the growing elderly population, who may be amenable in the future to large scale interventions and attempts to reduce the load of cognitive impairment on the health service in a systematic and rational way. Such interventional studies are being actively prepared by the group's work.

 Strengths and opportunities:

The theme group has the critical mass and specialist expertise to make a substantial and international contribution to the epidemiological analysis of cognitive impairment. With access to the Three-City Study, as well as other national and international data sets, such as Whitehall II, Gazel, E3N, CONSTANCES, and the Nurses' Health Study the group has made important contributions to the epidemiology of dementia and depression, with special regard to gender, occupation, diet, metabolic syndrome, adverse life events, modulation by 5-HTTLPR genotype and the chronic effect of solvent exposure. The group has further made a useful contribution to the study of genetics of dementia and dementia treatment trials as collaborators.The overarching theme of "Modelling the impact of reversing risk factors for dementia" is of particular translational value, as the researchers move on from listing and relational evaluations of risk factors to an interventionist strategy that, in the absence of quick solutions to the treatment of dementia, is likely to be crucial to national health. In addition, the group makes a fulsome contribution to mechanistic research, covering the important fields of neuropsychology, neuroimaging and bloodbiomarkers.

 Weaknesses and threats:

The quality of such epidemiological research will depend on the availability of new good quality data. The group have been excellent at networking and utilising national and international data sets, but the continued provision of new high quality data will be essential for its success. In particular, the feed-back from the group into new cohort studies would generate added value by generating data useful for analysis. In terms of international competition, new epidemiological studies with an imaging component, using cutting edge methods (Connectome, structural and functional connectivity) would benefit from the epidemiological expertise of the group. The imaging project (conventional and functional MRI) is a wide project which requires a strong collaboration with an imaging team experienced in methodology and post processing analysis.

 Recommendations:

The broad approach including 'resilience' and frequently allied conditions, such as depression in old age, are promising and should be pursued in the future.

A painstaking epidemiological strategy with careful evaluation of naturalistic studies, 'natural experiments' (as in the 'pieds noirs' study) and mass interventions (e.g. by change of diets) is the correct way to advance this topic further and should continue into the future.

Theme 3 should as such be preserved with high priority as an integral part of the unit. The leader of the Sleep theme is a very well-known researcher working in the field of neurology and sleep disorders. His work continues that of its predecessors, who made of Montpellier hospital one of the world most renowned sleep clinics.

The group continued to develop top clinical expertise in the Montpellier hospital and significantly increased the number of patients followed by the Gui de Chauliac Sleep Clinic. The center for rare diseases was created in 2007 and coordinates several major sleep centers in Paris and Lyon has a large cohort of hypersomniac patients. In the last 4 years the center received the cerebrospinal fluid samples from narcoleptics and hypersomniac patients from most of the French sleep centers to analyse their orexin levels

The group has demonstrated the association between excessive daytime sleepiness, hypersomnia and health risks (cardiovascular diseases, dementia an depression). This association underline the importance of orexine deficiency in the most severe causes of hypersomnias.

The theme 4 represents one of the best national and European scientific projects on sleep research, it is even surprising to see (according to the size of the group) the very high scientific production of the theme.

The team has a published 102 papers in the last 5 years (2008)(2009)(2010)(2011)(2012)(2013)

Assessment of the theme's academic reputation and appeal

The group collaborates with top international teams in Lausanne or in Stanford. A very strong effort is made to initiate more work with other national teams in many fields (psychiatry (Attention Deficit Hyperactivity Disorders), obstructive sleep apnea syndrome.

Assessment of the theme's interaction with the social, economic and cultural environment Promising results in the field of public health (vaccine and aging) have been obtained.

Potential new therapeutics are investigated with a pharmaceuticla company.

There is a good communication on sleep disorders and rare diseases at national level.

There are strong links with many pharmaceutical companies.

There is a limited amount of patents but promising expected results in the field of diagnosis and phenotyping techniques.

Assessment of the theme's organisation and life

The subtheme is mainly centralized on its activities in the sleep clinic of Gui de Chauliac. It interacts in a translational way with the epidemiological groups and it benefits of all the methodological expertise (i.e. statistical analysis) of the unit.

Assessment of the theme's involvement in training through research

The subtheme leader is responsible of the training program of the French sleep research society (DIU veille sommeil). The sleep clinic host students coming for the training of the DIU. In addition fellows working in the clinic do their Phd in the unit to reinforce the translational approach of the project.

Assessment of the five-year plan and strategy

After focusing for many years on narcolepsy, the sleep theme now opens more to excessive daytime sleepiness at large and comorbidities with aging and psychiatric disorders. This approach based on comorbidities of hypersomnia but also collaborative work with epidemiological teams form the INSERM unit make the project very original and promising.

The "sleep" theme does not present as many links with the other themes that one could expect (e.g. no clear links with the PTSD project). Up to now, if the reputation of the U 1061 is very clear in the field of mood and neurodegenerative disorders, the place of sleep was not perceived as promising as it could be.

Conclusion  Overall opinion of the theme:

This project focuses on ageing-related sleep problems within population-based cohorts and on sleep pathologies, notably hypersomnia, using clinical cohorts.

The program on sleep and ageing aims to determine the mechanisms involved in the relationship between sleep disturbances and comorbid disorders.

The study on sleep disorders will investigate the weight of environmental risk factors including vaccine & infection exposures. This original approach will help to understand mechanisms underlying hypersomnia, sleep fragmentation disorders and to identify novel therapies.

 Strengths and opportunities:

-national and international networks; -grants and platforms; -cohorts available.

 Weaknesses and threats:

The project is alsmost too ambitious considering the few permanent researchers involved and possibly all objectives will not be achieved.

 Recommendations:

Reinforced collaboration between clinicians and scientists.

Theme 4 is a bit isolated, and most of its research is based on neurology and hypersomnia. Stronger links with mood disorders and dementias could be reinforced, in particular, with a better definition of phenotyping techniques (ex. use of MSLT in cohort and epidemiological studies). There is room for more researchers to join theme 4, as it is one of the smaller among the four themes in the unit. A stronger explanation of interaction between themes and sub teams could help understand the long term strategy of the unit. Phenotyping strategies deserve to be better explained. ..':i,'i':"'i::i:::li:The report submitted by the AERES expert committee members was received '1:r ''i: from the University of Montpellier 1 on March 12,20L4 and examined by the -'.. . ,,.,,, , unit's Scientific Councilon March 1-8. The report was considered overallto , .,i'':"..,': fairly reflect the activities, strengths and weaknesses of the unit and we 'r:. ' therefore have no significant disagreement with its contents.

We would, however, like to add some further information not covered during the visit, which may help in the understanding of some of our current needs and limitations. The time-table, which was decided by the president of the committee, only allowed us one and a half hours to cover the overall scientific and administrative situation of the unit (50 members) and the presentation of four thematic groups each with numerous large national and international projects, and a technical platform. The result is that much was omitted although covered in our evaluation report. We would also like to correct some minor omissions/errors in the report.

1. The committee suggested the creation of a CRB. A CRB is being certified by the CHU of Montpellier and currently has provisional status. Anne-Marie Dupuy (co-leader of Theme 1) has been responsible since 2006-7 for the Biological Liquids Section of the Montpellier Hospitals, as well as being responsible for ministerial declarations and participating as an associate director of the Scientific Advisory Board of the Technical Committee' 2. lt is recommended that the unit gain access to younger cohorts for studies of cognition; notably with imaging data. While not only already having privileged access to the younger Gazel and Whitehall data banks, a member of the unit (C Berr, Theme 3) has actively participated in the development of the Constances Cohort (18-70 years), and K Ritchie (Theme 1) is on the Scientific Advisory Board of the U.K. 1946 Cohort (a cohort followed lrom in utero development since 1946) with free access to this unique platform. Both these data banks include imagery. Additionally in collaboration with lmperial College London we have recently begun the first mid-life clinical and biomarker study (including both PET and MRI imaging) of Alzheimer's Disease starting at age 49. http ://\#ww" prevent-d em *ntia.crgl edith. moreno@inserm.fr http:/iu 1 06 1 . montp. inserm.fr 3. Assessment of the Unit's Academic Reputation. Mention is made of our collaboration with the Universities of Melbourne (co-tutelle of PhDs) and Standford, but not more importantly of our European Associated Laboratory (lnserm-King's College, London) which has now existed for over ten years and ,,;,,';:rr,,l::.,,,,.has been the source of multiple research projects, a combined summer school ,,''-'" -"',,,:,and numerous student exchanges including a co-tutelle PhD programme.

4. In relation to Theme 1 it is noted that this team have published over 100 articles. The group has actually published over 300 articles (345. 5. Research into resilience is mentioned in relation to Theme 3, however, no dedicated work has yet been carried out by this group on resilience; this is the area of expertise of Theme L who have not only published in the area but have put in place a national research network on psychotrauma and resilience.

6. The need to attract geneticists is mentioned at several points in the document. While several members of our unit do have established international reputations in the area of molecular psychiatry (P. Courtet; A. Malafosse Theme 2) we would of course benefit from further reinforcement. J. Ryan (Theme 1) is a geneticist who completed her PhD on neuropsychiatric disorders in our unit and is currently a post-doctorate at Melbourne University. This collaboration continues with work in the epigenetics of depression in two young cohorts, but as yet we have not secured a permanent position for her.

7. With regard to the five year plan for Theme 4 (sleep pathologies) it is noted there are no clear links with the PTSD project of Theme 1. I Chaudieu (Theme 1) has in fact designed a multicentric project with members of the psychotrauma network in collaboration with Theme 4 which has, however, not yet been funded.

Montpellier, March 2:-.t, 2O!4 Karen RITCHIE, Ph.D. Head, Unit 1061

4

   Theme-by-theme analysis Theme 1: Affective disorders: bio-environmental risk factors and resilience Manager's name:

  with excellent impact factors especailly in Nature genetics (IF 35), Archives of general psychiatry (IF 12), and in neurological journals like annals of neurology, brain, neurology. It as also a strong publication line in sleep journals like sleep, journal of sleep research, sleep medicine or sleep medicine reviews.(IF 3 TO 11.2)

  ântt ât dË. 1Ê râ §hüÉ{àÇ rTiÉ#iq$ lnserm U 1061 HôpitalLa Colombière 39 Avenue Charles Flahault, BP 34493 34093 Montpellier Cedex 5 Té1. :04 99 614 568 ; Fax:04 99 614579 edith. moreno@inserm.fr http://u 1 06 1 . montp. inserm.fr AERES Evaluation -NEUROPSYCHIATRY: EPIDEMIOLOGICAL AND CLINICAL RESEARCH .

Workforce Theme workforce in Full Time Equivalents As at 30/06/2013 As at 01/01/2015

	Ms Marie-Laure ANCELIN and Ms Anne-Marie DUPUY
	FTE for permanent professors	0,50	0,50
	FTE for permanent EPST or EPIC researchers	2,70	2,70
	FTE of other permanent staff without research duties (IR, IE, PRAG, etc.)	2,80	3,80
	FTE for other professors (PREM, ECC, etc.)
	FTE for postdoctoral students having spent at least 12 months in the unit	1
	FTE for other EPST or EPIC researchers (DREM, etc.) excluding postdoctoral students	2	2,50
	FTE for other contractual staff without research duties	1,25	1
	FTE for doctoral students	2

TOTAL 12,25 10,50  Detailed assessments

	Assessment of scientific quality and outputs

Workforce Theme workforce in Full Time Equivalents

  Mr Philippe COURTET and Mr Alain MALAFOSSE

		As at	As at
		30/06/2013	01/01/2015
	FTE for permanent professors	1,2	1,5
	FTE for permanent EPST or EPIC researchers
	FTE of other permanent staff without research duties (IR, IE, PRAG, etc.)	0,50	0,50
	FTE for other professors (PREM, ECC, etc.)
	FTE for postdoctoral students having spent at least 12 months in the unit
	FTE for other EPST or EPIC researchers (DREM, etc.) excluding postdoctoral students	1,50	0,50
	FTE for other contractual staff without research duties	3,75	3,75
	FTE for doctoral students	2
	TOTAL	8,95	6,25

 Detailed assessments

Assessment of scientific quality and outputs

Workforce Theme workforce in Full Time Equivalents

  Ms Claudine BERR and Mr Jacques TOUCHON

		As at	As at
		30/06/2013	01/01/2015
	FTE for permanent professors	0,30
	FTE for permanent EPST or EPIC researchers	3	3
	FTE of other permanent staff without research duties (IR, IE, PRAG, etc.)	2	1
	FTE for other professors (PREM, ECC, etc.)		0,30
	FTE for postdoctoral students having spent at least 12 months in the unit
	FTE for other EPST or EPIC researchers (DREM, etc.) excluding postdoctoral students	1	1
	FTE for other contractual staff without research duties	2,20	2
	FTE for doctoral students	2
	TOTAL	10,50	7,30

 Detailed assessments

Assessment of scientific quality and outputs

Theme 4:

		Sleep pathologies
	Manager's name:	Mr Yves DAUVILLIERS
	Workforce
	Theme workforce in Full Time Equivalents	As at 30/06/2013	As at 01/01/2015
	FTE for permanent professors		0,30	0,30
	FTE for permanent EPST or EPIC researchers
	FTE of other permanent staff without research duties (IR, IE, PRAG, etc.)	0,50	0,50
	FTE for other professors (PREM, ECC, etc.)
	FTE for postdoctoral students having spent at least 12 months in the unit
	FTE for other EPST or EPIC researchers (DREM, etc.) excluding postdoctoral students
	FTE for other contractual staff without research duties	1,50	1,50
	FTE for doctoral students		1
	TOTAL		3,30	2,30
	 Detailed assessments
	Assessment of scientific quality and outputs