Denis Pierron
email: denis.pierron@univ-tlse3.fr

Veronica Pereda-Loth

Marylou Mantel

Maëlle Moranges

Emmanuelle Bignon

Omar Alva

Julie Kabous

Margit Heiske

Jody Pacalon

Renaud David

Caterina Dinnella

Sara Spinelli

Erminio Monteleone

Michael C Farruggia

Keiland W Cooper

Elizabeth A Sell

Thierry Thomas-Danguin

Alyssa J Bakke

Valentina Parma

John E Hayes

Thierry Letellier

Camille Ferdenzi

Jérôme Golebiowski
email: jerome.golebiowski@univ-cotedazur.fr

Moustafa Bensafi
email: moustafa.bensafi@cnrs.fr

Veronica Pereda- Loth

Smell and taste changes are early indicators of the COVID-19 pandemic and political decision effectiveness

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

F

ollowing similar decisions in China and Italy, a strict lockdown was enforced in France beginning on March 17, 2020 to block the progression of COVID-19 and alleviate pressure on hospitals. One issue currently faced by governments is how to conduct the progressive relaxation of the lockdown [START_REF] Gilbert | Preparing for a responsible lockdown exit strategy[END_REF] , which needs to be conducted systematically and carefully to prevent subsequent outbreaks while facilitating economic activity and recovery. On May 7, 2020, the French government categorized each geographical area as being red or green, depending on their COVID-19 prevalence. Compared to green areas, red areas were characterized by: (i) higher active circulation of the virus, (ii) higher level of pressure on hospitals (i.e., CCRU occupancy), and (iii) reduced capacity to test new cases (Fig. 1a). In each area, red/ green labels were used to define steps associated with the local relaxation of lockdown. The French Ministry of Health used the ratio of consultations for suspected cases of COVID-19 to general consultations at the emergency room (ER) in hospitals as an indicator to assess the active circulation of the virus (detailed in "Methods" section). Concurrently, changes in smell and taste are prominent symptoms of COVID-19 [START_REF] Menni | Real-time tracking of self-reported symptoms to predict potential COVID-19[END_REF][START_REF] Eliezer | Sudden and complete olfactory loss function as a possible symptom of COVID-19[END_REF][START_REF] Gautier | A new symptom of COVID-19: loss of taste and smell[END_REF][START_REF] Pellegrino | Corona viruses and the chemical senses: past, present, and future[END_REF] , as has consistently. been demonstrated in many countries (e.g., Iran 6 , Spain [START_REF] Beltrán-Corbellini | Acute-onset smell and taste disorders in the context of Covid-19: a pilot multicenter PCR-based case-control study[END_REF] , France [START_REF] Bénézit | Utility of hyposmia and hypogeusia for the diagnosis of COVID-19[END_REF] , Italy [START_REF] Giacomelli | Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study[END_REF] , Germany 10 , and the UK 2 , among others). More critically, these chemosensory changes generally occur earlier than other symptoms [START_REF] Giacomelli | Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study[END_REF] and may constitute more specific symptoms than fever or dry cough [START_REF] Menni | Real-time tracking of self-reported symptoms to predict potential COVID-19[END_REF][START_REF] Yan | Selfreported olfactory loss associates with outpatient clinical course in Covid-19[END_REF] . Accordingly, monitoring self-reported changes in smell and taste could thus provide early and specific information on the spread of COVID-19 in the general population and support health system monitoring to avoid daily CCRU admission overflows. Using data from a global, crowd-sourced study deployed in 30+ languages (Global Consortium for Chemosensory Research survey, GCCR, see "Methods" section), we tested whether changes in smell/taste at the population level could be used as an early indicator for local COVID-19 outbreaks. As pre-registered (see "Methods" section), our primary aim was to test the association between self-reported smell and taste changes and indicators of pressure in hospitals (COVID-related hospitalizations, CCRU admissions, and mortality rates) for each French administrative region over the last 3 months. Our secondary aim was to examine temporal relationships between the peak of smell and taste changes in the population and the peak of COVID-19 cases and the application of lockdown measures. The potential for self-reported smell and taste loss to serve as an early indicator of the number of COVID-19 cases-and hence hospital stress-was tested in a natural experiment by comparing France with Italy and the UK, which implemented lockdown with different timing and levels of stringency. Here, we show that self-reports of smell/ taste changes are closely associated with hospital overload and are early markers of the spread of infection of SARS-CoV-2.

Results

Changes in smell and taste are associated with overwhelmed healthcare systems. The relationship between self-reported changes in smell and taste by French residents (diagnosed as COVID-19+ or not, see "Methods" section and Supplementary Table 1) and estimators of local healthcare system stress was evaluated geographically. Figure 1a depicts the geographical distribution in red and green regions (as defined by the French government) and participants who self-reported changes in their smell and taste. Red areas of France account for 40.8% of the population. Green areas are clustered into a group with both a low number of self-reported chemosensory changes and a low number of admissions to CCRUs (Fig. 1b). Red areas show an opposite trend (Chi-square <1 × 10 -200 and Biserial correlations p < 1.3 × 10 -2 ). A strong relationship exists between self-reported changes in smell and taste and the number of admissions to CCRUs (R smell = 0.88, p = 8.9 × 10 -08 ). This correlation remained significant even after removing the two most impacted areas (Alsace and Ile de France, R smell = 0.72; p < 3 × 10 -04 ), indicating that the significant relationship is not driven solely by these two regions.

Strikingly, use of self-reported chemosensory changes produced a stronger correlation than the current governmental indicator of virus circulation (Fig. 1c). Overall, smell/taste changes are better correlated with the number of COVID-19 admissions to hospitals than the current governmental indicator i.e., the ratio of ER consultations for suspicion of COVID-19 to general ER consultations (R smell = 0.81, p = 6.71 × 10 -06 vs. R gov = 0.60, p = 3.35 × 10 -03 ); the same pattern was found for the number of COVID-19 related deaths (R smell = 0.75, p = 5.62 × 10 -05 vs. R gov = 0.58, p = 4.97 × 10 -03 see Supplementary Table 2). Further, when smaller geographical areas were considered (France is divided into 96 administrative units, called departments), these correlations remained highly significant (e.g., admissions to CCRUs: R smell = 0.76, p < 5 × 10 -19 ) (Fig. 1c). Moreover, the three relationships (change in smell/taste versus COVID-19-related hospitalization, resuscitations, and death) also remained highly significant when considering only individuals who were not clinically diagnosed by a medical professional but considering themself showing some symptoms of COVID-19 (e.g., admissions to CCRUs: R smell = 0.83, p = 1.65 × 10 -06 ). Potential sampling bias due to regional media coverage of our survey (Supplementary Table 3) and self-reported chemosensory changes by region was ruled out by confirming these variables were not correlated (R < 0.01, p > 0.9).

Notably, relationships between pandemic markers and online searches related to chemosensation were also significant in France. Google queries related to smell or taste loss ("perte odorat," "perte goût" in French) were correlated with the three measures of an overwhelmed healthcare system described above (e.g., CCRU admissions: R smell = 0.8, p < 4 × 10 -03 , see Supplementary Table 2).

Changes in smell and taste are early markers of the effectiveness of political decisions. Next, we examined the temporal dynamics in France of self-reported changes in smell/taste, the current governmental indicator (ratio of ER consults), and the number of CCRU admissions due to COVID-19 before and after the lockdown period. As shown in Fig. 1d, the peak of the onset of changes in smell/taste appeared 4 days after the lockdown and for these individuals, the first reported COVID-19 symptoms occur even earlier. Conversely, the governmental indicator of ER consults only peaked 11 days after the lockdown, while the peak of CCRU admissions was shifted later by 14 days. This is consistent with emerging data showing that COVID-19-related changes in smell and taste occur in the first few days after infection [START_REF] Bagheri | Coincidence of COVID-19 epidemic and olfactory dysfunction outbreak in Iran[END_REF][START_REF] Salje | Estimating the burden of SARS-CoV-2 in France[END_REF][START_REF] Levinson | Anosmia and dysgeusia in patients with mild SARS-CoV-2 infection[END_REF][START_REF] Klopfenstein | Features of anosmia in COVID-19[END_REF] . The robustness of smell and taste changes over time was assessed in two ways. First, we showed the peak of smell/taste changes remained the same regardless of our survey's completion date (Supplementary Fig. 1a). Second, we observed the exact same peak when analyzing a separate French survey performed on 950 individuals and focusing on smell alterations in the French population independently of COVID-19 (see "Methods" section): the peak of olfactory changes again occurred 4 days after the lockdown decision, and this was independent of survey completion dates (Supplementary Fig. 1B). The robustness of smell and taste changes was also observed over age (Supplementary Fig. 2A) and gender (Supplementary Fig. 2B). Finally, we also show that the observed peak does not correspond to seasonal occurrence of allergies in France based on the ratio of consultations for Allergy to general consultations at the emergency room (Supplementary Fig. 3).

Further, analyses of Google searches confirm this temporal relationship: on the same days where survey participants report experiencing their first symptoms (around March 18, 2020), there was a peak of Google queries for terms associated with early COVID-19 symptoms (fever, cough, aches, Supplementary Fig. 4A). A few days later, the peak of online queries for "taste loss" and "smell loss" is synchronized with the report of smell and taste changes (Supplementary Fig. 4B). One week later, queries for shortness of breath preceded the peak of CCRU admissions (Supplementary Fig. 4C). Collectively, these results indicate a significant fraction of French COVID-19 patients followed the same symptom time course, experiencing initial symptoms at the very start of the lockdown, which might be representative of a peak of infection a few days before the lockdown. This is consistent with the ultimate goal of the lockdown, which was to decrease the number of new infections following implementation. Thus, the period immediately prior to lockdown represents the expected peak of new infections. In France, a large population may have been infected two days before lockdown because that weekend was crowded and sunny and occurred over the course of election day. Further, there were busier train stations and supermarkets in anticipation of a shortage of supplies during lockdown [START_REF] Salje | Estimating the burden of SARS-CoV-2 in France[END_REF] .

These data suggest that the short-term efficacy of a lockdown could be monitored by tracking changes in smell and taste in the population. To assess whether such a prediction might generalize to other countries, we performed parallel analyses with data from Italy and the UK, where the lockdown measures were established with different levels of severity (see Fig. 2). We monitored the dynamics of confirmed COVID-19 cases, self-reported first symptoms, and self-reported taste and smell changes, and compared them as a function of the governmental stringency index. Immediately after lockdown, we found that the two countries with the higher stringency index experienced a more rapid decrease in both self-reported smell and taste changes and COVID-19 symptoms. Further, as expected, the evolution of confirmed COVID-19 cases differs according to the stringency index. The governments of Italy and France rapidly increased their stringency index, which led to a sharp decrease in COVID-19 symptoms and cases. In contrast, in the UK, the number of people in the UK reporting symptoms showed a slower decrease, presumably due to a less severe lockdown policy, and the number of confirmed cases remained high during the observation window. In each country, self-reported smell and taste changes can be regarded as a useful metric to predict the dynamics of confirmed COVID-19 cases. That is, when the number of new onsets of chemosensory changes decreases sharply (France and Italy), the number of confirmed COVID-19 cases also decreases, albeit with a lag of two weeks. On the contrary, a slow decrease in the number of new onset chemosensory changes is associated with a plateau of confirmed cases (UK).

Discussion

The present analyses reveal a strong spatial and temporal relationships between self-reported smell and taste changes and multiple indices of health care system stress, such as admissions to CCRUs. This is consistent with cumulative evidence showing a high prevalence of chemosensory alterations in patients affected by COVID-19 in Europe (France 8,14 , Italy 9 , UK [START_REF] Menni | Real-time tracking of self-reported symptoms to predict potential COVID-19[END_REF][START_REF] Lechien | Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study[END_REF][START_REF] Moein | Smell dysfunction: a biomarker for COVID-19[END_REF] ). Participants endorsed smell and taste changes only 3-4 days after their first symptoms. Such early chemosensory estimators may represent a cost-effective and easy way to implement alternative surveillance methods to large-scale virology tests, which are difficult to perform, costly, and time-consuming, especially during a pandemic.

A prominent question raised by these findings is whether the smell and taste changes observed in our study are solely related to COVID-19 or whether they can be explained by other temporal patterns, like seasonal illnesses or allergies. To the best of our knowledge, there are no existing studies that have explored the dynamics of sudden anosmia (as in COVID-19) throughout the year in France. Relationship between olfactory disturbances and seasons have been reported in Korea, Germany or US with a moderate increase of anosmia prevalence in spring [START_REF] Lotsch | A data science-based analysis of seasonal patterns in outpatient presentations due to olfactory dysfunction[END_REF][START_REF] Potter | Olfactory dysfunction from acute upper respiratory infections: relationship to season of onset[END_REF][START_REF] Kang | Epidemiology of anosmia in South Korea: a nationwide population-based study[END_REF] overlap, the amplitude of reported changes (either due to allergy or viral affection) were very limited compared to the present report. To further rule out the possibility, we examined whether the annual peak of allergies in France could explain the peak of smell and taste changes observed here. In analyzing existing French governmental data, we found that the annual peak of allergies in France occurred around week 30 (beginning of summer), multiple weeks after the observation window of the present study (from week 5 to week 20, Supplementary Fig. 3). Further, the French national aerobiological surveillance network (RNSA, https://pollens.fr), which follows pollen concentration in the atmosphere, has also indicated the first week of lockdown was very low risk for seasonal allergies. In addition, when considering Google Trends data, we did not observe any similar peaks in queries for smell/taste loss in the corresponding time period in previous years. Finally, a comparative study in Israel [START_REF] Karni | Self-rated smell ability enables highly specific predictors of COVID-19 status: a case control study in Israel[END_REF] showed that in COVID-19 suspected patient the frequency of smell change is almost ten time higher in a COVID-19 positive patients (68%) than in COVID-19 negative (8%). Considering that most of the participants of the present study are diagnosed with COVID-19 and that their description of a sudden loss of smell/ taste is consistent with the now typical presentation of COVID-19 symptoms, it is highly probable that COVID-19 infection is the main reason of their smell and taste change. Collectively, these data suggest the peak of smell and taste changes studied here are more consistent with sudden COVID-19 viral infections rather than an artifact due to seasonal illnesses.

The time lag between the onset of COVID-19-related symptoms and their declaration by the respondents of our study also deserves comment. Although immediate reporting of symptoms would have been ideal, such reporting is not possible within the context of the sudden first wave of a new viral pandemic. A similar time lag has been observed in other large-scale studies focusing on olfaction and COVID-19 [START_REF] Iravani | Relationship between odor intensity estimates and COVID-19 prevalence prediction in a Swedish Population[END_REF] . Indeed, this time lag is inevitable given the preparation time required for scientists and clinicians design and launch such a survey, with appropriate ethics approval, once anosmia and ageusia began to emerge as cardinal symptoms of COVID-19. The vast majority of participants completed the survey between April 10th and April 19th, 2020, and most of them declared a date of onset of their symptoms roughly a month earlier (although a small fraction of participants did indicate onset prior to 2020). A possible consequence of a time lag between survey completion and the effective date of symptom onset is that subjects' statements may have been influenced by major societal events such as the lockdown decision, potentially creating some recall bias. To examine whether the date of a major event like the lockdown might bias dates of reported smell and taste loss, we explored narrative descriptions provided by our participants. By analyzing responses to the optional open-ended question "Please describe the progression or order you noticed your symptoms", we observed that, for France, a mere 11 of 3705 people (who have filled the optional question) used the term "confinement" ("lockdown") in their description of the onset date. Separately, another factor that mitigates concerns about a potential recall bias is the stable nature of participant's statements, regardless of their date of completion. That is, logic suggests, the longer the time between the onset date of smell and taste loss and the reporting date, the greater the recall bias should be. However, our data clearly show that regardless of the date of completion, the onset date falls within the same period (Supplementary Fig. 1). Finally, other evidence against a potential recall bias comes from Google Trends data. Analyzing real-time Google queries in March, we observed a very particular trend in France (Supplementary Fig. 4). We first observed a peak of queries for terms associated with early COVID-19 symptoms (fever, cough, aches) synchronized with the declared onset of the first symptoms in the survey (around March 18th). A few days later, a peak of online queries for "taste loss" and "smell loss" was seen, and this was synchronized with the date reported of smell and taste changes in our survey. The striking concurrence between Google queries and reports in our survey argues against the idea that a recall bias could be driving the effects described here.

Another important factor to consider in our survey is the way the press and media might have influenced our findings. Indeed, when the survey was launched, smell and taste changes were reported as symptoms of COVID-19 in the national and local media, which might have influenced respondents to remind themselves of such symptoms and to then report these changes on the survey. Such an emphasis on smell and taste loss would have biased attempts to explore the prevalence of chemosensory deficits in COVID-19. However, the primary aim of the present investigation was not to focus on the prevalence of anosmia and ageusia with COVID-19, but rather to explore use of reported smell and taste loss as indicators of COVID-19 pandemic. Still, the media coverage of our survey could also have biased the selection of participants geographically, as some French regions received more media coverage than others. However, as reported above, there was no correlation between the number of participants in a given region and the intensity of media and press coverage for the survey in that same region. Finally, when participants were asked to describe the chronology of their symptoms, they did not refer to the media coverage as a prominent element influencing their awareness of their smell/taste changes. While this does not exclude an implicit and non-verbalized bias due to media coverage, this pattern suggests a genuine report of symptoms with a high occurrence of COVID symptoms just after the lockdown.

An interesting question raised by our findings is what impact they might have on government strategies in a pandemic. Following lockdown, the rapid decrease of self-reported changes in smell and taste in France may be representative of the effectiveness of this decision in reducing infection rates. Similarly, data from Italian participants show highly similar patterns, but with a one-week difference compared to the French data. This might reflect highly similar responses by the Italian and French governments. Conversely, the prevalence of chemosensory changes in the UK shows a more gradual decrease. The UK government began with advice to avoid pubs, clubs and theaters, and to work from home from March 16, with restrictions around March 18. However, a lockdown was not declared until March 23, and this was less stringent than those in France or Italy. Notably, new COVID-19 cases in the UK showed a plateau phase which is not observed in either France or Italy. Accordingly, we conclude that collecting online information about changes in smell and taste from residents (even retrospectively) may be a valuable metric of the effectiveness of reopening strategies related to the COVID-19 pandemic.

Practically, in areas where smell and taste changes are notable COVID-19 symptoms, the proportion of individuals who selfreport changes in their ability to smell or taste might be an early indicator of subsequent demand for healthcare. If confirmed, continuous monitoring of changes in smell and taste perception would then be a highly cost-effective, minimally invasive, and reliable way to track future COVID-19 outbreaks. When used this way, we caution that particular attention must be paid to potential selection bias. That is, self-report studies online can be impacted by multiple selection biases, including socioeconomic status, fluency with technology and willingness and interest in participating in scientific research. When considering the present data, at least 3 parameters may contribute to a selection bias in our sample: (1) the age, (2) the gender of the participants, and (3) the format and the advertising of the survey. Regarding participant' age, our study cohort (mean 40.7 years, sd = 12.4)) was quite similar to the French population mean (41.1 years, according to INSEE, https://www.insee.fr/fr/statistiques/ 1893198); however, we did only include individuals over 18 due to issues of consent, and administrative reasons, and seniors were also less represented. For gender, our sample contained a greater proportion of women (67%) compared to men, which might influence the results. However, additional analysis showed no differences in peaks of smell/taste changes across age or gender, minimizing concerns that such selection biases may have influenced present results (See Supplementary Fig. 2). We also tested the potential selection bias due to format and the advertising of the survey, by comparing the GCCR dataset with an independent second study performed on French residents (see "Methods" section). Remarkably we observed highly similar results across studies where advertising, inclusion criteria, and survey format were different.

Based on the present findings, we highlight the paramount importance and robustness of associations between smell/taste changes and COVID-19 and we strongly endorse the need for additional large-scale validation studies to assess the causality between the observed association between smell/taste changes and indicators of the COVID-19 pandemic. This could be achieved by setting up a simplified interface where selection biases are controlled for (age, gender, motivation, media coverage, socioeconomic level, etc.) through both traditional and online media-and whereby real time information about changes in smell and taste in the general population may be available to decision-makers. Subjects' participation in the questionnaire and the reliability of the answers should also be considered. In particular, if a participant knows how their answers may influence enforcement of lockdown, their answers might become less truthful. This motivation can be expressed through different forms of behavior. Whereas some individuals may tend to provide statements that minimize their symptoms in order to avoid strict containment measures, others will maximize their declaration to maintain the lockdown, or will provide honest answers in order to participate in the collective effort to better understand the COVID-19 pandemic. These motivational factors are a recurrent risk in online studies and different strategies should be held to control for them in future predictive studies. Based on the above, a large implementation of the study of smell and taste changes in institutional models should allow for monitoring of COVID-19 spread. This might be especially relevant in in areas in which testing proves difficult or delayed and for future outbreaks that may overlap with other seasonal viral diseases which share many of the symptoms (fever, cough etc.) but whose treatment or prevention (vaccination) are less demanding in terms of critical care than COVID-19. We advocate that self-report surveys should be used to enhance other strategies such as large-scale PCR tests and COVID-19 symptom assessments (including anosmia and ageusia) in primary/secondary care.

In summary, we propose that an increase in the incidence of sudden smell and taste change in the general population may be used as a valuable minimally invasive indicator of coronavirus spread in the population. To formally test the temporal relationship between chemosensory changes and spread of the disease, we recommend that a large-scale causal study in different countries be conducted on real-time monitoring of self-reported changes in the ability to smell or taste. Such a prospective study will allow for the creation of statistical models that can assist in prediction of future hospital admissions for COVID-19. Further, it could also help decision-makers take important measures at the local level, either in catching new outbreaks sooner, or in guiding the relaxation of local lockdowns, given the strong impact of lockdown on economic and social activities.

Methods

Online survey. This study is mainly based on data from the Global Consortium for Chemosensory Research survey (GCCR, https://gcchemosensr.org/)a global, crowd-sourced online study deployed in 30+ languages [START_REF] Parma | More than smell-COVID-19 is associated with severe impairment of smell, taste, and chemesthesis[END_REF] . The data analyzed here were collected from April 7 to May 14, 2020. The protocol complies with the revised Declaration of Helsinki and was approved as an exempt study by the Office for Research Protections at The Pennsylvania Study University (Penn State) in the U.S.A. (STUDY00014904; PI Hayes).

Participants in the GCCR questionnaire were recruited by word of mouth, as well as through social and traditional media (flyers, social media, television, radio) during the COVID-19 pandemic. It was well covered by the French press, as over 70 articles mentioned the project, at both the regional and national level (see Supplementary Table 3). Respondents received no monetary incentive for their participation. Inclusion criteria were as follows. (i) Questionnaire completion was allowed only to participants who indicated they had suffered from a respiratory disease in the past two weeks, whether they noticed a change in their taste/smell or not. (ii) Participants aged 18 years old or younger were excluded.

For the analyses conducted in this article, only individuals reporting a change in smell and/or taste perception were included, based on the question "Have you had any of the following symptoms with your recent respiratory illness or diagnosis?". Moreover, to exclude unreliable entries, participants must have reported a quantitative decrease of at least 5 on a 0-to-100 rating scale between their ability to smell and/or taste before and during their recent respiratory illness or diagnosis. Therefore, Due to this inclusion criteria, "smell/taste change" is equivalent to a quantitative decrease of participant ability to smell and/or taste. We then extracted individuals from the full dataset who reported living in France, Italy or the UK. As the country of residence was completed as a text entry, we allowed for typical variations (e.g., "United Kingdom" or "UK"), spelling mistakes, use of different languages (e.g., "Italie" or "Italia"), as well as subdivisions (e.g., "Scotland") and major cities ("Paris"). Metropolitan France was split into 13 so-called "regions" in 2016. However, we considered the former system where France was split into 22 regions here, since the organization of the health system mostly remains based on the structure built before 2016. An alternative, finer granularity, splits metropolitan France into 96 so-called "departments." To retrieve the French department and region of the participants, we used the city of residence they reported in the questionnaire and combined them with the French public website (data.gouv.fr, after a semi-manual correction of spelling). Participants came from all metropolitan departments but three (Mayenne, Creuse, Cantal). Consequently, the number of responses analyzed in France was between n = 1476 and 4720 depending on the analysis conducted (i.e., on whether the information of interest was present or missing and the date range of analysis, see Supplementary Table 1 for details). For comparison, between 264 to 1241 participants from Italy and between 243 to 750 participants from the UK were included. Most participants were women (FR:66.38%, IT:69.3%, UK:76.0%), and the mean age was around 40 [FR = 40.7 (sd = 12.4), IT = 41.1 (sd = 11.4), UK = 41.09 (sd = 12.1)]. In the French data, a total of 15% of individuals tested positive for COVID-19 (lab result) and 44% were diagnosed clinically by a medical professional from their symptoms. The remaining 41% were not diagnosed for COVID-19 but declared a change in perception of either smell or taste. The number of participants was normalized by region, by using the number of inhabitants in each region as estimated by the French public statistics office, INSEE. Finally, the time of onset of smell and taste change was assessed via responses to several optional open-ended questions. These included: "Please describe the progression or order you noticed your symptoms" and the time of onset of recent disease by the question: "At what date did you first notice symptoms of your recent respiratory illness? Provide your best guess or leave blank if you do not remember."

Complementary and independent French Survey. The data of another online survey were used to evaluate the robustness of the temporal evolution of smell and taste changes. This survey was conducted in the French population between April 8 and May 8, 2020 and aimed at characterizing chemosensory disorders in people with and without COVID-19, as well as their consequences on quality of life. The data of 950 respondents were eligible for comparison with data from the GCCR survey, i.e., responses where both the date of completion and the date of smell loss onset were provided. Only responses that were complete and from people who were responding to the questionnaire for the first time and were over age 18 were included. This survey was approved by the CNRS ethics committee. Data collection was strictly anonymous. The protocol complies with the revised Declaration of Helsinki and the study was approved by the ethics committee of the Institute of Biological Sciences of the CNRS on the 3rd of April 2020 (DPO #TRRECH-467). All individuals provided informed consent when participating in the survey.

Online trends. Trends of online queries by French region were performed using Google Trends, a tool returning the popularity of a search term in a specific state or region. Google is by far the most used search engine in France (>90% of internet searches, according to StatCounter Global Stats). We looked for the popularity of terms (listed in Supplementary Fig. 3, using default selection of "All categories" and "Web search"), within the timeframe of February 1, 2020 to May 10, 2020 (from the month of the first official COVID-related death in Europe to the end of lockdown in France). It should be noted that Google Trends does not provide the actual numbers of searches but rather a relative score from 0 to 100 (100 corresponding to the day with the greatest number of searches during the specified time period). To compare Google Trends scores between French regions, we transformed them by computing the relative number of queries per day in the region of interest. For example, despite a value of 100, the peak day might represent only 5% of the total number of queries related to the topic across the timeframe of interest (see above).

Healthcare system data. The French governmental indicator to estimate the circulation of the virus was calculated from the ratio of consultations for suspected COVID-19 to general consultations at the emergency room (ER) in hospitals. This ratio corresponds to the medical diagnostic for COVID-19 suspicion (codes CIM10: U07.1, U07.10, U07.11, U07.12, U07.14, U07.15, U04.9, B34.2, B97.2). The definition of COVID-19 has evolved rapidly during the lockdown period but the diagnosis is principally based on symptoms of COVID-19 considered as common such as fever, cough, and dyspnea (difficulty breathing). To the best of our knowledge, anosmia and ageusia were officially considered in France as putative symptoms of COVID-19 from a letter of the Direction Générale de la Santé (April 1st) and communication of the Haut Conseil de la Santé Publique (a letter dated April 8, published online April 15, following a letter from the CNP-ORL dated March 20). Areas with values of the French governmental indicator higher than 10% are considered having a high virus circulation. This indicator contributes to the assignment of a red/green label. Allergies incidence in previous years were calculated from the ratio of consultations for Allergy to general consultations at the emergency room (ER) in hospitals.

Data dealing with the health status across countries (number of COVID-19 cases and deaths for each day) were downloaded on May 22, 2020 from the European Centre for Disease Prevention and Control databank (ECDC, https:// www.ecdc.europa.eu/en). Data regarding healthcare system stress in France (hospitalizations, CCRU entries and deaths) were also downloaded on May 22 from the French Public Health website (Géodes, Santé Publique France, https:// geodes.santepubliquefrance.fr/#c=home). Here, we use the term CCRU (Critical Care Resuscitation Unit) to translate the French hospital service of "Réanimation." Raw data were normalized across regions with regard to their number of inhabitants as estimated by INSEE. The temporal evolution of the stringency of government response was retrieved from the Oxford COVID-19 (https://www.bsg. ox.ac.uk/research/research-projects/coronavirus-government-response-tracker).

Here, the stringency level of a country is computed according to which measures of a list of items (e.g., school closures, cancellation of public events, international travel controls, etc.) are undertaken. For the post-lockdown situation, the color assigned by the French government to each department was downloaded on May 12 from the government website. Only data before May 11 (the initial lift of the lockdown) were included in the analyses.

Statistical analyses. Statistical analyses were pre-registered at the Open Science Framework (OSF). Data were analyzed using R software (4.0) and its standard packages (maps, ggplot, etc.). Data were grouped at the national level (France, Italy, UK). In France they were also grouped at the regional level (according to the division into 22 regions in place prior to the 2016 reform). The rationale behind this is that the healthcare system is still structured following this organization, with University Hospitals in regional main cities serving patients of the surrounding departments. Participants from overseas French territories were not included in the geographical analysis because of too few data (n < 10). The relationship between (1) GCCR responses (or online queries), and (2) public health data was determined using parametric (e.g., Pearson correlations) statistics as allowed by the normal distribution of the variable of interest. The association between GCCR participant and red/green post-lockdown status was tested using Chi-square tests and Biserial correlations. Complementary analyses not planned in the pre-registration included: (i) the analysis using the independent French online survey (see section "Complementary and independent French Survey" of the methods), (ii) the correlation between regional media coverage and the number of responses to the online survey per region, (iii) the correlation at the level of department, (iv) the correlation excluding extreme points, and (v) the correlation with the government indicator. Pre-registered statistical analyses not presented here include: (i) Mann-Kendall trend test and Change-point Detection test to detect time series changes, and (ii) part of the Google Trends analysis.

dFig. 1

 1 Fig. 1 Changes in smell and taste as indicators of overwhelmed healthcare systems: geographic and time-related approaches. a French regions were assigned a green or red status by the French government to guide local relaxation of lockdown protocols. Dots represent people self-reporting smell and taste changes in a web-based survey. Base map is from OpenStreetMap and OpenStreetMap Foundation. b The number of COVID-19-related CCRU admissions (as of May 11, 2020) correlated with the number of self-reported chemosensory changes (between March 1 and May 11, 2020, total n = 3832). Green dots correspond to regions with a post-lockdown level labeled green, and red triangles indicate regions considered red. Values are standardized based on the number of inhabitants (inhab.) for each regions. The two red triangles with CCRU admissions >5 are Alsace and Ile de France. The gray band represent the confidence interval of the linear smooth (formula 'y ~x') R and p represent value of the test for association between paired samples, using one of Pearson's product moment correlation coefficient, without correction for multiple comparisons. c Colored bar represent the value of computed correlation coefficients (confidence intervals are depicted as thin black bars) between the number of CCRU admissions per area and i) the number of people reporting smell and taste changes (n = 3832, blue), and ii) the governmental indicator (Gov. indicator), ratio of ER consults for COVID-19 (orange). Analyses were done both at the level of metropolitan regions (Reg) and departments (Dep). d Temporal relationships in France between smell/taste change symptom onset (blue solid line, n = 1476), the governmental indicator (orange dashed line), and COVID-19 cases in CCRUs (gray bars) around the lockdown period (vertical dashed line). Data are 7-day running averages, normalized to the day with the highest value.

Fig. 2

 2 Fig. 2 Evolution of COVID-19 indicators before and after the lockdown in France, Italy and the UK. The daily proportion of first symptoms is shown as a violet line (France, n = 4720, Italy, n = 1241, UK, n = 750). The daily proportion of smell/taste changes is shown as a blue line (France, n = 1487, Italy, n = 264, UK, n = 263). The daily proportion of COVID-19 confirmed cases from the European Centre for Disease Prevention and Control (ECDC) is shown as a red dashed line. Each panel shows both raw data (thin line) and the corresponding 7-day running average (thick line). The government response stringency index is shown as the background color.

  ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-18963-y 6 NATURE COMMUNICATIONS | (2020) 11:5152 | https://doi.org/10.1038/s41467-020-18963-y | www.nature.com/naturecommunications

Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article.

NATURE COMMUNICATIONS | (2020) 11:5152 | https://doi.org/10.1038/s41467-020-18963-y | www.nature.com/naturecommunications

Acknowledgements

This work was supported financially by EXTREM-O (CNRS MITI), CONFINEZ2 (CNES), the CORODORAT grant (IDEX-Lyon-Université de Lyon), by the French government, through the UCAJEDI "Investments in the Future" project managed by the ANR grant No. ANR-15-IDEX-01. The authors thank Sébastien Buthion, Conceição Silva, Brigitte Perucca, Clément Blondel, Stéphanie Younès, François Maginot, and their teams from the CNRS communication units, as well as the Global Consortium for Chemosensory Research (GCCR). Deployment of the GCCR survey in multiple languages by the Pennsylvania State University (Penn State) was partially supported by funds from James and Helen Zallie and the Penn State Sensory Evaluation Center.

Data availability

The authors declare that the data supporting the findings of this study are available within the paper and its supplementary information files. (Source Data file). Source data are provided with this paper.

Code availability

R scripts are available on the osf server (https://osf.io/gew7p/).

Author contributions

Conceived, designed the study, and wrote the paper: D.P., V.P.-L., C.F., J.G., M.B. Data acquisition and curation: D.P., V.P., M.M., M.M., E.B., O.A., J.K., M.H., J.P., R.D., C.D., S.S., E.M., M.C.F., K.W.C., E.A.S., T.T.D., A.J.B., V.P., J.E.H., T.L., C.F., J.G., M.B. Performed analysis: D.P., V.P.-L., C.F., J.G., M.B., M.M.a., M.M.o., E.B. Edited and approved the final manuscript: D.P., V.P., M.M., M.M., E.B., O.A., J.K., M.H., J.P., R.D., C.D., S.S., E.M., M.C.F., K.W.C., E.A.S., T.T.D., A.J.B., V.P., J.E.H., T.L., C.F., J.G., M.B.

Competing interests

The authors declare no competing interests.


Isabelle Saniour

Jean-Marie Verret

Cécile Rabrait-Lerman

Frank Pilleul

PhD CREATIS Olivier Beuf
email: olivier.beuf@creatis.insa-lyon.fr

J.-M Verret

Feasibility and characterization of a safe susceptibility-matched endorectal coil for MR spectroscopy

Keywords: Endorectal coil, susceptibility-matching material, RF heating

come

INTRODUCTION

Colorectal cancer is the third most common cause of death among adult cancer patients in the United States [START_REF] Costa-Silva | Magnetic Resonance Imaging of Rectal Cancer[END_REF] . The prognosis and the treatment course strongly depend on proper disease staging, which requires examination of the different layers of the rectal wall. For the initial staging of rectal cancer, endorectal ultrasound imaging is presently the most appropriate technique available, especially in the early T1 and T2 stages (following the Tumor Node Metastasis [TNM] classification).

The assessment of local recurrence is particularly accurate with magnetic resonance imaging (MRI) phased array coils, but they have poor specificity and sensitivity in the early stages of colorectal cancer [START_REF] Torricelli | Rectal cancer staging[END_REF] . Indeed, the signal-to-noise ratio (SNR) provided by MR surface array coils is insufficient at clinical fields (1.5 T and 3 T), and the achievable spatial resolution is, in this specific case, unsatisfactory. Since endorectal coils provide a significantly higher local signal sensitivity, higher spatial resolution may be achieved [START_REF] Stoker | Endoluminal MR Imaging of the Rectum and Anus: Technique, Applications, and Pitfalls[END_REF] . Endorectal MRI is thus believed to be a promising imaging examination.

The use of this type of coil has been controversial, however, because the signal distribution in the MR images may be inhomogeneous and the field of view (FOV) is limited. Artifacts caused by the coupling between the radiofrequency (RF) electric field and the conductive materials may affect images acquired with endorectal coils. These artifacts have been reported in the MRI literature as the "RF field non-uniformity." [START_REF] Dempsey | Investigation of the factors responsible for burns during MRI[END_REF] In fact, the reception cable, connecting the coil to the MR scanner, is sensitive to the electric component of the RF excitation field. Consequently, sheath currents are generated in the reception cable ground. At 3 T, the wavelength (λ) in air of the RF magnetic field for protons is 234 cm; however, λ depends on the electric permittivity of the medium and is given by:

0 0 r r c c f f        (1)
where c 0 is the velocity (m/s), f corresponds to the frequency (Hz), λ 0 is the free space wavelength (m), and ε r is the relative permittivity of the medium (without a unit).

First, this RF field non-uniformity will produce an inhomogeneous MR image thus altering the apparent coil sensitivity profile and leading to hypo-intense areas (black bands). Second, it will be the source of RF heating hazards in the surrounding tissues [START_REF] Armenean | IRM Interventionnelle : Risques de brûlure du patient et du radiologue[END_REF][START_REF] Konings | Heating Around Intravascular Guidewires by Resonating RF Waves[END_REF] . RF heat suppression circuits (such as RF traps) attenuate the amplitude of the electric currents circulating in the ground of the reception cable. Three architectures of RF traps are mainly used: conventional passive RF traps [START_REF] Harrison | RF coil coupling for MRI with tuned RF rejection circuit using coax shield choke[END_REF][START_REF] Wynn | Tunable resonant cable trap[END_REF] , floating traps [START_REF] Seeber | Floating shield current suppression trap[END_REF] , and active RF traps [START_REF] Zanchi | Feasibility of Active Cable Trap to Attenuate MRI-Induced RF Currents[END_REF] . Floating and active RF traps are attractive and efficient techniques but more complicated to implement compared with passive traps. The passive RF trap is a widely used solution. Such circuits are easier to realize and potentially compact in size, but numerous traps need to be placed along the cable in order to achieve a complete suppression of RF heating. The location of the RF traps affects the efficiency of RF heat suppression, and they should be placed on the maxima of the standing wave circulating in the reception cable [START_REF] Peterson | Common mode signal rejection methods for MRI: Reduction of cable shield currents for high static magnetic field systems[END_REF] .

To date, endorectal coils have been mainly evaluated for examinations of the prostate (prostate endorectal coil, PEC) or the rectal wall (colorectal endorectal coil, CEC). In vivo 1 H magnetic resonance spectroscopy (MRS) has shown to have clinical value in the diagnosis of brain, breast and prostate cancer. For instance, MRS provides relevant information on the metabolism of prostate cancer by locating and measuring levels of citrate, choline, creatine and polyamines [START_REF] Heerschap | In Vivo Proton MR Spectroscopy Reveals Altered Metabolite Content in Malignant Prostate Tissue[END_REF][START_REF] Scheenen | Multiparametric Magnetic Resonance Imaging in Prostate Cancer Management: Current Status and Future Perspectives[END_REF] . The use of endorectal coils improve SNR and give access to higher spatial and temporal resolution that may be also useful for diagnosing and monitoring of Inflammatory Bowel Disease Whereas clinical CEC migration is usually prevented by the organ itself (with the tightening of the colon [START_REF] Dorez | In vivo MRS for the assessment of mouse colon using a dedicated endorectal coil: initial findings[END_REF] ), manufactured coils are usually built with a plastic casing around an in-plane loop (or even two as is the case for the "Noras" two-channel endoanal coil) thus creating an air cavity [START_REF] Dwarkasing | Chronic Anal and Perianal Pain Resolved With MRI[END_REF] . A magnetic susceptibility artifact will then be created by the air-tissue interface between the coil and the surrounding tissues of the rectal wall. Depending on the geometry, a large difference in magnetic susceptibility between the two media can produce significant B 0 magnetic field inhomogeneity and magnetic field susceptibility gradients at the interface between the two media.

The MRS is very sensitive to B 0 magnetic field inhomogeneity and thus requires susceptibilitymatching strategies [START_REF] Powell | Comparison of comfort and image quality with two endorectal coils in MRI of the prostate[END_REF] . A previous clinical study of patients with prostate cancer used a PEC inflated with a perfluorocarbon compound (PFC) instead of air and thereby significantly improved B 0 uniformity showing a full width at half maximum (FWHM) reduced by a factor of 2. Another study compared MRS examinations of the prostate with a PEC inflated with air, PFC, or barium sulfate suspension at 100% w/v and demonstrated a significant and similar decrease in the FWHM for PFC and barium sulfate. The authors thus recommended barium sulfate since it is less expensive than PFC [START_REF] Lee | Pyrolytic graphite foam: A passive magnetic susceptibility matching material[END_REF] . Furthermore, PFC produces no visible signal on proton MR images whereas barium sulfate produces low-intensity signal.

The present feasibility study aimed at characterizing a safe susceptibility-matched endorectal coil for MR examination of the rectal or colonic wall. Temperature measurements and specific absorption rate (SAR) calculations were performed to assess the safety of the endorectal coil.

Several miniaturized RF traps were built and incorporated in the reception cable to achieve efficient RF heating reduction and a temperature increase of less than 1 ° C, following the IEC-60601 requirements. The coil sensitivity pattern with and without traps was also compared.

Secondly, after a comparison of Ultem TM (Sabic, Riyadh, Saudi Arabia) with other susceptibilitymatched materials already described in the literature, a susceptibility-matched endorectal coil incorporating Ultem TM material was built. Finally, the performance of this coil for spectroscopy acquisitions was assessed using phantoms containing metabolite solutions.

METHODS

All experiments were performed on a GE MR750 3 T system (General Electric Healthcare, Milwaukee, WI, USA) using a custom-made endorectal receiver coil (60 mm length, 6 mm width), as shown in Figure 1. A variable number of miniaturized passive RF traps, parallel LC circuit consists of a fixed inductor (L = 200 nH) and a variable capacitor (2-22 pF), were incorporated in the reception cable for RF heat suppression. We varied the capacitor until the trap was tuned to 128 MHz. The impedance of the trap was estimated using the S21 parameter with and without the trap. The trap adds an impedance of around 700 kΩ.

Safety of the endorectal coil: RF heating reduction

Experimental temperature measurements

First, local temperature measurements were performed with and without miniaturized RF traps incorporated in the reception cable to assess RF heating reduction below the authorized level. The endorectal coil was placed in a cylindrical phantom (120 mm height and 200 mm diameter), as shown in Figure 2. It contained 1.5% agar-agar gel doped with 0.9% NaCl (phantom 1), whose electrical conductivity was σ = 1 S/m, which is a suitable medium for heat propagation. Four fiber optic probes were taped on the endorectal coil only and not on the cable: three at the distal extremity and one at the proximal base of the coil and connected to a temperature measurement device -0.1 ˚C resolution, 0.4 Hz sampling rate (Tempsens device from Opsens, Quebec, Canada).

These locations were determined in accordance with previous studies demonstrating that heating concentrations occur at the distal extremities of a conductive object This assumption is applicable for small-sized elongated endorectal coils. Furthermore, as a preliminary step, temperature measurements were performed by moving the tip of the optical fiber along the distal extremity of the endorectal coil during the acquisition, until no superior temperature increase was found. Fastspin echo (FSE-XL)-the GE optimized version of fast-spin echo, which includes blurring cancellation for improved quality-axial images were acquired with the endorectal coil, first without any RF traps and then with five RF traps integrated into the reception cable. The cable path and cable length were kept the same.

The degree of RF heating depends on various parameters: the local electric fields induced by the energy transmitted to the phantom or tissue, the properties of the tissue, as well as the dimensions and geometry of the coil, the length of the cable and the position of the traps along the cable. The amplitude of the electric field is proportional to the amplitude of the RF magnetic field emitted at a constant duration. Indeed, a short TR produces a more intense time-averaged electric field. Moreover, the quadratic increase in temperature with the flip angle was confirmed experimentally by Armenean et al. [START_REF] Armenean | IRM Interventionnelle : Risques de brûlure du patient et du radiologue[END_REF] in the case of True-FISP or FIESTA sequences. Hence, there is a tradeoff between flip angle and repetition time. In our experiments, TR was kept short to enable a high average electric field, and a 35° flip angle was applied in order to avoid melting of the surrounding agar-agar gel and thus modification of its thermal properties.

For temperature measurements, the reception cable length, the cable path, the acquisition sequence, and the scan parameters were set for the worst-case scenario (the maximum heating). A FIESTA (equivalent to True-FISP or balanced FFE) sequence was used; it consists in a steady-state free precession sequence where gradients are balanced on all axes over a single TR. The parameters of the sequence were: acquisition time = 96 s, flip angle = 35˚, FOV = 48x48 cm², matrix = 128x128, bandwidth = 250 kHz, and TE/TR = 0.99ms/2.7ms. The receiver cable was an RG58 coaxial cable whose length remained constant at 310 cm and which incorporated between 0 and 5 RF traps. The RF traps were placed as shown in Figure 2. The trap bulk size was kept restricted: 7 mm outer diameter, which is the diameter of the air core inductance and only enlarges the RG58 cable diameter by 2 mm. Inside the bore magnet, the receiver cable path passed through the maxima of the electric field. These maxima were located using an electric dipole linked to an LED HLMP 4015 (Agilent Technologies, Santa Clara, CA, USA) whose luminous intensity thus reflected the intensity of the electric field. Finally, the RF traps were shielded, in order to prevent them from receiving currents generated by the magnetic field. The shield consisted of a copper casing surrounding the RF trap. resulting in a near-null magnetic field inside the copper casing. This was realized by using a 0.1-mm copper tape wrapped around the body of the RF trap.

Numerical estimations of SAR

Based on temperature variation measurements, the local SAR values can be estimated using he a generic Bioheat Transfer Thermal Modal [START_REF] Yeung | RF safety of wires in interventional MRI: Using a safety index[END_REF] . However, an agar-agar phantom was used for this experiment and there is no perfusion. Thus,the local SAR values were numerically estimated using a simplified bioheat equation and the parameters related to the perfusion and the metabolic heating were not considered:

    B T ρc κ T ρ SAR B T T A t          . . ( 2
)
where SAR is in W/kg, T is the temperature of the medium in °C, t is the time in s, ρ is the density in kg/m 3 , c is the specific heat, κ is the thermal conductivity, B is a coefficient related to blood perfusion, T B is the blood temperature in °C, and A is the basal metabolic rate.

The numerical estimations were performed with Matlab R2012b (The MathWorks Inc., Natick, MA, USA) using the PDE toolbox. The same coil geometry previously described, and an agar-agar phantom (70 mm thickness, 200 mm diameter) were designed and imported to Matlab. The thermal properties of the agar-agar gel were assigned to the disk (k = 0.55 W/(m.°C), ρ = 998 kg/m 3 , c = 4200 J/(kg.°C)). Using equation ( 2), the temperature distribution in an agar-agar phantom was simulated.

The simulation was first performed with an arbitrarily high local SAR value (100 W/kg) at the two proximal and distal sides of the coil where the temperature increase is the highest. The mesh element (the "hot spot") yielding the maximum temperature increase ΔTsim was selected and compared with the experimental temperature increase, ΔTexp. The estimation was then iterated with different values of local SAR, following a dichotomy process; the local SAR value was estimated.

The input power is given by the lumped port that simulates the coaxial cable. The temperature distribution was simulated for a duration of between 0 and 360 s (temporal resolution of 0.01 s).

For each mesh element (16,192 triangular mesh elements covering the surface), the corresponding temperature increase was computed. The size of the mesh element was approximately 1.9 mm 2 ensuring a tight mesh of the surface.

Comparison of susceptibility-matched materials

Several candidates for susceptibility matching were investigated in order to reduce the magnetic susceptibility artifact. The susceptibility of human tissues was considered close to water susceptibility (a classic assumption). Ultem TM as shifts in pixel position ∆x. However, the same pixel shifts will be much more visible for an object of small dimensions than for an object of larger dimensions. Assuming a cylindrical shape, x/a was computed, where a is the radius of the cylinder creating the distortion (20). x/a was equal to 2.70 for air, 2.02 for barium sulfate, 0.42 for PFC, and finally 0.035 for Ultem TM .

MR images were acquired with an HD T/R knee array coil (GE Healthcare, Milwaukee, WI, USA) on a 60-mm-diameter cylinder filled with saline water with 4.5 g of salt per liter of distilled water (phantom 2, Figure 3), thus simulating, from a magnetic susceptibility point of view, the human tissues which is usually considered within 15% [START_REF] Shrivastava | A Generic Bioheat Transfer Thermal Model for a Perfused Tissue[END_REF] of the magnetic susceptibility of water. The central hole (6 mm diameter) allowed for the insertion of an Ultem TM cylinder (6 mm diameter, 60 mm length) whose dimensions were identical to the endorectal coil. The peripheral holes (5 mm diameter) were regularly placed (every 60 °) around the central hole and facilitated the insertion of high-resolution NMR tubes. The tubes were located 1 cm away from the center of the phantom and contained air, water, barium sulfate, or PFC. Three locations labeled 1, 2, and 3 must be considered.

Locations 1 and 2 housed the susceptibility-matched materials assessed (Ultem TM , PFC, or barium sulfate). Location 3 housed an empty tube that serves as a reference for the air-water interface and describes the artifacts that appear when the magnetic susceptibility artifact is not considered.

The phantom axis was oriented orthogonally to the B 0 magnetic field; this orientation makes it possible to highlight the B0 inhomogeneity and therefore the magnetic susceptibility artifact. For a given susceptibility difference between two media and a given shape (cylindrical or other), artifact amplitudes will depend on the orientation of the object regarding the magnetic field B 0 . For a cylinder, it is maximal when the cylindrical axis is orthogonal to B 0 . The phantom thus had an orthogonal orientation during the experiments. The difference in susceptibility between two media results in artifacts in the shape and signal intensity due to pixel shifts in the readout direction [START_REF] Shrivastava | A Generic Bioheat Transfer Thermal Model for a Perfused Tissue[END_REF] . The pixel shifts occur in the readout direction (with the exception of echo planar imaging) and can be formulated as Δx = ΔB z (x,y)/G R with G R the readout gradient in the x direction. The magnetic susceptibility artifact was maximized with a low readout gradient amplitude (narrow receiver bandwidth for a given FOV). The slice thickness was set to 2 mm to limit slice deformation during the selection process in the presence of inhomogeneity. The shim values were kept the same across all acquisitions in order to observe differences arising from the susceptibility modifications only.

MRS using a susceptibility-matched endorectal coil

Having tested different susceptibility-matched materials, an endorectal coil incorporating Ultem TM was compared with an endorectal coil without filling material and referenced as "standard." The standard endorectal coil encompassed an air cavity. The susceptibility-matched endorectal coil uses Ultem TM as a solid support for the double loop structure of the coil, thus suppressing this air cavity. The endorectal coil used is a surface coil. The coil is composed of two rectangular loops in series, as shown in Figure 1. This design was chosen to optimize the radial uniformity of the coil, while keeping a similar SNR (compared with a single rectangular loop) [START_REF] Schenck | The role of magnetic susceptibility in magnetic resonance imaging: MRI magnetic compatibility of the first and second kinds[END_REF] . This RF coil is a single-channel receiver coil similar in design to a double-channel receiver coil with two rectangular loops in geometrical quadrature [START_REF] Armenean | Optimization of endoluminal loop radiofrequency coils for gastrointestinal wall MR imaging[END_REF] . Tuning and matching of the coil were performed with a serial capacitive tuning and matching circuit using capacitors (ATC 100A), and active decoupling was performed with a PIN diode (Temex 80106) placed in parallel with the coil, which detunes the coil during the transmit phase.

The performance of the coils was first assessed by quality factors Q L measured on the bench with a network analyzer E5071C ENA Network Analyzer (Agilent Technologies, Santa Clara, CA, USA).

The loaded quality factor Q L was measured: The endorectal coil was inserted in a tube placed inside a small bottle of saline water with 4.5 g of salt per liter of distilled water (phantom 3), creating losses similar to those obtained with a larger water phantom. For both endorectal coils, the quality factor was measured with this same phantom. Bench tests were performed with and without RF traps, while keeping the total cable length at 175 cm.

Then, to assess the relevance of using a susceptibility-matched material as a support for the endorectal coil, single-voxel PRESS acquisitions were performed to compare the FWHM of proton MR spectra obtained with the standard and susceptibility-matched endorectal coil. The endorectal coils were inserted in the central hole of a cylindrical phantom previously used for the comparison of susceptibility-matched material (Figure 3).

Furthermore, for examination of the rectum, the patient is usually in supine position and thus the lumen (until the left colonic flexure) defines a small angle with the B 0 magnetic field. Therefore, PRESS acquisitions were performed in the xy plane with 0 °, 15 °, 30 °, and 45 ° angulations between the phantom axis and the B 0 magnetic field direction. The pre-scan parameters (transmit and receive gains, central frequency and shim values) were defined with the endorectal coil aligned with B 0 and then kept identical throughout the experiments. The NMR tubes contained choline or creatine solutions at 50 mmol/L.

For the first series of data, the voxel was prescribed on a small volume of 4×4×4 mm 3 (the minimum volume that can be prescribed with a standard PRESS sequence on the MR scanner in clinical mode) inside an NMR tube (Figure 4a). For the second series of data, the prescription of the voxel was realized on a larger volume of 10×24.8×25.5 mm 3 including the endorectal coil (susceptibility-matched or not) and two NMR tubes containing metabolite solutions. In both cases, the other parameters were: TE/TR = 35 ms/1800 ms, spectral bandwidth = 5 kHz, number of sampling points = 4096, number of accumulations = 128, and scan duration = 230.4 s (Figure 4b).

For the choline and creatine singlets, the baseline level was computed as the mean of the signal over a definite region of the spectrum [-2ppm; -1ppm] where there are no metabolites. The FWHM was then determined to be insensitive to baseline suppression errors.

Finally, to assess the relevance of using an endorectal coil, the SNR of the susceptibility-matched endorectal coil was compared with the SNR of a clinical 32-channel surface coil. A cubic phantom containing water with 4.5 g of salt per liter of distilled water and doped with gadolinium at 0.57 mmol/L, in order to reduce the T1-value (phantom 4, Figure 8), was used for SNR comparison. First, SNR profiles were acquired with proton density-weighted FSE-XL imaging. Then the SNR of a singlevoxel PRESS acquisition was compared for both the susceptibility-matched endorectal coil and the 32-channel torso array coil. The endorectal coil was able to acquire a spectrum on a restricted volume 4×4×4 mm 3 unlike the 32-channel coil, which was simply not sensitive enough. Therefore, in order to gain a sufficient SNR for the 32-channel coil, the spectra had to be acquired on a larger volume: 10×10×10 mm 3 . The normalization of SNR with volume allows the comparison to be made, even though acquisitions were performed on different volumes.

Results

Without any RF heating suppression circuits, the maximum increase in temperature was 7 °C (Figure 5a). The introduction of five RF traps decreased it to 0.4 °C for a cable length of 310 cm. Thus RF heating was below the authorized level in clinical mode, which is 1 °C 26 . Furthermore, local SAR estimates indicate that for five RF traps (Table 1, Figure 5b), the maximal local SAR is 5 W/kg and below the IEC-60601 standard, which requires an SAR of < 10 W/kg estimated over a 10-g mass. On

MR images acquired with the fast-spin echo images, the incorporation of five RF traps suppressed the black band artifacts marking the RF field non-uniformity (Figure 5c,d) and restored the expected coil sensitivity pattern.

As expected, visible image distortions occurred in the presence of air-water interfaces. These distortions appeared as arrowhead shapes on fast-spin echo images and as irregular shapes on gradient echo images (at location 3 in Figure 6) [START_REF] Dybdahl | International Electrical Commission System for Conformity Testing and Certification of Electrotechnical Equipment and Components (IECEE). Patient protection at risk in IEC 60601-1 3rd edition[END_REF] and demonstrate the need for a susceptibilitymatched material. Barium sulfate created a slight visible distortion on both fast-spin echo and gradient echo images. PFC and Ultem TM did not produce any visible distortion, neither on fast-spin echo nor on gradient echo images.

The comparison plots of spectra obtained on two metabolites showed a similar SNR for both coils (Figure 7), which was already expected from the bench tests results. The loaded quality factor Q L achieved with the endorectal coil was 88 and dropped to 84 with the adjunction of five RF traps.

With the endorectal coil built with Ultem, the Q L achieved was 100 and dropped to 91 with the adjunction of five RF traps.

For both RF coils, with and without Ultem, the insertion of five RF traps created a slight 4% and 10% decrease in the quality factor, respectively. Furthermore, a reduced linewidth was obtained for an endorectal coil using Ultem compared with an endorectal coil of the same geometry but encompassing an air cavity. These reduced linewidths were observed for both metabolites tested (choline and creatine). For a 0 ° angulation, FWHM was decreased by using the susceptibilitymatched endorectal coil: by 28% for choline and 38% for creatine. For a 15 ° angulation, FWHM was decreased by 37% for choline and 49.7% for creatine (Table 2). MR images acquired with a susceptibility-matched endorectal coil showed no distortions despite parameters being set to maximize the magnetic susceptibility artifact.

The SNR of the 32-channel surface coil was uniform across the FOV whereas the SNR of the endorectal coil decreased with distance. The SNR profiles showed a superior SNR for the endorectal coil for a distance between 0 and 3.5 cm from the center of the endorectal coil. In spectroscopy, the volume-normalized SNR was between 3 and 7 times greater using the endorectal coil (examples of spectrum in Figure 7). These results are consistent with the SNR derived from the image sensitivity profiles with the distance: at 1 cm, the SNR of the endorectal coil was around 400 and the SNR of the 32-channel coil was between 50 and 75, yielding a ratio between 5 and 7.8 (Figure 8).

Discussion

In the present study, the safety of the endorectal coil was ensured with the incorporation of several RF traps. Indeed, without any RF traps, significant heating (up to 7 °C) occurred. In addition, the incorporation of five passive RF traps along the cable connecting the endorectal coil to the scanner enabled efficient RF heating reduction.

Based on these temperature measurements, the local SAR estimates were found to be inferior to the required level and lend confidence to the assumption that no significant heating may occur.

This method of local SAR estimation does not account for the third dimension, which should not be a problem since the agar-agar gel phantom may be considered homogeneous. However, the impact of the presence of the coil may modify the simulated temperature distribution. It was therefore important to conduct local 3D SAR simulations that also confirmed the location of hot spots for this specific case of elongated planar endorectal coil.. The results confirmed that hot spots are located at proximal and distal extremities, verifying that optical fiber sensor was accurately positioned to measure the local temperature. The temperature measurements were conducted with a 310-cmlong reception cable. A shorter cable would imply inferior RF heating and would not allow us to measure the effect of each trap on the temperature decrease.

The size of the RF traps was also kept to a minimum (outer diameter below 7 mm) to allow for an easy insertion through the rectum of the patient.

The RF traps made it possible to experimentally minimize the RF field non-uniformity (Figure 5c,d). From a physical standpoint, this artifact is due to the standing wave (sheath currents) occurring in the reception cable and manifested by black curves disrupting the sensitivity of the coil.

Electromagnetic simulations are not the main focus of this article but these could be performed to provide a theoretical confirmation of this phenomenon.

The strategy of incorporating several RF traps in the galvanic connection between the coil and the scanner is not the only one that can be adopted to reduce the electric field artifact, and some ongoing studies have assessed the feasibility of an optical connection both for the NMR signal received and for the active optical decoupling of the reception coil. This strategy would directly suppress the electric field artifacts, but at the cost of greater design complexity [START_REF] Beuf | Magnetic Resonance Imaging for the Determination of Magnetic Susceptibility of Materials[END_REF][START_REF] Ayde | Potentialities of an Electro-Optic Crystal Fed by Nuclear Magnetic Resonant Resonant Coil for Remote and Low-Invasive Magnetic Field Characterization[END_REF] .

Our experiments confirmed that a susceptibility-matched endorectal coil significantly enhanced the ability to acquire non-distorted images whether using fast-spin echo or gradient echo sequences. It should be noted that several studies have shown that Ultem may have a larger signal distribution at higher static magnetic field, 4.7 T 30 and 9.4 T 31 . However, at 3 T, PFC and Ultem TM were found to be superior to barium sulfate 100% w/v since they yielded no visible distortion and no signal from these materials could be observed, thus avoiding unwanted signal in the regions immediately surrounding the endorectal coil. Therefore, Ultem TM has comparable performance to PFC and is superior to barium sulfate using both FSE-XL and GRE sequences. However, because we need to integrate the susceptibility-matched material inside the coil, Ultem TM has the extra advantage of being a solid and a machinable plastic. PFC, on the contrary, is a liquid and requires a more complex integration with the coil with possible liquid leakage.

This absence of image distortion indicates a better B 0 homogeneity, which was confirmed by the MRS acquisitions. For every metabolite, the spectra acquired with the susceptibility-matched endorectal coil showed a consistent decrease in the FWHM (~30 %) compared with the original endorectal coil, and this tendency was confirmed for small angulations of the phantom. As expected, improved B 0 homogeneity involves a narrower linewidth with less potential overlap. The quantitative values of the FWHM were found to be inferior to those obtained in the literature [START_REF] Lee | Pyrolytic graphite foam: A passive magnetic susceptibility matching material[END_REF][START_REF] Babcock | Multinuclear nmr investigations of probe construction materials at 4.7 t[END_REF] ; however, the latter values were obtained in vivo, unlike the present work performed on phantoms.

It has been shown that colorectal cancer produces metabolic changes that can be seen on spectra [START_REF] Choi | Use of Perfluorocarbon Compound in the Endorectal Coil to Improve MR Spectroscopy of the Prostate[END_REF] . This makes MRS an interesting modality for noninvasive chemical analysis of local tumors and may avoid the systematic use of histology studies. For example, choline and citrate metabolites are pertinent biomarkers of prostate cancer [START_REF] Duarte | Metabolic signatures of cancer unveiled by NMR spectroscopy of human biofluids[END_REF] . Thus, the improved quality of the spectra obtained with susceptibility-matched materials seems very promising. Besides, compared with the SNR obtained with a 32-channel torso coil, which is often used in the examination of the abdomen and rectal wall [START_REF] Kurhanewicz | Multiparametric magnetic resonance imaging in prostate cancer: present and future[END_REF][START_REF] Roach | Magnetic resonance imaging of anal cancer[END_REF] for rectal cancer staging, the SNR of the endorectal coil is very significantly superior within a radius of 3.5 cm, corresponding to the targeted region of interest. This would be relevant for in vivo MRI and even more so in MRS [START_REF] Beaumont | MR Evaluation of Rectal Cancer: Current Concepts[END_REF] where in vivo metabolite concentrations are lower than in the phantom used. Hence, the extra SNR could be used to either reduce the voxel size or to reduce the acquisition time.

In conclusion, Ultem TM is a suitable susceptibility-matched material for endorectal coils: It can significantly cancel magnetic susceptibility artifacts at the coil-tissue interface, it does not depict any visible proton signal, and is a solid material that can be used as support for loop conductors.

With the adjunction of five RF traps located at regular intervals along the reception cable, RF heating is reduced below authorized levels and the coil sensitivity profile is restored. The comparison with a 32-channel array coil demonstrated a superior SNR in a 3.5-cm radius around the endorectal coil.

Since the rectum tightens around the endorectal coil, the rectal wall would be located at approximately 4-5 mm from the center of the endorectal coil. It will thus be possible to achieve a significantly smaller volume of examination in the rectal or colonic wall close to the lumen with an adequate SNR.

Tables

Table 1. Temperature rise ΔT as a function of the number of RF traps (based on give measurements) and subsequent SAR estimations.

ΔT is the difference between the final temperature, at the end of the FIESTA sequence, and the initial temperature, at the start of the FIESTA sequence.

Number of traps

Finally

  , an FSE-XL sequence was acquired with TE/TR = 29.1 ms/1500 ms, echo train =10, slice thickness = 2 mm, matrix = 320 × 256, FOV = 70 × 70 mm 2 , pixel bandwith = 27.1 Hz/px, and a gradient echo (GRE) sequence was acquired with TE/TR = 15.8 ms/300 ms, flip angle = 30 °, slice thickness = 2 mm, matrix = 512 × 384, FOV = 80×80 mm 2 , and pixel bandwith = 46.5 Hz/px.

  [START_REF] Dorez | In vivo MRS for the assessment of mouse colon using a dedicated endorectal coil: initial findings[END_REF]

  (i.e., Polyetherimide: C 37 H 24 O 6 N 2 ) is sometimes used as a plug for high-resolution NMR of liquids (susceptibility-matched sample plugs at Doty Scientific The consequent maximum B 0 field inhomogeneity due to the magnetic susceptibility difference with water is 0.24 ppm for Ultem TM versus 11.2 ppm with barium sulfate or 2.3 ppm with PFC. Ultem TM thus theoretically creates a B 0 field inhomogeneity much smaller than other susceptibility-matched materials especially at intermediate field. B 0 field inhomogeneities generate MR image distortions that can be measured

	Inc., Columbia, SC, USA) and is a solid plastic with a second kind of magnetic susceptibility
	compatibility with human tissues. A comparison of different susceptibility-matched material was
	performed with Ultem

TM

, air (no susceptibility-matched material), barium sulfate at 100% w/v, and perfluorocarbon compound FC-72 (C 6 F 14 ) so-called PFC.

Table 2 .

 2 FWHM measurements for spectra acquired with either the Ultem TM matched double-loop endorectal coil or reference (air filled) double-loop endorectal coil for each metabolite.

		0	1	2	3	4	5
	Temperature increase ∆T of	7.0 ± 0.3	1.77 ± 0.15	1.64 ± 0.03	1.55 ± 0.09	1.38 ± 0.05	0.40 ± 0.06
	miniaturized RF traps (°C)
	SAR estimations (W/kg)	80	20	19	18	16	5

Acknowledgments:

This work was co-funded by the ANRT and General Electric Healthcare (General Electric Healthcare, Milwaukee, WI, USA) and performed within the framework of the LABEX PRIMES (ANR-11-LABX-0063) of Université de Lyon, within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) run by the French National Research Agency (ANR).