Turck Turck

Jacqueline Castenmiller

Stefaan De Henauw

Karen Ildico

Helle John Kearney

Katrine Knutsen

Alexandre Maciuk

Inge Mangelsdorf

Harry J Mcardle

Androniki Naska

Dominique Turck

Carmen Pelaez

Kristina Pentieva

Frank Thies

Sophia Tsabouri

Marco Vinceti

Jean-Louis Bresson

Alfonso Siani

Louis Bresson

Stefaan

DNA from strand breaks: evaluation of a health claim

Keywords: Coffee, C21, DNA damage, DNA strand break, health claim

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

Table of contents

Background and Terms of Reference as provided by the requestor Regulation (EC) No 1924No /2006 harmonises the provisions that relate to nutrition and health claims, and establishes rules governing the Community authorisation of health claims made on foods. As a rule, health claims are prohibited unless they comply with the general and specific requirements of this Regulation, are authorised in accordance with this Regulation, and are included in the lists of authorised claims provided for in Articles 13 and 14 thereof. In particular, Article 13(5) of this Regulation lays down provisions for the addition of claims (other than those referring to the reduction of disease risk and to children's development and health), which are based on newly developed scientific evidence, or which include a request for the protection of proprietary data, to the Community list of permitted claims referred to in Article 13(3).

According to Article 18 of this Regulation, an application for inclusion in the Community list of permitted claims referred to in Article 13(3) shall be submitted by the applicant to the national competent authority of a Member State, which will make the application and any supplementary information supplied by the applicant available to the European Food Safety Authority (EFSA).

Interpretation of the Terms of Reference

EFSA is requested to evaluate the scientific data submitted by the applicant in accordance with Article 16(3) of Regulation (EC) No 1924/2006. On the basis of that evaluation, EFSA will issue an opinion on the scientific substantiation of a health claim related to: Coffee C21 and protection of DNA from strand breaks.

The present opinion does not constitute, and cannot be construed as, an authorisation for the marketing of Coffee C21, a positive assessment of its safety, nor a decision on whether Coffee C21 is, or is not, classified as a foodstuff. It should be noted that such an assessment is not foreseen in the framework of Regulation (EC) No 1924No /2006. . It should also be highlighted that the scope, the proposed wording of the claim, and the conditions of use as proposed by the applicant may be subject to changes, pending the outcome of the authorisation procedure foreseen in Article 18(4) of Regulation (EC) No 1924/2006.

2.

Data and methodologies

Data

Information provided by the applicant Food/constituent as stated by the applicant According to the applicant, the food for which the health claim is made is 'Coffee C21, a blend of pure Arabica roast coffees (Coffea arabica L.) without any non-coffee ingredients. The roasting is accomplished with regular coffee manufacturing roasters by applying heat to the dry beans until the desired roast degree to provide the desirable composition is obtained. Coffee C21 (roasted) is defined by the following composition of key ingredients extractable by a standardised procedure mimicking usual household conditions: 10.18 mg/g of caffeoylquinic acids (CQA), 3.82 mg/g of trigonelline and 1.10 mg/g of N-methylpyridinium (NMP) (AE 10%). Coffee C21 is consumed as a beverage'.

Health relationship as claimed by the applicant

According to the applicant, 'consumption of Coffee C21 leads to a reduction of the amount of spontaneous DNA strand breaks in white blood cells, which are measured by the comet assay'.

Mechanism by which the food/constituent could exert the claimed effect as proposed by the applicant

The applicant claims that 'intense roasting of coffee enhances the ability of coffee extracts to upregulate the nuclear factor erythroid 2-related factor 2 (Nrf2), a key positive regulator of gene expression of cell defence/cell repair genes. Dark roast coffee was found to be more efficient than light roast coffee in the activation of Nrf2'. Coffee C21 exerts its action by two pathways: a direct pathwayscavenging of free radicals by antioxidants in dark roast coffee, and an indirect pathwayactivation of endogenous protective responses via modulation of gene expression'. Wording of the health claim as proposed by the applicant

The applicant has proposed the following wordings for the health claim: 'regular consumption of Coffee C21 contributes to the maintenance of DNA integrity in cells of the body'.

Specific conditions of use as proposed by the applicant

According to the applicant, the target population for the intended health claim is 'part of the general population, which drinks coffee'. The daily consumption of two to three large cups (in total 500-750 mL) over the day is recommended by the applicant to obtain the claimed effect.

Data provided by the applicant

The health claim application on Coffee C21 and protection of DNA from strand breaks pursuant to Article 13.5 of Regulation 1924/2006, was presented in a common and structured format as outlined in the Scientific and technical guidance for the preparation and presentation of applications for authorisation of health claims.

As outlined in the General guidance for stakeholders on health claim applications, it is the responsibility of the applicant to provide the totality of the available evidence.

Methodologies

The general approach of the NDA Panel for the evaluation of health claim applications is outlined in the EFSA General guidance for stakeholders on health claim applications (EFSA NDA Panel, 2016).

The scientific requirements for health claims related to antioxidants, oxidative damage and cardiovascular health are outlined in a specific EFSA guidance (EFSA NDA Panel, 2018).

The application does not contain data claimed as confidential or proprietary.

Assessment

In line with the General scientific guidance for stakeholders on health claim applications (EFSA NDA Panel, 2016) in assessing each specific food/health relationship which forms the basis of a health claim the NDA Panel considers the following key questions: i) the food/constituent is defined and characterised; ii) the claimed effect is based on the essentiality of a nutrient; OR the claimed effect is defined and is a beneficial physiological effect for the target population, and can be measured in vivo in humans; iii) a cause and effect relationship is established between the consumption of the food/constituent and the claimed effect (for the target group under the proposed conditions of use).

Each of these three questions needs to be assessed by the NDA Panel with a favourable outcome for a claim to be substantiated. In addition, an unfavourable outcome of the assessment of questions (i) and/or (ii) precludes the scientific assessment of question (iii).

Characterisation of the food/constituent

The food proposed by the applicant as the subject of the health claim is 'Coffee C21', a special blend of pure roast coffee beanseither ground or as intact beansfrom different Arabica varieties (Coffea arabica L.), without any non-coffee ingredients. The beverage, coffee, is brewed from the ground coffee beans using hot water.

The roasting is carried out with regular industrial coffee roasters whereby heat is applied to dry beans. The process of roasting induces qualitative and quantitative changes in the chemical composition of the coffee beans.

Coffee C21 is standardised by the concentration of CQA, trigonelline and the thermal degradation product NMP.

CQA, trigonelline and NMP can be measured by established methods [START_REF] Lang | Quantitative studies on roast kinetics for bioactives in coffee[END_REF]. The minimum amount of caffeoylquinic acids, trigonelline and NMP in ground Coffee C21 is 9.16 mg/g, 3.44 mg/g and 0.99 mg/g, respectively, as claimed by the applicant (EFSA NDA Panel, 2015). As the concentrations of CQA, trigonelline and NMP depend on the degree and the duration of roasting, the desired standardised composition of Coffee C21 is obtained by blending different Arabica roast coffees (i.e. prepared under different roasting conditions in terms of load, temperature and time). The applicant stipulates that the extraction efficiency from the ground coffee powder, when prepared with a drip filter coffee machine and using a tap-water-to-coffee-powder ratio of 20:1, amounts to > 90% for CQA, trigonelline and NMP.

The Panel considers that the food, Coffee C21standardised by its content of CQA, trigonelline and NMP, which is the subject of the health claim, is sufficiently characterised in relation to the claimed effect. The Panel notes that different techniques of coffee brewingbut using the same ground coffee powdermay yield substantial differences in concentrations of CQA, trigonelline and NMP in the final coffee drink [START_REF] Caprioli | The influence of different types of preparation (espresso and brew) on coffee aroma and main bioactive constituents[END_REF].

3.2.

Relevance of the claimed effect to human health

The claimed effect proposed by the applicant is reduction of DNA damage by decreasing spontaneous DNA strand breaks. The proposed target population is 'part of general population, which drinks coffee'.

DNA strand breaks occur spontaneously during the DNA repair process but can also be induced by, e.g. environmental factors (such as mutagenic or pro-oxidant chemicals, radiation). Such DNA strand breaks alter DNA properties, may induce anomalies during DNA replication and translation and require repair for maintenance of cell functioning and survival. Direct measurements of DNA strand breaks can be obtained in vivo by using the traditional comet assay (single cell gel electrophoresis -SCGE) (EFSA NDA Panel, 2018).

The Panel considers that protection of DNA from strand breaks is a beneficial physiological effect.

Scientific substantiation of the claimed effect

A claim on Coffee C21 and reduction of DNA damage by decreasing spontaneous DNA strand breaks has already been assessed by the Panel with an unfavourable outcome (EFSA NDA Panel, 2015).

The applicant performed a literature search in PubMed using the following key words: 'Coffee AND DNA damage', 'Coffee AND DNA strand break(s)', 'Coffee AND Comet assay', 'Caffeine AND DNA damage AND trial', 'Chlorogenic acid AND DNA damage AND trial', 'Trigonelline AND DNA damage AND trial', 'Methylpyridinium AND DNA damage AND trial', 'Niacin AND DNA damage AND trial'. In addition, reference lists of relevant retrieved articles were searched manually.

Seven publications reporting on six human intervention studies were identified by the applicant as pertinent to the health claim [START_REF] Misik | Impact of paper filtered coffee on oxidative DNA-damage: results of a clinical trial[END_REF][START_REF] Bakuradze | Consumption of a dark roast coffee decreases the level of spontaneous DNA strand breaks: a randomized controlled trial[END_REF]Richling et al., unpublished study report, 2017;[START_REF] Shaposhnikov | Coffee and oxidative stress: a human intervention study[END_REF][START_REF] Hochkogler | Daily consumption of a dark-roast coffee for eight weeks improved plasma oxidized LDL and alpha-tocopherol status: a randomized, controlled human intervention study[END_REF][START_REF] Pahlke | Dark coffee consumption protects human blood cells from spontaneous DNA damage[END_REF][START_REF] Schipp | Consumption of a dark roast coffee blend reduces DNA damage in humans: results from a 4-week randomised controlled study[END_REF]). Two publications [START_REF] Hochkogler | Daily consumption of a dark-roast coffee for eight weeks improved plasma oxidized LDL and alpha-tocopherol status: a randomized, controlled human intervention study[END_REF][START_REF] Pahlke | Dark coffee consumption protects human blood cells from spontaneous DNA damage[END_REF] report on the same study.

The Panel notes that among the studies identified by the applicant, two studies [START_REF] Misik | Impact of paper filtered coffee on oxidative DNA-damage: results of a clinical trial[END_REF][START_REF] Shaposhnikov | Coffee and oxidative stress: a human intervention study[END_REF] assessed the effects of coffee types which did not comply with the specifications provided for Coffee C21. The Panel considers, therefore, that no conclusions can be drawn from these studies for the scientific substantiation of the claim.

Four placebo-controlled, randomised, single-blind, parallel studies [START_REF] Bakuradze | Consumption of a dark roast coffee decreases the level of spontaneous DNA strand breaks: a randomized controlled trial[END_REF][START_REF] Richling | The effect of coffee consumption on DNA integrity in blood cells -The Kaiserslautern Study[END_REF][START_REF] Pahlke | Dark coffee consumption protects human blood cells from spontaneous DNA damage[END_REF][START_REF] Schipp | Consumption of a dark roast coffee blend reduces DNA damage in humans: results from a 4-week randomised controlled study[END_REF] investigated the effect of Coffee C21 on DNA strand breaks using a similar design. The sample populations of the studies were healthy, nonsmoking, habitual coffee drinkers accustomed to the required amount of coffee to be consumed during the study, comprising both males and females, except for the study by [START_REF] Bakuradze | Consumption of a dark roast coffee decreases the level of spontaneous DNA strand breaks: a randomized controlled trial[END_REF], in which only male subjects were recruited. Subjects were between 19 and 50 years of age and had a BMI between 19 and 32 kg/m 2 . The studies had a parallel design and run-in periods of 4 weeks during which all subjects were asked to consume (warm) water in prespecified quantities and to avoid consuming coffee and caffeine-containing products and also foods rich in polyphenols, but otherwise maintained their usual diet. Compliance was assessed in all studies by measuring the NMP-tocreatinine ratio in spot urine samples. A concentration of > 0.2 nmol/lmol was taken as indicative of coffee consumption. In all studies coffee was prepared using a pad machine and the coffee powder complying with the specifications given in Section 3.1.

During the last 7 days of the run-in and the intervention periods, participants recorded their food intake. Blood samples were taken at the end of the run-in ('baseline') and at the end of the intervention period. The primary outcome in all studies was DNA strand breaks in peripheral white blood cells. DNA strand breaks were assessed by the comet assay (OECD, 2016) and the results expressed as tail intensities (TI%). Power calculations (80% power) were based on the studies by [START_REF] Bakuradze | Antioxidant-rich coffee reduces DNA damage, elevates glutathione status and contributes to weight control: results from an intervention study[END_REF][START_REF] Bakuradze | Consumption of a dark roast coffee decreases the level of spontaneous DNA strand breaks: a randomized controlled trial[END_REF]. The study by [START_REF] Bakuradze | Consumption of a dark roast coffee decreases the level of spontaneous DNA strand breaks: a randomized controlled trial[END_REF] was already evaluated by the Panel in the previous assessment of the claim on Coffee C21 (EFSA NDA Panel, 2015). A total of 90 subjects were randomised (stratified by BMI and using a computer-generated randomisation list) into two groups (n = 45 per group) before the run-in period (750 mL/day water). The intervention group consumed 750 mL/day Coffee C21 without milk in three equal portions per day for 4 weeks; the control group drank equal volumes of water. Six subjects (three per group) dropped-out during the run-in period for private reasons. The statistical analyses were carried out in the population of completers (n = 42 per group).

At baseline, there was no statistically significant difference in the mean TI% between groups. During the 4-week intervention period, the mean AE SD TI% decreased in the intervention group and increased in the control group (from 0.32 AE 0.11 to 0.27 AE 0.09 TI% in the intervention group and from 0.31 AE 0.12 to 0.37 AE 0.15 TI% in the control group; i.e. mean difference at the end of the study AE SE À0.10 AE 0.03 TI%, analysis of covariance (ANCOVA) p = 0.0002).

Notwithstanding possible methodological limitations (e.g. randomisation before the run-in period; drop-outs during the run-in and statistical analysis on completers only), the Panel considers that this study provides some evidence that daily consumption of Coffee C21 (750 mL/day) for 4 weeks decreases DNA strand breaks in habitual coffee drinkers after coffee withdrawal over the previous 4 weeks.

In the study by [START_REF] Schipp | Consumption of a dark roast coffee blend reduces DNA damage in humans: results from a 4-week randomised controlled study[END_REF], a total of 100 subjects were randomised before the run-in period (stratified by gender and BMI by using a computer-generated randomisation list) into two groups (n = 50 per group). The intervention group consumed 500 mL/day Coffee C21 without milk in four equal portions per day for 4 weeks; the control group drank equal volumes of warm water.

One subject in the intervention group dropped-out because of acute illness and one subject in the control group was excluded because of non-compliance with coffee restriction during the run-in period (NMP to creatinine ratio in urine samples > 0.2 nmol/lmol). In addition, for one subject in the intervention group the sample to be analysed with the comet assay was destroyed by accident prior to its evaluation. For the intention-to-treat (ITT) analysis, missing values were imputed by carrying forward the baseline observation. Results were presented for the ITT population (all randomised, n = 100) and the per protocol (PP) population (all compliant participants who finished the study with no missing end of trial outcomes, n = 97, n = 48 in the intervention and n = 49 in the control group).

At baseline, mean AE SD TI% were significantly higher in the intervention group versus the control group (1.08 AE 0.36 vs. 0.92 AE 0.34 TI%, p = 0.029, t-test). For the PP population (as reported in the unpublished study report provided to EFSA by the applicant), there was a statistically significant decrease in TI% in the intervention group and no significant changes in the control group resulting in mean AE SD TI% at the end of the study of 0.86 AE 0.28 vs. 0.92 AE 0.33 TI%, respectively. The difference between groups in absolute changes from baseline was statistically significant in the ITT (À0.22 TI%, no further details provided) and the PP population (mean difference AE SD À0.23 AE 0.49 TI%; p = 0.03, Wilcoxon Rank Sum Test (WRST)).

The Panel notes that the higher TI% in the intervention group compared with the control group at the end of the run-in period (i.e. baseline) has not been explained by the applicant. The Panel also notes that the statistical analysis presented by the applicant did not account for the imbalances that were observed at baseline, particularly since correlation analysis provided in the unpublished study report (provided to EFSA by the applicant) indicated that the magnitude of the reduction in TI% depended on the corresponding baseline value. It was observed that higher reductions in TI% were associated with higher baseline values. For this reason, subgroup analyses were presented in the unpublished study report in subjects with baseline TI% values above and below the overall baseline mean value. Based on the WRST analysis, a significant difference in TI% changes was observed between the intervention and control group in those individuals with baseline TI% below the overall mean, but not in those individuals with baseline TI% values above the mean. When EFSA proposed to take into account baseline values in the analysis, the applicant argued that based on a comparison of variances at baseline and at the end of the study in the intervention group, the impact of differences at baseline on the outcome was negligible in this study. The Panel considers that neither the presented information on the subgroup analyses nor on the comparison of variances allows to attribute differences in changes between groups to the actual intervention (Coffee C21) rather than to existing differences in TI% at baseline. Therefore, the Panel considers that no conclusions can be drawn from the study for the scientific substantiation of the claim. [START_REF] Pahlke | Dark coffee consumption protects human blood cells from spontaneous DNA damage[END_REF] randomised subjects after the run-in period (stratified by gender and BMI by using a computer-generated randomisation list) into two groups. The intervention group consumed 750 mL/day Coffee C21 without milk in three equal portions per day for 8 weeks; the control group drank equal volumes of warm water.

In the publication, it is reported that 96 subjects were randomised (n = 48 per group). In the unpublished study report, a number of 99 (n = 49 and 50) is reported in the text and 98 (n = 49 and 49) in the subject flow chart. This flow chart also indicates that two randomised subjects (one per group) dropped out during the run-in period. The Panel notes that the reporting is not consistent between the publication and the study report as well as between the text and the flow chart of the study report, both with respect to the number of subjects randomised and the timing of randomisation (before or after the run-in period).

One subject in the intervention group dropped out during the study. In the publication, it is reported that 10 subjects were excluded because of non-compliance, while in the corresponding unpublished study report (provided to EFSA by the applicant), the number was 9. The information provided in the study report is as follows. Seven subjects were excluded because of non-compliance to coffee restriction, i.e. four subjects during the run-in and three subjects in the control group during the intervention period. In the intervention group, two subjects were excluded because no NMP was detected in urine, which is indicative of no coffee consumption. The number of compliant subjects who finished the study was n = 42 in the intervention and n = 44 in the control group. The Panel notes that subjects who did not adhere to coffee restriction during the run-in phase were nonetheless randomised into the study but withdrawn thereafter from the analysis because of non-adherence to the protocol during the run-in period.

Among the set of samples analysed each day, one random sample was chosen and subjected to UV-B irradiation (as positive control) to verify the performance of the comet assay. For one of these random samples, the results for the positive control were not as required according to the protocol. As this indicated an issue with the performance of the comet assay, the whole sample set analysed on that day (n = 11, i.e. 5 in the intervention and 6 in the control group) was eliminated from the PP analysis. Finally, the PP population consisted of 37 participants in the intervention and 38 in the control group.

The results were presented for the ITT population (n = 96) and the PP population (all compliant participants who adhered to the protocol and had evaluable samples, n = 75; 78% of the ITT population). For ITT analysis, missing values were imputed by carrying forward the baseline observation.

At baseline in the PP population, there was no statistically significant difference in the mean TI% between the groups (mean AE SD: intervention vs. control: 0.53 AE 0.21 vs. 0.49 AE 0.22 TI%). At the end of the intervention period in the PP population, TI% was reduced on average by 0.15 TI% in the intervention and by 0.05 TI% in the control group (i.e. mean AE SD TI% at the end of the study: 0.38 AE 0.11 TI% and 0.44 AE 0.13 TI%, respectively). In the ITT population, TI% decreased by on average 0.02 TI% in the intervention group and increased by on average 0.10 TI% in the control group (i.e. 0.51 AE 0.21 and 0.48 AE 0.22 TI%, respectively, at baseline vs. 0.49 AE 0.35 and 0.58 AE 0.37 TI% at the end of the study).

The difference between groups in absolute changes from baseline was statistically significant both in the ITT (WRST, p = 0.047) and the PP (ANCOVA, p = 0.026) population. The choice of the statistical tests used was based on the Shapiro-Wilk test for normality. Following a request from EFSA to justify why different statistical tests were used for the ITT and the PP population considering that the assumption of normality relates to the distribution of the outcome variable in the population from which the sample is drawn and not to the distribution in the sample itself, the applicant argued that owing to the 'systematic selection process of excluding subjects with special behaviour' to obtain the PP population, the 'PP sample population and ITT sample population cannot in general be regarded as originating from and representing the same general population'. The Panel notes that, if the characteristics of the subjects included in and excluded from the PP analysis are not comparable, the principle of randomisation may not hold for the PP population. This would be supported by the observed differences between the ITT and the PP populations with respect to changes in TI% from baseline to the end of the study in the control group (i.e. increase by 0.10 TI% vs. decrease by 0.05 TI%, respectively), which suggests that subjects excluded from the PP analysis had different characteristics than subjects included in the PP analysis.

For the ITT analysis, baseline observations were carried forward to impute missing values and therefore changes from baseline will be zero for all imputed values. The Panel notes that if the same number of zero values are imputed in each group, these imputed values will have no impact on the result in statistical analyses based on differences in ranks (as is the case in the non-parametric WRST test), while they could have an impact on the results in analyses based on continuous variables (e.g. parametric ANCOVA).

The Panel considers that, owing to the important methodological limitations (i.e. number of subjects randomised unclear, exclusion of a substantial number of subjects from analysis, limitations of the ITT analysis due to the method used to impute missing data and the subsequent approach towards statistical analysis, possible violation of the principle of randomisation in the PP population), no conclusions could be drawn from this study for the scientific substantiation of the claim.

In the study by Richling et al. (unpublished study report, 2017), that was conducted in the same study centre as the study by [START_REF] Bakuradze | Consumption of a dark roast coffee decreases the level of spontaneous DNA strand breaks: a randomized controlled trial[END_REF], a total of 99 subjects were randomised after the run-in phase (stratified by gender and BMI by using a computer-generated randomisation list) into two groups (n = 49 in the intervention and n = 50 in the control group). The intervention group consumed 750 mL/day Coffee C21 without milk in three equal portions per day for 4 weeks; the control group drank equal volumes of warm water.

Two subjects in the control group dropped out during the intervention. One subject in the intervention group was excluded from the PP analysis because of non-compliance to coffee abstention during the run-in period. Results were presented for the ITT population (all randomised, n = 99) and PP population (compliant participants who finished according to the protocol and who had evaluable samples, n = 96 (n = 48 per group)). For ITT analysis, missing values were imputed by carrying forward the baseline observation. The Panel notes that one subject who did not adhere to coffee restriction during the run-in phase was nonetheless randomised into the study but withdrawn thereafter from the analysis because of non-adherence to the protocol during the run-in period.

At baseline in the PP and ITT population, there was no statistically significant difference in the mean TI% between the groups (mean AE SD: 0.61 AE 0.12 and 0.62 AE 0.15 TI% in the intervention and the control group, respectively, both for the ITT and the PP population). At the end of the intervention period, there were no statistically significant differences in TI%, analysed by ANCOVA, between the intervention and the control group (i.e. mean AE SD TI% 0.63 AE 0.14 TI% and 0.67 AE 0.13 TI%, respectively), both in the ITT and the PP population.

The Panel considers that this study does not show an effect of daily consumption of Coffee C21 (750 mL/day) for 4 weeks on DNA strand breaks in habitual coffee drinkers after coffee withdrawal over the previous 4 weeks.

Overall, the Panel notes that out of the two studies from which conclusion could be drawn, one study [START_REF] Bakuradze | Consumption of a dark roast coffee decreases the level of spontaneous DNA strand breaks: a randomized controlled trial[END_REF] provides some evidence that daily consumption of Coffee C21 (750 mL/day) for four weeks decreases DNA strand breaks in habitual coffee drinkers after coffee withdrawal over the previous four weeks. The statistically significant findings of this study were not replicated in another study [START_REF] Richling | The effect of coffee consumption on DNA integrity in blood cells -The Kaiserslautern Study[END_REF] performed under similar conditions in the same study centre. The Panel also notes that no studies performed in a different setting, from which conclusions could be drawn, are available.

Studies on the mechanism of action as proposed by the applicant

The applicant claims that physiological effects of coffee consumption in humans may depend on the level of roasting because changes in composition occur during the roasting process.

The applicant proposes potential mechanistic pathways for dark roast coffee to exert an effect on DNA integrity, namely: a) A direct pathway through scavenging of free radicals by antioxidants present in dark roast coffee and hence preventing oxidative damage to DNA strands. b) Indirect pathways active through modulation of gene expression by coffee constituents leading to activation and upregulation of endogenous cellular DNA protective responses (mainly, but not exclusively, via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant/electrophile response element (ARE/EpRE) system).

Regarding the direct pathway, the applicant noted that recent evidence from animal and human studies convincingly showed that plasma concentrations of coffee constituents with antioxidant capacity were far too low to explain efficient DNA protective radical scavenging. Therefore, this pathway was not considered relevant by the applicant in the context of this claim application.

In relation to the indirect pathway, the applicant cited the following studies that were conducted either with coffee as such or single coffee constituents: 3 human studies (Boettler et al., 2011a;[START_REF] Volz | Effect of coffee combining green coffee bean constituents with typical roasting products on the Nrf2/ARE pathway in vitro and in vivo[END_REF][START_REF] Pahlke | Dark coffee consumption protects human blood cells from spontaneous DNA damage[END_REF], 6 animal studies [START_REF] Cavin | Induction of Nrf2-mediated cellular defenses and alteration of phase I activities as mechanisms of chemoprotective effects of coffee in the liver[END_REF][START_REF] Paur | Degree of roasting is the main determinant of the effects of coffee on NF-kappaB and EpRE[END_REF][START_REF] Balstad | Coffee, broccoli and spices are strong inducers of electrophile response element-dependent transcription in vitro and in vivo -studies in electrophile response element transgenic mice[END_REF][START_REF] Salomone | Coffee enhances the expression of chaperones and antioxidant proteins in rats with nonalcoholic fatty liver disease[END_REF][START_REF] Vicente | Coffee modulates transcription factor Nrf2 and highly increases the activity of antioxidant enzymes in rats[END_REF][START_REF] Shi | Activation of Nrf2 pathway and inhibition of NLRP3 inflammasome activation contribute to the protective effect of chlorogenic acid on acute liver injury[END_REF] and 11 in vitro studies [START_REF] Bakuradze | Antioxidant effectiveness of coffee extracts and selected constituents in cell-free systems and human colon cell lines[END_REF][START_REF] Kalthoff | Coffee induces expression of glucuronosyltransferases by the aryl hydrocarbon receptor and Nrf2 in liver and stomach[END_REF][START_REF] Paur | Degree of roasting is the main determinant of the effects of coffee on NF-kappaB and EpRE[END_REF]Boettler et al., 2011a,b;[START_REF] Volz | Effect of coffee combining green coffee bean constituents with typical roasting products on the Nrf2/ARE pathway in vitro and in vivo[END_REF][START_REF] Sauer | Activation of the transcription factor Nrf2 in macrophages, Caco-2 cells and intact human gut tissue by Maillard reaction products and coffee[END_REF][START_REF] Fratantonio | Low nanomolar caffeic acid attenuates high glucose-induced endothelial dysfunction in primary human umbilical-vein endothelial cells by affecting NF-kappaB and Nrf2 pathways[END_REF][START_REF] Jung | Cellular antioxidant and anti-inflammatory effects of coffee extracts with different roasting levels[END_REF][START_REF] Priftis | Roasting has a distinct effect on the antimutagenic activity of coffee varieties[END_REF][START_REF] Shen | Caffeic acid inhibits HCV replication via induction of IFNalpha antiviral response through p62-mediated Keap1/Nrf2 signaling pathway[END_REF].

The applicant claimedon the basis of human studies, animal studies and in vitro studiesthat many phytochemicals in the human diet, including coffee constituents, can modulate the Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 system, leading to translocation of Nrf2 to the cell nucleus and upregulation of gene expression for antioxidant and other cell defensive pathways. The applicant further claimedon the basis of the literature providedthat this is associated with better prevention or repair of DNA strand breaks (as determined by the comet assay), and that this is further confirmed by experimental Nrf2 knockdown studies in animals that showed abolishment of the DNA protective potential of phytochemicals.

As regards the many specific coffee constituents (and their potential alterations during processing of the coffee beans), the Panel notes that the literature on both the effects and the mechanisms of action of the different coffee constituents is incomplete, diverse and not consistent, and that inferences on the link with DNA integrity are in most instances reported in hypothetical and speculative terms. Indeed, none of the studies provided by the applicant unequivocally demonstrates that the proposed changes in cytosolic and nuclear concentrations of Nrf2, the expression and activity of ARE/ EpRE-dependent enzymes, or any other cellular cascade triggered by coffee constituents, directly affects DNA strand breaks in humans and as such improves DNA integrity. In particular, the only human intervention study that investigated DNA strand breaks and Nrf2 translocation, which was provided by the applicant and is described above [START_REF] Pahlke | Dark coffee consumption protects human blood cells from spontaneous DNA damage[END_REF], did not allow conclusions to be drawn on the link between Nrf2 translocation and DNA strand breaks, owing to the methodological limitations of this study. The other human studies that were provided by the applicant (Boettler et al., 2011a;[START_REF] Volz | Effect of coffee combining green coffee bean constituents with typical roasting products on the Nrf2/ARE pathway in vitro and in vivo[END_REF], compared in one-arm sequential trials Nrf2-gene transcription levels in periods in which subjects refrained from coffee consumption and restricted the amounts of polyphenols in the diet with periods of coffee consumption, but did not investigate DNA strand breaks.

The Panel considers that the human, animal and in vitro studies submitted do not provide evidence for a mechanism by which coffee (including Coffee C21) could protect DNA from strand breaks.

Weighing of the evidence

In weighing the evidence, the Panel takes into account that out of the two human intervention studies, from which conclusion could be drawn, one study provides some evidence that daily consumption of Coffee C21 (750 mL/day) for 4 weeks decreases DNA strand breaks in habitual coffee drinkers after coffee withdrawal over the previous 4 weeks. However, the results of this study were not replicated in another study conducted under similar conditions in the same study centre. The Panel notes that no studies performed in a different setting, from which conclusions could be drawn, are available. The Panel also takes into account that no evidence has been provided for a mechanism by which coffee (including Coffee C21) would protect DNA from strand breaks.

The Panel concludes that a cause and effect relationship has not been established between the consumption of Coffee C21 standardised by its concentrations of CQA, trigonelline and NMP, and protection of DNA from strand breaks.

Conclusions

On the basis of the data presented, the Panel concludes that:

• The food/constituent, Coffee C21 standardised by its concentrations of CQA, trigonelline and NMP, which is the subject of the health claim, is sufficiently characterised in relation to the claimed effect.

• The claimed effect proposed by the applicant is reduction of DNA damage by decreasing spontaneous DNA strand breaks. The target population proposed by the applicant is 'part of general population which drinks coffee'. Protection of DNA from strand breaks is a beneficial physiological effect.

• A cause and effect relationship has not been established between the consumption of Coffee Steps taken by EFSA 1) This application was received by EFSA on 1/7/2019.

  Abstract................................................................................................................................................... 1. Introduction.................................................................................................................................... 1.1. Background and Terms of Reference as provided by the requestor...................................................... 1.2. Interpretation of the Terms of Reference........................................................................................... 2. Data and methodologies .................................................................................................................. 2.1. Data............................................................................................................................................... 2.2. Methodologies................................................................................................................................. 3. Assessment..................................................................................................................................... 3.1. Characterisation of the food/constituent............................................................................................ 3.2. Relevance of the claimed effect to human health............................................................................... 3.3. Scientific substantiation of the claimed effect .................................................................................... 4. Conclusions..................................................................................................................................... Documentation as provided to EFSA .......................................................................................................... Steps taken by EFSA ................................................................................................................................ References............................................................................................................................................... Abbreviations ...........................................................................................................................................

  Coffee C21 and protection of DNA from strand breaks www.efsa.europa.eu/efsajournal 4 EFSA Journal 2020;18(3):6055

  Coffee C21 and protection of DNA from strand breaks www.efsa.europa.eu/efsajournal 6 EFSA Journal 2020;18(3):6055

  C21 and protection of DNA from strand breaks.Documentation as provided to EFSAHealth claim application on Coffee C21 and protection of DNA from strand breaks pursuant to Article 13(5) of Regulation (EC) No 1924/2006 (Claim serial No: 0487_DE). Submitted by Tchibo GmbH, € Uberseering 18, D-22297 Hamburg, Germany.

Coffee

  C21 and protection of DNA from strand breaks www.efsa.europa.eu/efsajournal 10 EFSA Journal 2020;18(3):6055 2) The scope of the application was proposed to fall under a health claim based on newly developed scientific evidence pursuant to Article 13(5) of Regulation (EC) No 1924/2006. 3) The scientific evaluation procedure started on 12/8/2019. 4) On 10/9/2019, the Working Group on Claims of the NDA Panel agreed on a list of questions for the applicant to provide additional information to accompany the application. The scientific evaluation was suspended on 24/9/2019 and was restarted on 9/10/2019, in compliance with Article 18(3) of Regulation (EC) No 1924/2006. 5) On 29/10/2019, the Working Group on Claims of the NDA Panel agreed on a list of questions for the applicant to provide additional information to accompany the application. The scientific evaluation was suspended on 25/11/2019 and was restarted on 5/12/2019, in compliance with Article 18(3) of Regulation (EC) No 1924/2006. 6) During its meeting on 25/2/2020, the NDA Panel, having evaluated the data, adopted an opinion on the scientific substantiation of a health claim related to Coffee C21 and reduction of DNA damage by decreasing spontaneous DNA strand breaks.

www.efsa.europa.eu/efsajournal

EFSA Journal 2020;18(3):6055 18314732, 2020, 3, Downloaded from https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2020.6055 by Cochrane France, Wiley Online Library on [09/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Competent Authority of Germany following an application by Tchibo


come

How did the French higher Education system respond to the Covid-19 pandemic?

Formulation of the problem

The Global Pandemic so far has disrupted four academic years in France: 2018-2019, 2019-20, 2020-21, 2021-22. France experienced three periods of general lockdown:

• March 16, 2020 to May 11, 2020: the strictest (2 months)

• October 30 to December 15, 2020 (1,5 months)

• April 3 to May 3, 2021 (28 days) With the COVID crisis, the level of education disruption was unprecedented. The lockdown in particular was completely new for the French society as well as for the Educational sector and HEI.

It poses a problem of crisis management capacity for HEI and pushes the sociologists to cross their usual frames of analysis concerning HE with those of a sociology of risk society:

Even if the Coronavirus pandemic remains exceptional, Crisis has become a concept of the present time, it has become a hallmark of modern society (Freudenburg, 1992).

The presentation is structured by three main questions:

-What are the concerns of institutional actors, i.e. the agenda of the crisis and its temporality? (1) -What are the characteristics of the French higher education governance in this crisis situation? (2) -How does risk management differ according to the type of Higher education institutions and what were the weaknesses/strengths of each of these types in relation to the COVID risks? (3)

Method

The analysis carried out is essentially documentary and consisted in a thematic analysis of the French national and regional press. The search has been extended over the entire period of the crisis -from March 2020 to June 2021-and Concerned the perimeter of the HEI offering Undergraduate Diploma.

How did the French Higher Education System respond to COVID-19 pandemic?

Christelle Manifet Associate professor CERTOP-University of Toulouse France

Universities (55%), University Institutes of Technology (UIT) (4%), Advanced Technician Programs in High Schools (10%), Preparatory classes for the Grandes Ecoles (3%), other public and private schools offering undergraduate programs (21%), Private institutions are mainly religious institutes (13), engineering schools and business schools (50), other technical schools, some of which may be financed to varying degrees by the public authorities. 18% of students are specifically enrolled in private higher education institutions.

The measures taken by the main actors of the system were also systematically identified in support of a consultation of the main institutional websites. Some reports that related directly or indirectly to this crisis management in HEI have been also consulted as much as possible.

Limits: Beyond the fact that this digital press review and analysis cannot suffice for the scientific validation of the observations, it also has other shortcomings: official documentation as well as the media had a rather global view of the problems faced by the entire educational sector in the face of the virus. And the preoccupations were turned towards the cycles that concerned the youngest: the elementary school in particular. Finally, what was happening in higher education as such was not documented with precision in the French Press. And, moreover, the Ministry of Higher Education did not keep a precise statement of the pandemic impact on its perimeter of competence, neither with regard to public nor private establishments.

Part I: HEI in Pandemic conditions: Emergency and Contingency... but Continuity

Emergency and Contingency…

Scientific publications on crisis management point out the importance of temporality in a crisis. They demonstrate that, spontaneously, social actors are seized by the emergency and trapped by it.

Reaction to events, unpreparedness and instability of official decisions then dominate rather than prevention and planification, and resilience and recovery.

In this case, the pandemic management was closely dependent on the incidence rates of the virus, the number of hospitalizations compared with the hospital reception capacities.

The Graph represents the temporality of the crisis in French soil with its main events and public decisions. In the background of the slide, one can see the evolution of the number of covid-19 patients hospitalized since March 25, 2020. In critical care units in dark, in other services in light.

The crisis circle repeated three times…

The three periods of Lockdown are closely caused by the COVID data in Hospitals, but what it is observed in the third period in particular, between the second and the third lockdown, is a trend of dissociation.. This dissociation illustrates the conflict during the whole crisis between the necessity to fight against this virus and the desire, this impulsive movement to continue to act as if it was almost normal.

Emergency and Contingency BUT Continuity…

What the actors of the higher education system -and it was the same elsewhere-were constantly trying to do during the whole COVID crisis was to ensure the continuity of the teaching service even under degraded conditions.

This concern manifested itself in the priority given to face-to-face teaching, or, in any case, to any device allowing to be as close as possible to the situation of normality. Then, if the face-to-face teaching became too complicated to implement, the institutions best pre-familiarized with digital tools easily switched to alldistance teaching, which most often consisted in reproducing classic classroom teaching but with the means of teleconferences.

And this movement for continuity was as strong as that to counter the spread of the virus.

Four National and General scenarios have been elaborated to manage the pandemic.

First, individualized isolation and quarantine for those infected or closed-contacts, and shutdown of institutions on a case-by-case basis.

Second, containment of the outbreaks or risk of outbreaks, called 'clusters'. Third, the general Lockdown aimed to restrict as much as possible the movements, the circulations and the opportunities of meeting which has had the effect of slowing down all non-essential activities and has led to the closure of all institutions receiving the public, apart from Educational Institutions which have been managed specifically: closure had not been systematic.

Four, relaxation periods when easing of restrictions implies a battery of barrier measures to avoid another containment.

These scenarios were neither specific to the higher education sector.

Articulated to this pandemic management plan, HEI have deployed their own plan of continuity, with three main scenarios, ranging from "face-to-face teachning with barrier gestures and measures, and special measures for cases in isolation" to the "entirely distance learning" including "hybrid teaching" with a reduced-capacity reception. Then, the "total closure" of insitutions, when it happened, did not mean that teaching and learning activites ceased. They were taking a digital turn.

These three scenarios could coexist or overlap and could fit in variable ways with COVID's threat management plan.

For example, Lockdown did not necessary mean 'total remote learning. Educational Institutions were uniformly closed during the first Lockdown and invited to put in place online solutions, whereas during the second, Hybrid Teaching could have been the norm. It is the same during the easing restrictions periods where a large part of universities finally decided to stay in quasi-entirely remote learning conditions.

Part II. Scenarios of Continuity in Pandemic conditions

A first scenario of "Isolation of infected persons, contact tracing and individualized quarantine, and shutdown of institutions on a case-by-case basis"

When a case is positive to Covid, the "contact tracing" is set up to identify the persons staff and/or students who could be symptomatic and/or ill and to recommend to all of them to remain in isolation at home for fourteen days, then 7 days.

At the beginning of the epidemic's spread, the rule of principle was that three cases of Covid-19 theoretically led to the closure of a class. Actually, the decisions made may have varied based on a case-by-case basis and then, relaxed as the pandemic took hold over time rather than being quickly evacuated.

The management of students in isolation has been progressively formalized, protocols have been put in place in the largest institutions: course materials by email, relying on the pre-existing digital work environment to continue studying, relying on their peers who could still attend class. There were no distance learning courses organized for those in isolation.

The most formal arrangements made for them, however, were for replacement tests when they missed exam periods.

The second scenario consisted in managing epidemic outbreaks concentrated in specific places, so called 'clusters'.

Thus, the arrival of the virus on the French territory has manifested itself in this form.

High-risk areas have been identified, as of the end of February 2020. In an article in the Montreal press on 10/03/20, travel returners from high-risk areas in France, in particular students, were invited to stay at home for fourteen days before returning to school. The same day (6 days before the First general Lockdown), the University of South Brittany announced the confinement of 300 students out of its 1900 enrolled, because they were living in cluster municipalities.

Gradually, cluster management shifted from reaction to prevention. Decreed on the 23th of March 2020: "any gathering, meeting or activity of more than 100 people, in closed or open environments" were prohibited.

Whereas others institutions receiving public were required to close, educational institutions were not, but had to find ways to avoid excessive groupings. Actually, in the first period of the outbreak characterized by unpreparedness, the focus was essentially on closing campuses, online teaching and testing.

It was not until the start of the academic year in September 2020 that institutions, to a large extent, tried to put in place an organization for Hybrid teaching.

But, according to Le Monde of October 26, 2020, each day the list of universities and other HEI affected by contamination grew longer, and some of them closed their doors for two weeks and switched to distance learning. Centrale Lyon, Sciences Po or Polytechnique were quoted as having to close their doors. Then, the intensity of the incidence of the virus forced a lot to waive and switch to an-all online learning.

The same article in Le Monde reported that one third of the clusters were due to schools and universities, and the sector had even overtaken the business sector for the first time in terms of the number of clusters reached (285 versus 195 as of 26/10/20, Le Monde website). More than ten clusters were identified in universities, as of September 13, 2020, according to the Ministry of Higher Education, but the latter did not carry out an ongoing survey of the clusters and closure.

A third scenario of General Lockdown has imposed itself on the French public authorities, more than they would have liked.

Educational Institutions were uniformly closed for the first time between March 16 and May 3, 2020, that is to say 3 weeks of school at home and 2 weeks of confined spring vacations.

The beginning of the 2020 school year started under the instruction of opened institutions, but as the incidence rate (nb of cases/100,000 inhabitants) increased in September and October, the French government decided to decree a second containment from October 30, which however was translated into very different declinations according to the cycles and years of study, as well as according to the status (public/private) and size characteristics of the institutions. Thus, all universities were subject to distance learning, while elementary school remained open. Colleges were open, although some colleges may have been affected by half-capacity rule and hybrid teaching, i.e., half-group attendance, every second day/or week. Half-capacity and hybrid teaching had been imposed on all high schools, which were required to give priority attendance to students in their senior year in preparation for the baccalaureate diploma exams. All schools that remained open were subject to a stricter sanitary protocol, mainly, the wearing of masks, which became mandatory in November 2020 for those over 6 years old.

At the announcement of the third lockdown, the government resolved, as in the first lockdown, to close primary schools and high schools from April 6, 2021 and for three or four weeks.

Then, the conditions of Lockdown clearly varied between the three periods, since while the first period was the strictest and the most homogeneous, the second was the most heterogeneous of the three. Not all educational institutions were necessarily closed, and differences in treatment as well as differences in the application of the instructions became apparent over time.

The whole period of this COVID-19's crisis has been favorable to the deployment of online teaching tools, especially during the lockdown phases. The private market for distance learning has been boosted and institutions and public authorities have engaged in public-private partnerships to ensure the continuity of their missions. Tools on the scale of the French Ministry of Education were also put in place, notably the resources of the Centre National de l'Enseignement à Distance (CNED), which were made accessible to all pupils and students and their families, covering primarily primary and secondary school programs but also offering certain short programs of higher education (Advanced Technician Programs). French universities and others Higher Education institutions that also do research were already using the WEB for academic research and for distance learning. Technological equipment required was already in place, which also explains why in these higher education institutions, priority has been given to distance learning methods, based on online lectures or asynchronous learning activities, video or audio lessons, online examinations, etc.

The Fourth scenario features the interstitial periods between the lockdown phases when relaxation measures were put in place but the viral threat was still present and still imposed restrictions.

Then the barrier measures were put in place. The wearing of masks became mandatory in November 2020 until march 2022. Evening and night curfew were put in place, then vaccination strongly recommended, selfisolation and self-tests in case of symptoms... In these periods, lockdown measures were lifted, vigilance continues in an effort to avoid another lockdown.

In higher education, as well as in upper secondary education, the two main tools used to keep institutions open were the lowering of the reception capacity on campuses and hybrid teaching, mixing face-to-face and distance learning.

Half-capacity attendance every second day/or week, face-to-face classes one day a week, Priority attendance given to First year's students, training courses...

Behind the seemingly simple principle of dividing group sizes by two or more, the implementation proved to be much more complex in campuses with large numbers of students and where the opportunities for mixing were endless.

The media reported that teams had been working for weeks between July and September 2020 to ensure that students would be able to return to school, creating COVID cells and continuity plans, reorganizing and desynchronizing timetables, reorganizing traffic in shared spaces, and establishing rules for differentiated presence not only by training group, but also by level of study and type of training... A large number of articles were dedicated to this 'logistical headache of the university facing the covid-19'.

Part III: Three main features of the HE governance in pandemic conditions

Firstly, Complexification and high Dependency

The crisis introduced an unprecedented decision-making circuit due to the fact that the crisis factor was a foreign body to the educational system and that the main system of risk management was controlled by an exogenous system of action. The HE system was forced to acculturate to a new culture of health security and sanitary protocols: incidence and mortality rates, capacity of hospitals, barrier actions, scrupulous cleaning of work spaces, containment and curfew, closure, isolation of contact cases, tests, vaccination, etc. A set of devices had to be known and used, a set of recommendations had to ben integrated to HE plans, a lot of new protocols have been put in place in the organizations.

The agenda in higher education was also largely determined by advances in scientific knowledge about the virus, as well as by the state of industrial production of protective devices (masks, tests, hydro alcoholic gels, air purifiers, vaccines...).

For example, the race to develop vaccines began in early 2020 Concretely, the rate of vaccination began to rise significantly on the French territory one year later, from mid-March 2021 with a rate of vaccinated people of almost 70% at the end of August 2021. This helped the country to take control of the virus: even neither the vaccine, nor the 'Health Pass' were made mandatory in higher education, the actors counted on the largescale vaccination of their staff and clientele to organize a quasi-normal start to the 2021-22 academic year, "in person, without restrictive capacities, without a mandatory health pass but with mandatory masks and barrier gestures".

Secondly, Uncertainty, Controversy and Lack of Trust

A main characteristic of the Higher Education governance in this crisis was that decisions were made in a context of high uncertainty. Procedures were unprecedented and decisions were ephemeral. The high uncertainty particularly tested individuals and organizations, "their ability to apprehend the unexpected, their capacity to make effective decisions, their resilience to resume normal activity and continue their operations (Combalber, 2012, p. 42).

This high uncertainty notably manifested itself by a constant balance between health security ad the provision of education. This search for balance prevailed, although everyone knew that no option was ideal. Then, uncertainty was the ground for controversy.

Controversy was strong on several issues without it always being possible to know whether a majority was emerging in one direction or another:

-Did HEI were nests of clusters or not? Social media and Streets hosted these debates. Often, the measures taken were responses to categorical grumbling, from teachers, students, parents, companies.

A decision made the day before could be reversed the next day.

The organization of the 2020-21 academic year, which have been extended from July until the end of October, was exemplary in this respect. While the Minister of Higher Education had advocated during the summer the vague principle of a 'quasi-normal' start for the new academic year, a new instruction followed, this time from the Prime Minister, to limit the reception capacity between 50% and 20%, whereas at the end of October, the President announced that the universities would be switching to a complete distance learning. At the local level, this uninterrupted series of contradictory instructions was not without explaining the fatigue of staff and users alike, as well as the rise in attitudes of mistrust towards the authorities.

An other illustration is in the side-effects of the all-online learning considering the risks of dropping out and isolation. As the measures taken were particularly restrictive, distance learning proved to be the appropriate solution, which made it possible to save the most important, knowledge transfer. Then, came the concern for correcting its side-effects on students'mental health, their resource, motivation, perseverance and performance.

The press multiplied the testimonies of students: "I didn't want anything. It was as if my life was on pause. It's hard to hang on", or "10 universities ask to reopen their doors as of January with a reception capacity of 50%"

or "They're fed up with courses on Zoom: for the students, the 'college' is a nightmare". On January 20, 2021, a demonstration was organized by students to demand the reopening of the campuses. On January 27, 2021, the president announced that "the students had the right to return to the campus, respecting a maximum capacity of 20%".

It is a bill published in Le Monde on 17/03/21 by doctors and a university professor that acted as a warning to the French government. These academics warned that the psychological consequences on young people of measures such as isolation and screen work would have to be repaired. Immediately afterwards, the government launched a psychological support campaign in Higher education institutions based on the communication device of 'three psychology vouchers'.

Thirdly, Equivocal governance. Centralization and Dispersion

The governance of the French higher education system, known as centralized, is it really that centralized in the light of the crisis?

The equivocal governance of this crisis concerned the relative concomitance but contradiction between Emergency and Uncertainty.

Emergency implies a relative centralization of the decision. And the French president took the lead without too much hesitation, even reshaping the way in which the Health system would take on this crisis. The state of health emergency, decreed on 17/10/20 and prolonged by laws until the one of 31 May 2021, granted greater margins of maneuver to the executive power, and installed an ad hoc task force around the president, in this case a scientific committee and a restricted council of national defense and security.

In contrast, uncertainty implies decentralization. Now, the decision-making system found it difficult to settle down completely to a crisis management, which implied relying less on hierarchy and formal procedures than on a common frame of reference for a decentralized system, supported by the agility of teams and students in the institutions.

Most of the time, the central authority has sinned for having said too much, or not enough. Too much, because its instructions greatly restricted local capacities for self-organization according to specific situations, and not enough, because local actors had to make do with these instructions, which remained abstract and did not provide them with the steps to follow.

Governance was also contradictory in that this Covid-risk has generated solidarity and fraternity feelings, with the idea that everyone was on the same boat, fueled by a continuous stream of presidential and ministerial announcements. But, as the crisis dragged on, it was clear that this was not the case and that working and studying conditions were not the same everywhere.

Quoting the French poet, Jean de La Fontaine, « Not all died but all were affected » (Animals sick with plague, Fables, 1678-1679).

The central instructions did not explicitly enroll, in a common framework, the entire sector of higher education The press reported on this 'double standard', or this 'variable geometry sense of justice'.

In Le Monde (website, 3/11/20), a university professor was indignant about the inequality created in higher education by the difference in treatment between university students and future students of "grandes écoles".

In the regional newspaper Ouest France of February 3, 20, one noted 'the great difference between public and private schools' with a rule of 50% in class in public schools, and a rule of 100% in private schools.

In Le Monde on March 29, 2021, three days before the third lockdown, an article quoted the number 2 of the general secretariat of Catholic education (1200 high schools in the network, 26400 students) announcing that the status quo would be privileged in the network, with rules of distancing and strict barrier gestures.

Many private secondary and higher education institutions took the opportunity to communicate that their activity was 100% face-to-face. Under these conditions of partial instructions, some public sector institutions also played the game to remain as much as possible in face-to-face conditions.

Small is beautiful or further threats for Mass-oriented Higher Education Institutions in Risk Societies?

Contingency determination? What seems to have acted most in favour of maintaining a face-to-face activity rather than moving to hybrid or totally distance formats was the size of the institution and/or the groups of students gathered in campuses and/or classes rather than the place and status of institutions in the public higher education order or in relation to the public/private or non selective/selective distinction. The size was a decisive variable, that made it possible or not to respect the rules of social distancing and to control the social tightness of the groups.

However, the only fact that this contingency was a so determining factor in the actor's beahaviours shows

French political leaders as well as French society as a whole give value to the differentiation of the French higher education system. No one had much of a problem with the fact that the restrictions were not the same for every provider of HE.

The management of this particular crisis shows once again that Differentiation, Market-driven, Competition and elitism are the new motto of the French HE system. As it is said in the website of The Ministry of Higher Education 'Higher education is free'.

-

  To confine or not to confine? -To close or to keep open? -To make vaccines compulsory or not? -To maintain in-person or online exams? -To favor complete remote learning or hybrid teaching?

/HEI during Pandemic. Emergency and Contingency Mode… Focus on continuity

  , the evolution of the number of covid-19 positive patients hospitalized since March 25, 2020, Legend: in critical care units in dark, in other services in light (Source: https://www.francetvinfo.fr/)

	1st lockd own 03/16 to 05/11 Feb. 28 activation of a national emergency plan Increase of Feb. 14 1st proved death of covid on French soil Clusters IIncrease of Easing restrictions barrier measures, individual isolations and case-by-case closures	2 nd lockd own 10/30 to 12/15 A trend dissociation Increase of can be observed here between Public decisions and Covid-19 data	3 rd lock do wn 04/ 03 to 05/ 3	Isolation for Individuals General Lockdown Crisis cycle Repetition or exit, containment Cluster with the end of the pandemy The rate of vaccination began to Easing restrictions rise significantly in France from mid-Marc 2021, with almost 70% of adult people vaccinated at the end of august 2021
	Clusters	Clusters
	in the background

  In an Instagram story, the government spokesman, Gabriel Attal, stated on October 30, 2020, in the wake of a press conference by the Prime Minister, Jean Castex: "Since the subject of Advanced technician Programs, University Institutes of Technology and Preparatory Classes was not finally addressed in the press conference, I would like to inform you that classes will continue to be held in person". (Remarks taken up by the journalist Olivier Esteves in a retrospective analysis article, Le Monde, January 14, 2021).

(Universities, University Institutes of Technology, Advanced Technician Programs and Preparatory classes, Public and Private engineering schools, nor a fortiori the other private Institutions (18% of the French students).

Universities for higher education, and public high schools for secondary education, were the main targets of the restrictions, while other types of education, minorities in number and with limited capacity, either fell between the cracks of the public sector (public and selective institutions) or considered themselves as not concerned (the Private sector).