PharmD Germain Perrin
email: germain.perrin@aphp.fr

PhD Armelle Arnoux

PharmD Sarah Berdot

MD, PhD Sandrine Katsahian

MD, PhD Nicolas Danchin

PharmD Brigitte Sabatier

Association between exposure to effervescent paracetamol and hospitalization for acute heart failure: a case-crossover study

ABSTRACT:

We investigated whether effervescent paracetamol, as an important source of non-dietary sodium and fluid load, is associated with a transient increase in the risk of hospitalization for acute heart failure (AHF). We conducted a unidirectional case-crossover study using data from the 1/97 th representative sample from the French healthcare database. Subjects aged 18 years or more, hospitalized for AHF during the 2014-2016 period were included. Exposure to effervescent paracetamol was compared between a risk period (i.e. 15 days immediately prior to admission for AHF) and three earlier 15-day control periods, to test a possible trigger effect of effervescent paracetamol intake on AHF. Adjusted odds ratios (aOR) were estimated with a conditional logistic regression. We identified 4,301 patients hospitalized for AHF. We found that 5.7% of AHF subjects were exposed to effervescent paracetamol during the risk period, as compared with 4.1% during the control periods (aOR 1.56 [CI 95% : 1.27 -1.90], p < 0.001). This association was also found in the subgroup of subjects with hypertension (aOR 1.45 [CI 95% : 1.13 -1.87], p = 0.004, n = 2,648) and in the subgroup of subjects aged 83 years or more (aOR 1.70 [CI 95% : 1.28 -2.24], p < 0.001, n = 2,238). A similar analysis, considering exposure to non-effervescent paracetamol, did not support the existence of an indication bias likely to explain the association observed for effervescent paracetamol. This study suggests an association between effervescent paracetamol and admission for AHF and should be confirmed with other complementary study designs. Many factors have been associated with the decompensation of chronic heart failure (CHF), including episodes of tachyarrhythmia or infection, excessive rise in blood pressure or non-adherence to drug therapy or to controlled salt and fluid intake 1-3 . Additionally, many drugs have been identified as possible triggering factors of acute heart failure (AHF), including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, negative inotropic substances or cardiotoxic cancer treatments 1,2 . In 2016, the American Heart Association published a list of drugs which are recognized or suspected to cause or exacerbate heart failure 4 . These recommendations highlighted the risk associated with exposure to sodium-containing drugs among heart failure patients. This miscellaneous group of drugs includes intravenous sodium chloride, intravenous antibiotics, effervescent tablets, and some specific non-effervescent oral formulation. To date, the iatrogenic risk associated with exposure to such high-This article is protected by copyright. All rights reserved. sodium containing drugs has been poorly evaluated [START_REF] Perrin | Cardiovascular risk associated with high sodium-containing drugs: A systematic review[END_REF] , particularly among heart failure patients, and is based on the recommendation for restricting dietary sodium intake in CHF patients, from 1.5g/day to 3g/day, depending on the guideline considered, the type and severity of heart failure 2,6 . Beside the non-dietary sodium load, effervescent tablets are also associated with a significant fluid intake (required for drug administration), whereas restriction of fluid intake is generally recommended for patients with more severe congestive symptoms. A large nested case-control study found that patients diagnosed for incident non-fatal myocardial infarction, incident non-fatal stroke, or who died for a vascular cause, were more likely to be prescribed such high-sodium containing drugs [START_REF] George | Association between cardiovascular events and sodium-containing effervescent, dispersible, and soluble drugs: nested casecontrol study[END_REF] . Additionally, a crossover randomized trial found that exposure to 3g effervescent paracetamol per day, in a group of hypertensive subjects, was associated with a significant rise in blood pressure assessed by 24-hour ambulatory blood pressure measurement, as compared to a control period of exposure to 3g noneffervescent paracetamol [START_REF] Benitez-Camps | Effect of effervescent paracetamol on blood pressure: a crossover randomized clinical trial[END_REF] . We found that exposure to effervescent tablet is frequent in a large health check-up population in France 9 , with 26.9% of the subjects declaring the use of at least one effervescent tablet during the last 30-day period. In this study, 7.3% of the subjects declared a consumption of at least 2-3 effervescent tablets per week during the last 30-day period. We did not find difference in exposure between normo-and hypertensive subjects, questioning the possibility of a large utilization of such drugs in high-risk populations, especially CHF patients. In France, 18 million boxes of effervescent paracetamol have been refunded by the healthcare insurance system in 2017, for 66.7 million inhabitants [START_REF]Open Medic : base complète sur les dépenses de médicaments interrégimes[END_REF] .

In the context of a triggering effect of an excessive sodium intake on AHF onset, and of the high sodium content of effervescent tablets of paracetamol, the aim of this study was to evaluate whether exposure to effervescent paracetamol, as a source of non-dietary sodium load and fluid intake, could be associated with hospitalization for decompensated heart failure.

METHODS:

Results of the study are reported according to the RECORD-PE guidelines [START_REF] Langan | The reporting of studies conducted using observational routinely collected health data statement for pharmacoepidemiology (RECORD-PE)[END_REF] .

Ethics

The EGB database contains only anonymized data and its access is legally authorized without having to consult with the national data protection agency (CNIL). The study protocol was submitted to the appropriate INSERM and CNAMTS entities, as legally required. In addition, an ethics committee approved the study protocol (registration number N°2018-06-02). The need for patient informed consent was waived because of the anonymous nature of the data. This article is protected by copyright. All rights reserved.

Data sources

This study used health administrative data retrieved from the French National Health Insurance sample (EGB: Échantillon Généraliste des Bénéficiaires). EGB is a permanent 1/97 th representative sample of the nationwide healthcare insurance database (Système National d'Information Interrégimes de l'Assurance Maladie, SNIIRAM) and includes data from more than 660,000 individuals in 2014. SNIIRAM, and by extension EGB, is linked to the national hospital database (Programme de Médicalisation des Systèmes d'Information, PMSI) [START_REF] Moulis | French health insurance databases: What interest for medical research?[END_REF][START_REF] Tuppin | French national health insurance information system and the permanent beneficiaries sample[END_REF] .

Study design

We performed a unidirectional case-crossover analysis [START_REF] Maclure | The case-crossover design: a method for studying transient effects on the risk of acute events[END_REF] . In this study design (a self-controlled design derived from the case-control study), only patients with AHF are included (i.e. no control group of subjects without AHF is used), and each subject acts as his or her own control, at different time points (or periods) prior to the AHF episode (see Figure 1). In this study design, if exposure is more frequent during the risk period, as compared to control periods, exposure is suspected to trigger AHF. A triggering factor is associated with a case-crossover odds ratio (OR) > 1, and a preventive (or deterrent) factor with a case-crossover OR < 1. This design allows controlling for time-invariant confounding factors which are not retrievable from EGB database (i.e. genetics, race, eating behaviors including salt consumption, substance abuse). To exclude a possible intrinsic effect of paracetamol on heart failure (since paracetamol per se might have a possible pro-hypertensive effect [START_REF] Turtle | A systematic review of the effect of paracetamol on blood pressure in hypertensive and non-hypertensive subjects: The effect of paracetamol on BP[END_REF] ), and to prevent confounding by indication (paracetamol might be prescribed for causes potentially triggering heart failure decompensation, such as infection), a similar analysis was performed with exposure to non-effervescent paracetamol as an active comparator.

As the temporal trend of the rate of effervescent paracetamol refunding remained stable throughout the control periods, we did not perform any case-time control analysis (see Figure S1). This design is well suited in the case of intermittent treatments such as pain relief medications, which is the case in our study.

Identification of patients hospitalized for AHF

This article is protected by copyright. All rights reserved.

Patient admissions for AHF were retrieved from the EGB using a validated identification algorithm [START_REF]Méthodologie médicale de la cartographie des pathologies et des dépenses, version G7 (années[END_REF] .

We included all patients, aged 18 years or more, admitted in a medical, surgical and obstetrical department during the considered year for heart failure (International Classification of Diseases ICD-10 code I50 as a main diagnosis), or for an acute complication of heart failure with an associated or related code I50. Acute complications considered were: hypertensive heart disease with heart failure (I11.0), hypertensive heart and chronic kidney disease with heart failure and kidney disease (I13.0), hypertensive heart and chronic kidney disease with heart failure and with renal disease (I13.2), hypertensive heart and chronic kidney disease with heart failure, not specified (I13.9), chronic passive congestion of liver (K76.1) or pulmonary edema (J81) during the considered year. The study period was between 01-01-2014 and 31-12-2016. For a patient with multiple hospital admissions during the study period, only the first hospital stay was selected in the analysis.

Exposure assessment

Drug exposure (to effervescent paracetamol in the main analyses, and to non-effervescent paracetamol and NSAIDs in complementary analyses) was assessed during four periods: a risk period (15-day period just before the hospital admission for AHF), and three control periods (30 to 45 days, 60 to 75 days and 90 to 105 days before admission for AHF) (Figure 1). Exposure during risk and control periods was defined with at least one reimbursement of the drug during the period. This binary definition of the exposure status corresponds to the extended analysis method described by Greenland [START_REF] Greenland | A unified approach to the analysis of case-distribution (case-only) studies[END_REF][START_REF] Maclure | Should we use a case-crossover design?[END_REF] which has been recently applied to French National Healthcare database to conduct casecrossover analysis [START_REF] Tubiana | Dental procedures, antibiotic prophylaxis, and endocarditis among people with prosthetic heart valves: nationwide population based cohort and a case crossover study[END_REF][START_REF] Paternoster | Risk of bleeding associated with nonsteroidal anti-inflammatory drug use in patients exposed to antithrombotic therapy: a casecrossover study[END_REF] . Medications were identified using the Presentation Identifying Code 13 (CIP-13, the list of CIP-13 codes used for data extraction is given in Table S1). For paracetamol (effervescent and non-effervescent), each reimbursement was expressed as an equivalent paracetamol Defined Daily Dose (DDD), calculated by multiplying the number of boxes by the number of tablets per boxes, and by the dosage in paracetamol of each tablet. This result was divided by 3,000 mg (corresponding to the DDD of paracetamol, according to the World Health Organization 21 ). A high exposure group was defined by a total DDD above the median (DDD of all exposures retrieved during both risk and control periods); and a low exposure group when the total DDD was below this median.

Three case-crossover analyses were performed: effervescent paracetamol (main analysis), noneffervescent paracetamol (active comparator, to test a possible indication bias) and NSAIDs (positive control). Dose-response analyses are also reported for effervescent and non-effervescent paracetamol.

Confounding and descriptive variables

This article is protected by copyright. All rights reserved.

Confounding and descriptive variables were retrieved from the EGB database, either with a recorded chronic condition (Affection Longue Durée, ALD, a system which allows the reimbursement of healthcare expenditures associated with a list of specific medical conditions, including hypertension, peripheral vascular disease, or diabetes), or with a corresponding hospital discharge diagnosis, in the 3 calendar years preceding the hospital stay for AHF.

Sensitivity and complementary analyses

In order to test the robustness of the results, we performed a similar analysis, using alternative definition for the windows of exposure: the risk period was extended to the 30-day period just before hospital admission for AHF, and the three prior control periods were between 60 to 90 days before admission for control 1, 120 to 150 days before admission for control 2 and 180 to 210 days before admission for control 3. Finally, we performed additional analysis restricted to patient with history of hypertension, and in older subjects (i.e. with age equal to or over median age of the whole sample of AHF subjects), which are factors associated with increased salt sensitivity of blood pressure (15-day exposure periods, one reimbursement per period for the later complementary analysis).

Statistical analysis

Continuous data are presented as median and interquartile range. Categorical data are summarized with number and percentage. To evaluate the risk increase of hospitalization for AHF among subjects taking effervescent paracetamol, we used a case-crossover analysis, in which only cases admitted for AHF were included (no control group of subjects who were not admitted for AHF matched with AHF cases). In the sample of AHF subjects, exposure to effervescent paracetamol was assessed during the 15-day period just before AHF admission, and during three prior 15-day control periods (see Figure 1).

Adjusted case-crossover odds ratios were estimated using a conditional logistic regression model, stratified on individuals. In this model, the outcome was the period (1 = risk period or 0 = control period), whereas drug exposure status (see Exposure assessment above) was the independent risk factor [START_REF] Nazari | Case-crossover and case-time-control studies: concepts, design, and analysis[END_REF] . Only subjects with discordant exposure status (i.e. exposed during risk period and unexposed during control periods, or exposed during control periods and unexposed during risk period) were used to estimate the case-crossover odds ratios.

Statistical significance was defined as p-value < 0.05 (two-sided). All analyses were performed using the R Core Team. R Foundation for Statistical Computing, Vienna Austria, version 3.4.4). For This article is protected by copyright. All rights reserved. conditional logistic regression analysis, the Survival R package (version 3.2.7) was used [START_REF] Therneau | survival: Survival Analysis[END_REF] . More information about the implementation of case-crossover design in R is available in a recent paper [START_REF] Zhang | Case-crossover design and its implementation in R[END_REF] .

RESULTS:

A total of 4,305 subjects were retrieved from the EGB database between 01-01-2014 and 31-12-2016 with a first episode of hospitalization for AHF. Four subjects aged < 18 years were excluded. We finally included 4,301 patients in the analysis (flowchart of the study is given in Figure 2), corresponding to 4,301 risk periods and 12,903 control periods. The median age was 83.0 years (interquartile range: 75 -88) and 53.4% were women. History of hypertension was found in 61.6% of subjects, and history of diabetes in 34.3%. Patient characteristics are reported in Table 1.

Patterns of drug utilization in the 30-days period before admission for AHF

More than half of heart failure subjects (50.5%) were treated with diuretics in the 30-day period before the first hospitalization for HF. Furthermore 9.0% of AHF subjects had a reimbursement of effervescent paracetamol during this period. Utilization of non-effervescent paracetamol was markedly higher, with 34.6% of subjects with at least one reimbursement. Concomitant exposure to diuretics and effervescent paracetamol was found in 5.2%, and concomitant exposure to effervescent paracetamol and angiotensin-converting enzyme (ACE) inhibitors in 3.4% (see Table 1).

Case-crossover analysis

In AHF subjects, exposure to effervescent paracetamol was more frequent during the risk period (5.7%) as compared with 4.1% during control periods (see Table 2). Results of the case-crossover analysis are reported in Table 3. The associated adjusted case-crossover aOR was 1.56 [95% Confidence interval CI 95% : 1.27 -1.90]) with no evidence for a dose-effect relationship, with an aOR 1.66 [CI 95% : 1.31 -2.11] and 1.39 [CI 95% : 1.02 -1.90] in the low and high exposure groups, respectively. Table S2 shows the distribution of concordant and discordant matched pairs for the presence or absence of effervescent refunding during the case and control periods.

Association between period and exposure to non-effervescent paracetamol just missed significance in the main analysis, with an aOR of 1.11 [CI 95% : 0.99 -1.24] whereas this association marginally reached significance only in the low exposure group (aOR 1.16 [CI 95% : 1.01 -1.32]). This article is protected by copyright. All rights reserved.

Finally, we found a positive association which did not reach significance between exposure to NSAIDs and study period (aOR 1.25 [CI 95% : 0.92 -1.70]).

Sensitivity and complementary analysis

In the 30-day time windows sensitivity analysis, the association of AHF with effervescent paracetamol remained significant with an aOR 1.24 [CI 95% : 1.04 -1.47], and a stronger association in the high exposure group (aOR 1.95 [CI 95% : 1.52 -2.51]). This association was also positive and significant in the non-effervescent paracetamol analysis (aOR 1.21 [CI 95% : 1.09 -1.33]). For NSAIDs, the association was positive, though non-significant (aOR of 1.26 [CI 95% : 0.99 -1.60]), consistent with the principle analysis (see Table S3).

In the subgroup of subjects with history of hypertension, the association was stronger while considering exposure to effervescent paracetamol (aOR 1.45 [CI 95% : 1.13 -1.87]) as compared with exposure to non-effervescent paracetamol (aOR 1.18 [CI 95% : 1.03 -1.36]), with, again, no evidence for a dose-relationship effect. In the subgroup of hypertensive subjects, association between NSAIDs exposure and period was significant (aOR 1.50 [CI 95% : 1.01 -2.19]). Concordant results were found in the analysis in subjects aged 83 years or more, with a positive relationship in the effervescent paracetamol analyses (aOR 1.70 [CI 95% : 1.28 -2.24]), and no relationship in the non-effervescent paracetamol analyses (aOR 1.03 [CI 95% : 0.88 -1.20]). Exposure to NSAIDs and study period were positively associated, but non-significantly (aOR 1.27, [CI 95% : 0.78 -2.08]) (see Table 3).

DISCUSSION:

This case-crossover study found a positive association between effervescent paracetamol exposure and hospitalization for decompensated heart failure (aOR 1.56 [CI 95% : 1.27 -1.90]), notably in older patients and those with history of hypertension.

Major validity conditions for using this design were verified: exposure to effervescent or noneffervescent paracetamol and to NSAIDs can be transient, AHF is a rare abrupt-onset event. Minor validity assumptions were also verified: the opportunity of being exposed is expected to be the same during the case and control periods. Even though we did not find any time trend in effervescent paracetamol in the 20-month period preceding admission for AHF, such time-trend was clearly observed for non-effervescent paracetamol with a continuous decreasing rate of exposure to noneffervescent paracetamol in the months preceding admission (see Figure S1). This time trend may have contributed to the positive association observed in the sensitivity analysis with a broader time This article is protected by copyright. All rights reserved. window of 30 days which increases the uncertainty in the timing of exposure [START_REF] Gault | Self-controlled designs in pharmacoepidemiology involving electronic healthcare databases: a systematic review[END_REF] . No time trend was found for NSAIDs rate of exposure (see Figure S2).

Major interests of using case-crossover design is the control for important unmeasured or unmeasurable confounders, such as genotype associated with salt-sensitive phenotype, ethnicity or, to a lesser extent, consumption of dietary sodium [START_REF] Maclure | When should case-only designs be used for safety monitoring of medical products?: CASE-ONLY DESIGNS FOR SAFETY MONITORING[END_REF] , which are cofounder generally not controlled for in cohort or case-control studies based on large medico-administrative databases.

Biological hypothesis that can explain such association include the rise in blood pressure, and the interference with diuretic therapy efficacy with the non-dietary sodium load. Benitez-Camps et al.

found, in a randomized crossover trial that the magnitude of elevation of systolic blood pressure associated with exposure to 3g/day of effervescent paracetamol among hypertensive subjects was  4.0 mmHg 8 . Such effect size could be sufficient to trigger an AHF episode, particularly in older individuals in whom left ventricular compliance is decreased. Additionally, excessive drug induced Sodium intake may negatively interfere with diuretic therapy efficacy, notably for loop diuretics, since excessive sodium intake may induce a natriuresis without contracting the extracellular fluid volume in CHF patients, leading to diuretic resistance [START_REF] Ellison | Diuretic Therapy and Resistance in Congestive Heart Failure[END_REF] . Finally, iatrogenic fluid intake associated with effervescent paracetamol might increase the risk of congestive symptoms and cardiac decompensation in more severe patients.

Classification bias related to effervescent and non-effervescent paracetamol exposure through selfmedication with over-the-counter (OTC) paracetamol, an information not retrievable from EGB database, is limited in this context. Indeed, OTC use of paracetamol among chronic heart failure patients is expected to be marginal, since the ALD system in France allows the free refunding of prescribed drugs considered to be related to a list of chronic conditions, including heart failure or several rheumatologic conditions. Additionally, we previously showed in a French sample of 1,043 subjects, that participants exposed to effervescent tablets through self-medication had an estimated drug-induced sodium intake in the past 30-day period substantially lower than subjects exposed through a medical prescription (2.2 ± 2.7g and 11.3 ± 14.5g, respectively, p < 0.001) [START_REF] Perrin | Evaluation of exposure to effervescent drugs in a large health check-up population in France: a cross-sectional study[END_REF] . This reflects the fact that subjects who have a reimbursement of paracetamol are more likely to take the medication on a regular basis.

Absence of indication bias was convincingly demonstrated in our study, by performing the same analysis with non-effervescent paracetamol as an active comparator, notably in the subgroup of older subjects, where we found an OR of 1.70 for effervescent paracetamol and 1.03 for non-effervescent.

Protopathic bias is not expected to be a pitfall in our analysis, since first symptoms of cardiac decompensation (i.e. dyspnea, weight gain, edema and fatigue) are not usual indications for paracetamol use. This article is protected by copyright. All rights reserved.

Absence of dose-effect relationship in our study can be related with the central hypothesis for using reimbursement data as a proxy for drug exposure with large electronic healthcare databases [START_REF] Palmaro | Overview of drug data within This article is protected by copyright. All rights reserved. French health insurance databases and implications for pharmacoepidemiological studies[END_REF] . This approximation may be difficult to apply in the case of intermittent exposure, and particularly in the case of paracetamol, since multiple behaviors can be associated with paracetamol acquisition: over prescription by the general practitioner and/or over dispensing by the pharmacist, potentially associated with the will for the patient to create a stock of drug at home (since paracetamol can be a useful drug for a myriad of clinical conditions). More generally, these results highlight the limitation of using refunding data to study dose-response relationship in case of drugs associated with intermittent pattern of exposure, due to the important uncertainty associated with the phenomenon of attrition between dispensing and actual ingestion [START_REF]Guide on Methodological Standards in Pharmacoepidemiology[END_REF] .

We found a positive association between exposure to NSAIDs and hospitalization for AHF, which failed to reach significance in the main analysis, but which was significant among hypertensive subjects. These results are in concordance with the literature in terms of direction and relatively modest amplitude of association, in particular with results from the Rotterdam cohort [START_REF] Feenstra | Association of nonsteroidal antiinflammatory drugs with first occurrence of heart failure and with relapsing heart failure: the Rotterdam Study[END_REF] and from other studies [START_REF] Huerta | Non-steroidal antiinflammatory drugs and risk of first hospital admission for heart failure in the general population[END_REF][START_REF] Arfè | Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study[END_REF] . The higher risk observed in the subgroup of hypertensive subjects was expected, since NSAIDs increase blood pressure through prostaglandin inhibition in the kidneys [START_REF] White | Cardiovascular effects of the cyclooxygenase inhibitors[END_REF] .

We found that frequency of exposure to effervescent paracetamol was high 30 days before hospital admission for heart failure decompensation. This could suggest that existing recommendations have had a limited impact on the healthcare professionals, particularly community pharmacists, since the preference for an effervescent formulation is usually expressed by the patient at the time of dispensing, and not explicitly indicated explicitly as such on medical prescriptions. Given the mean age of the heart failure sample (median 83 years, corresponding to the cutoff used in the subgroup analysis), many reasons could explain the preference for the effervescent formulation: it reduces the risk of pulmonary inhalation in high-risk patients (e.g. with neurological disorders or dementia), it allows an increase of fluid intake in dehydrated elderly subjects, and it eases administration of the medication in subjects with dysphagia or swallowing difficulties. A study of oral solid medicines preference among older adults, using the Medicines Acceptability Questionnaire [START_REF] Scott | Validation and Feasibility of the Medication Acceptability Questionnaire to Investigate Tablet and Liquid Alendronic Acid with Older Hospital Patients[END_REF] showed that effervescent tablets were the most acceptable formulations, in both dysphagic and non-dysphagic older subjects [START_REF] Liu | Acceptability of oral solid medicines in older adults with and without dysphagia: A nested pilot validation questionnaire based observational study[END_REF] . In all these clinical situations, sodium-free alternatives are available, such as orodispersible tablet or powder for oral solution.

Limitations of the study:

The first limitation related to the use of medico-administrative databases is the absence or inaccuracy of coding (discharge and associated diagnosis), particularly, due to the absence of specific ICD-10 This article is protected by copyright. All rights reserved. codes specifically identifying type or severity of heart failure. Thus, we were not able to focus our analyses on patients with more severe congestive symptoms, who are more likely to experience detrimental iatrogenic consequences of liquid and sodium loads. A second limitation is found in the process of attrition in which drugs that are dispensed are not necessarily ingested by patient. The absence of information about self-medication and drug adherence can introduce a residual classification bias, which can reduce the power of the analysis. Finally, as for all observational studies, no formal causal relationship can be established between related factors, and additional analyses with complementary study designs are required for risk confirmation.

CONCLUSION:

We found that approximately one heart failure patients over ten had a reimbursement of effervescent paracetamol 30 days before hospitalization. We found a positive association between exposure to effervescent paracetamol and hospitalization for AHF, notably among hypertensive and older subjects. Given the existence of paracetamol in multiple sodium-free formulations, including formulations suitable for patients with swallowing difficulties (i.e. orodispersible tablets or powder for liquid solution), our data suggest that the use of effervescent paracetamol should be strongly discouraged among heart failure patients.

REFERENCES:

1.

Ponikowski b Cut-off corresponding to the median age of the 4,301AHF subjects.

FIGURE LEGENDS:

AHF: Acute Heart Failure, OR: Odds Ratio. between risk and control periods, STEP 4: crude case-crossover OR estimation (adjusted casecrossover odds ratio is obtained after confounding adjustment with a conditional logistic regression).

Similar analysis was performed considering non-effervescent paracetamol as an active comparator in risk and control periods, and oral NSAIDs as a positive control.

  Key words: pharmacoepidemiology, adverse drug reaction, quality use of medicines, medication safety, drug safety INTRODUCTION:

Figure 1 .

 1 Figure 1. Implementation of the case-crossover analyses. STEP 1: definition of the time frame of case (n = 1) and control periods (n = 3) before admission for acute heart failure, STEP 2: evaluation of the exposure status in each of the four periods, STEP 3: description of exposure pairs distribution

  selection of risk and control periods prior AHF admission STEP 2: evaluation of exposure status in each period for each AHF patients STEP 3: description of exposure pairs distribution STEP 4: crude case-crossover OR estimationThis article is protected by copyright. All rights reserved.

Figure 2 :

 2 Figure 2: Flowchart of the study.

Table 2 .

 2 P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37: 2129-2200. Exposure to effervescent paracetamol according to period of inclusion of 4,301 subjects admitted for AHF included in case crossover study, 2014-2016.

	2.	Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of
	heart failure: a report of the American College of Cardiology Foundation/American Heart Association
	Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62: e147-239.
	3.	Fonarow GC. Factors Identified as Precipitating Hospital Admissions for Heart Failure and
	Clinical OutcomesFindings From OPTIMIZE-HF. Arch Intern Med 2008; 168: 847.
	4.

Page RL, O'Bryant CL, Cheng D, et al. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association. Circulation 2016; 134.

Table 3 :

 3 Association between exposure to effervescent paracetamol and admission for AHF in the case-crossover study, 2014-2016.

		15-day time windows a	15-day time windows a	15-day time windows a
		(n = 4,301)		Hypertension subgroup	Age ≥ 83 years subgroup b
				(n = 2,648)		(n = 2,238)
	Drug exposure	Odds ratio	p-	Odds ratio	p-	Odds ratio	p-value
		(CI 95% )	value	(CI 95% )	value	(CI 95% )
	Non-exposure	1.0		1.0		1.0

. AHF: Acute Heart Failure, CI: confidence interval, OR: Odds ratio, NSAIDs: non-steroidal antiinflammatory drugs, a Adjusted for: co-prescription of diuretics, ACE inhibitor and corticosteroids inflammatory drugs.

Funding information

This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors.

Conflict of interest disclosure

None to declare.

Data availability

The data that support the findings of this study are available from third party (data owner).

Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the authors with the permission of third party.

Word count: 3,501


Vincent Zoma

Foundations of community territorial planning policy of WAEMU

Keywords: territorial planning, regional integration, WAEMU

After the independences, some West African countries opted to unite within the framework of regional integration to face the multiple problems of their development. It is in this perspective that the West African Economic and Monetary Union (WAEMU) has been created in 1994. However, despite the creation of this Union, the Member States of the Union meet some difficulties in the implementation of their regional integration policy, the objective of which is to promote their development. Then they opted for the adoption of a Community territorial Planning Policy (PATC) in 2004. Thus, this theoretical research aims to study the foundations of the WAEMU community territorial planning policy. The study reveals that this Community policy is essentially based on factors linked to the evolution of the organization of the regional space, the missions of the Union, the weaknesses of national territorial planning policies and the need community solidarity.

Introduction

Since the end of the Second World War, the attempts at multilateral cooperation on a regional basis have multiplied throughout the world. From that time, the craze for regional integration then spread to other continents (V. Zoma, 2019) [11] . To be competitive, several countries have tried to strengthen their integration by building new regional groupings or by giving new impetus to existing groupings. This regional integration movement has taken shape in almost all the continents of the planet (I. Yonlihinza Abdou, 2005) [4] . Africa has not remained on the sidelines of this craze for regional integration which concerns almost all continents in the context of globalization. The importance of regional integration, which aims to accelerate and strengthen economic and social development, has long been recognized by African decision-makers (P. [START_REF] Diagne | For West African Unity: Micro-States and Economic Integration[END_REF]; C.N.U.C.E. D, 2009). According to M. Somda (2018, p.71), "in this globalized world, the African continent, despite its natural wealth and its economic potential, is in a precarious situation and is struggling to find its bearings". A. [START_REF] Diouf | Africa: regional integration in the face of globalization[END_REF] specifies that unlike other regions of the South, Africa remains poorly equipped to both face its constraints and take advantage of its opportunities. Its fragility reside above all in its extreme fragmentation resulting from what is called its "balkanization" coming from the Berlin Congress of 1885 when this continent was divided between the colonial powers. Moreover, in West Africa, faced with development problems, particularly in the areas of transport infrastructure, education, energy, food, etc., the States of this region, being aware that they cannot objectively face each of these endemic problems alone, have been led to pool efforts through the establishment of supranational structures of a sectorial nature such as the Inter-State Committee for the Fight Against Drought in the Sahel (CILSS) and of a general nature such as the Economic Community of West African States (ECOWAS) and the West African Economic and Monetary Union (WAEMU) within the framework of regional integration. Concerning WAEMU particularly, the member countries of this region have opted for the path of regional integration in view of their lackluster economic realities. Indeed, in order to consolidate the West African Monetary Union (WAMU), created on May 12, 1962 by the founding States of the Central Bank of West African States (CBWAS), a Treaty was signed creating WAEMU on January 10, 1994 in Dakar.

Notwithstanding the creation of WAEMU, the Member States of the Union encounter difficulties in the implementation of their regional integration policy, the objective of which is to promote their development. It is in this context that the Community Territorial Planning Policy (PATC) [1] was adopted by the WAEMU Commission in 2004 with a view to strengthen regional integration and thus to promote the development of the Member States of this regional space. This present article, which is a theoretical research, aims to study the foundations of the WAEMU community territorial planning policy. This study, based mainly on documentary research of WAEMU, reveals that the Union's community territorial planning policy has essentially four foundations. These are factors related to the evolution of the organization of the regional space, the missions of WAEMU, the weaknesses of national policies for territorial planning and the need for community solidarity.

The evolution of the organization of the regional space

The organization of space is a long-term process. In general, a space is organized more or less continuously over a period of several centuries (V. Zoma, 2019) [11] . Indeed, man has always planed space to satisfy his needs. In the traditional societies of the States that are today members of WAEMU, the occupation of space before the colonial period was guided by the satisfaction of security needs, the availability of cultivable land, the presence of game, the need for mobility, organizational considerations, etc. Regionally, before the colonial period, the great empires (Ghana, Mali, etc.) were linked by trade way that allowed these traditional societies in the region to exploit the differences and complementarities of ecological spaces between the forests areas and those of the savannas (WAEMU, 2003). The colonial period saw the creation of a network of towns, trade and traffic markets (waterways, roads, railways) according to the interests of the settlers (WAEMU, 2003, op.cit.,), even if, J. Debrie (2001) [5] considers that, as regards the motives for European penetration, it is difficult to identify the real reasons for this penetration and its exploitation. In a general way, this new framework linked to European penetration was at the origin of territorial divisions whose main objective was the administrative control of men and space as well as the military domination of the States (WAEMU, 2003, op.cit.). After the independences, the nascent States retained within their respective borders the achievements of colonization, by embarking on administrative, institutional and structural reforms aimed at territorial planning (PDM, 2000). A. Gandhi (2009, p.14) specifies that "Each state had chosen to go it alone by copying the model of its former colonizer to build a nation and build its own future". According to Municipal Development Partnership (PDM, 2000, op.cit.), the plans developed at the time would mark the organization of territories both at national and regional level under the leadership of the States. However, this orientation was gradually abandoned with the fight against rural exodus and the adoption of Structural Adjustment Programs (SAPs) from the 1980s. Indeed, when the economic crisis hit in the 1980s, the SAPs give priority to the restoration of major macro-economic balances over spatial development preoccupations. Following two decades of Structural Adjustment Policies dominated by macroeconomic considerations, there was an appeal to politicians by intellectuals and experts from the region who met in October 2000 in Cotonou [2] to examine the conclusions of the study on "long-term prospects in West Africa". This study raised the alarm on the fact that if nothing is done to slow down or even stem the trends, half of the West African population could concentrate on the coastal strip between Lagos and Abidjan, by 2020-2030. It was therefore necessary to consider appropriate measures to avoid this, since such a situation would contribute to aggravating the imbalances and problems already experienced by the region (WAEMU, 2011). The Cotonou call was followed by the interpellation of the Commission by the Member States of the Union to restart the medium and long-term planning and programming processes. The use of community territorial planning is therefore justified by the historical evolution of the organization of the regional space but also by the missions of WAEMU in this area.

The missions of WAEMU

WAEMU was created on January 10, 1994. It brings together eight West African states that share the CFA Franc. Map 1 identifies the member states of the current WAEMU. WAEMU constitutes the emergence of a new level of territorial management in West Africa. This region is experiencing average population growth rates of 3% per year in 2007, and 6.5% in 2013 with a predominantly young population. This dynamism and the young character of the population are assets that could be used in development efforts. However, they are likely to lead to changes capable of dangerously affecting community harmony by worsening regional disparities. It is therefore urgent to properly target these disparities in order to better correct them within the framework of the cohesion and regional integration policy (WAEMU, 2011, op.ci.t). The correction or reduction of regional disparities in WAEMU is taken into account in the Community territorial planning policy and is based on the following facts at the institutional level: 1. It is an instruction of the Treaty of the Union which prescribes in its additional protocol No. II the establishment of a policy of development of the Community [3] territory with a view to the balance of the different components of its territory; 2. The need to support the States in their desire to relaunch at the national level, the implementation of territorial planning policy after the Structural Adjustment Programs which have shown their limits; 3. the progress made by the Union in the development and implementation of sectorial policies requires a framework of orientation and harmonization so that it is no longer a matter of sight in the actions to be undertaken; 4. The urgency of detecting, preventing and anticipating major sectorial and territorial developments in order to adapt to global developments and requirements; 5. The need to take into account and better direct migratory movements, to reduce the dysfunctions observed in the community space, to better position the region in the continental context and to link it to the rest of the world. The elaboration of the Community territorial planning policy is then justified by the missions of the WAEMU, but also by the elements revealed by the diagnosis of the unenviable national territorial planning policies.

Weaknesses of national territorial planning policies

The study has made it possible to highlight four main weaknesses or difficulties of the Member States of the Union in the implementation of national territorial planning policies. Firstly, there is the disparate level of the state of definition of territorial planning policies and the domination of the "project approach". Indeed, most of the member countries of the Union did not have a truly well-defined national policy in terms of territorial planning before 2004. In other words: Territorial planning actions were part of environment, equipment, sanitation, hydraulics or rural development projects. In some cases, these policies were included in regional planning and programming documents (WAEMU, 2003, p.17). The absence of a real national territorial planning policy was accompanied by the domination of the "project approach". This approach was encouraged by donors and resulted in a lack of coherence and coordination. Also, this gap was accompanied by the weaknesses of the communication systems in terms of territorial planning. Concerning the weaknesses of the information and data exchange systems on territorial planning, the services in charge of territorial planning, in most of the member countries of the Union, did not have a collection system and data management. This weakness made it difficult to make an overall assessment of territorial planning in most of the member territories of the Union. Only Benin and Burkina Faso had carried out new thematic studies in the context of territorial planning before the adoption of the community territorial planning policy (WAEMU, 2003, op.cit.). In addition to the weaknesses of the information and data exchange systems, there is the lack of technical and financial means in the States of the Union in terms of territorial planning. The framework document of the community territorial planning policy shows that the financial contribution of the countries of the Union has remained relatively low within the structures in charge of territorial planning. Territorial planning was financed in most of the States of the Union by development partners before the adoption of a community policy. The countries that have taken initiatives to finance their policy have been left alone with their implementation. The absence of a real regional development policy is also due to "the fragmented knowledge of the advantages and constraints of their territory". The monographic studies were largely outdated and no longer gave a real image of the countries (land use, location of human settlements, nature reserves, communication ways, waterways, etc. (WAEMU, 2003, p. 23-24). In addition to the shortcomings of technical and financial means, there are institutional and human resource weaknesses within the Member States of the Union in the field of territorial planning. A. [START_REF] Diop | Regional integration in West Africa: the challenge of decentralized crossborder cooperation[END_REF] show that the establishment of community institutions of a technical nature (OMVS, OMVG, etc.), through the signing of treaties and agreements whose objective is to strengthen the economic, monetary and political partnership between member states of the region. These various institutions have made significant progress, particularly at the political and institutional level. However, in the member countries of the Union, before the adoption of the community territorial planning policy, the structures and officials who led the territorial planning were very unstable. Indeed, "they often changed supervision and ownership during government reshuffles. Also, these structures had very few competent design frameworks to carry out a real territorial planning policy" (WAEMU, 2003, p.19). This gap has led to perpetual repetition of the reflections and/or actions undertaken, resulting in a sort of dullness. Solidarity at the community level should then be considered to face the challenges and issues of the region.

Need for community solidarity

The diagnosis of territorial planning policies in the States of the Union shows the need for community solidarity in the face of the common challenges to be met on the one hand and on the other hand in the face of the issues of great importance to be defended and safeguarded. Concerning the community challenges to be met, the demographic and urban problems, the persistence of poverty as well as the disparity in the levels of economic development are concerns of paramount importance for the WAEMU Member States. Faced with demographic problems, the countries of the Union present very great inequalities in demographic terms. Indeed, the highly varied population, with types of structured and heterogeneous societies on the linguistic and cultural levels, presents a very unequal spatial distribution, with centers of high concentrations, visible on the coasts, rail and road nodes as well as in urban centers. Beside these exceptional concentrations, there are vast spaces of demographic depressions which correspond to desert areas and mountainous areas. Demographic problems manifest themselves essentially at three levels in the community space:  An imbalance between economic growth and population growth;  An imbalance in the spatial distribution of the community population;  Migration from the interior to coastal countries (WAEMU, 2003, op.cit.). These demographic problems therefore constitute a challenge for regional integration, and one of these corollaries is evident in urban centers. According to the framework document for community territorial planning policy, most cities in the member countries of the Union were characterized by accelerated urbanization before 2004. The supremacy of capital cities is such that the WAEMU space hasn't real cities only these political or economic capitals. This situation is detrimental to economic activities which can't flourish fully, across space without a minimum of spatial organization. In addition to demographic problems and that of urban centers, the poverty of populations and economic inequalities can explain certain urban and demographic problems in the States of the Union. According to A. Diop and M. Diallo (2013), the institutional approach to regional integration that has been put in place has certainly made it possible to make progress, but the African model of regional integration has not taken into account socio-economic logic populations. However, G. [START_REF] Poujol | The food circuits of the Ouagadougou-Accra corridor: conditions for inclusive development, Doctoral thesis in geography and spatial planning[END_REF] underlines that imagining the future of regional integration in the WAEMU space without the informal sector, practiced above all by the populations in almost all localities, seems impossible, as this sector is essential, because it is transverse. According to the framework document of the community development policy (WAEMU, 2003, op.ci.t), in the great majority of the populations of the WAEMU's space, the standard of living remains very low. The persistence of poverty is partly due to the disparity in the levels of development of the member countries of the Union. This disparate level of development of the Member States is accompanied by the weakness of the production support sectors. Thus, regional disparities and the weakness of production support sectors are not likely to promote or facilitate the regional integration of WAEMU, which also has its challenges to defend and safeguard. The development of regional complementarities, the rebalancing of development poles and the exploitation of cultural values are important issues in the WAEMU regional integration process. Thus, apart from the development of complementarities to consolidate the internal market, the rebalancing of the development poles of the region is also a concern. Regional integration must take advantage of the complementarity of the economies of States, mainly between the coastal zone and the continental zone. Also, the Union has a currency which is a support for its construction. This should benefit from greater support through dynamic and competitive economies. The implementation of community development projects on the basis of potential is one of the means to achieve this. It is therefore necessary to rebalance the development poles of the WAEMU space. Indeed, since 2002, the Ivorian crisis has highlighted the insufficiency and the great imbalances of the network and the connections between the coastal cities and those of the interior of the region (WAEMU, 2003, op.cit.). According to the same source, the Union could fully play its role of integration, if it pursues policies which encourage the promotion of development poles and which contribute to a better rebalancing of the population and the emergence of genuine networks functional cities. The development of complementarities and the rebalancing of development poles are challenges for the community policy for territorial planning. This policy should also exploit regional cultural values, because WAEMU: Is characterized by great cultural diversity and a significant diaspora which are potential factors for development. The reference to these cultural dimensions could be used for technological improvement, the choice of the model of society to be built, consumption to be valued, ambitions and interests to be defended (WAEMU, 2003, p.27). Border regions also deserve to be revalued around the concept of "border countries" in order to give life to historical entities cut off by state borders (WAEMU, 2003, op.ci.t). Along the same lines, A. Diop and M. Diallo (2013) argue that instead of relying solely on the mobilization of all States for the construction of a community space, we must also encourage real integration through the definition of "concentric circles" regrouping two or three States.

Conclusion

This research is a study of the factors that favored the adoption of the community territorial planning policy of the West African Economic and Monetary Union (WAEMU). The study shows that the evolution of the organization of the regional space, the missions of the Union, the weaknesses of national planning policies as well as the need for regional solidarity to take up and face the challenges and community issues constitute the main foundations of community territorial planning policy. As well as the weaknesses of countries' territorial planning policies and the need for solidarity community, constitute the main bases for the development of community territorial planning policy.

Map 1 :

 1 WAEMU Member StatesThis map 1 shows the WAEMU member states. The Union is in fact made up of 8 countries (Benin, Burkina Faso, Côte d'Ivoire, Mali, Niger, Senegal, Togo and Guinea Bissau) which covers an area of 3,506,126 km2 and had 120.2 million inhabitants in 2017 (WAEMU, 2018). The Union is part of a vast spatial framework which is based in the West and South on the Atlantic Ocean, then on the Saharan regions in the North.


Laurence Croguennec
email: laurence.croguennec@icmcb-bordeaux.cnrs.fr

Jessica Bains

Michel Ménétrier

A Flambard

Emilie Bekaert

Ph C Jordy

Claude Biensan

Delmas

Ph Biensan

C Delmas

O 1.8 F 0.2 " materials by different routes: is there fluorine substitution for oxygen?

Keywords: Lithium-ion battery, positive electrode material, layered oxide, Li(Ni,Mn,Co)O 2, fluorine substitution, coating, X-ray diffraction, NMR spectroscopy, solid state electrochemistry

    Synthesis of "Li1.1(Ni0.425Mn0.425Co0.15)0.9O1.8F0.2" materials by different routes: Is there fluorine substitution for oxygen?

That LiF was shown to be present as small particles in some grain boundaries, but not as a continuous layer covering the particles surface. Improved cycling stability was observed for these LiF-"coated" materials, showing that effective fluorine substitution for oxygen is not required for an improvment of these layered oxides cyclability: a surface modification can be sufficient and can have also a huge impact.

Introduction

Recently, the layered transition metal oxide Li 1+x (Ni y Mn y Co 1-2y ) 1-x O 2 has attracted much attention due to its large capacity, good cyclability and large thermal stability at high voltage in the highly deintercalated state [1-6]. These systems consist of Ni 2+, 3+ , Mn 4+ and Co 3+ ions; Mn 4+ being electrochemically inactive, it provides significant structural stability during electrochemical cycling (there is no detrimental effect of the Jahn-Teller distortion associated with Mn 3+ ) [2,7-10].

In order to improve the electrochemical performance of these materials, two approaches were developed: (i) ionic substitution to increase the structural stability of the layered oxide [11-14] and (ii) surface modification to decrease its catalytic effect on electrolyte degradation and thus to decrease the impedance during cycling [15]. LiF addition to Li 1+x (Ni y Mn y Co 1-2y ) 1-x O 2 materials used as positive electrode in lithium batteries was shown to improve their cycling performance and thermal stability in the charged state [16]. But conflicting explanations are proposed in literature to explain the effect of fluorine: most of the authors considered that fluorine substitution for oxygen is effective since changes in cell parameters were for instance observed using Xray diffraction [17-22], while others assumed [16] or proved using X-ray Photoelectron Spectroscopy analyses [23] that fluorine is only present as an LiF surface layer.

Recently, we showed also using 7 Li and 19 F MAS NMR analyses that no fluorine substitution for oxygen occurs in "Li 1+z/2 (Ni 0.425 Mn 0.425 Co 0.15 ) 1-z/2 O 2- z F z " (0 ≤ z ≤ 0.2) formed in two steps ((i) coprecipitation of the layered oxide and (ii) addition of LiF as a solid state reaction), but there is formation of an LiF "coating" (this denomination was not considered to mean that this

Experimental

Materials of "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 " composition were prepared using two different methods. The first synthesis method was a usual solid state reaction between transition metal oxides, lithium carbonate (99 % Alfa Aesar) and lithium fluoride (99.9 % Prolabo), used as fluorine precursor. prepared with molar ratio 0.45 / 0.2 / 0.3825 / 0.3825 / 0.045, mixed for 1 h in a Turbula ® shaker-mixer and milled three times during 30 min. in a planetary mill using 7 agate balls (Ø 13 mm) in an agate jar (45 mm in diameter and 50 cm 3 in volume). This mixture was finally calcinated two times in a gold crucible at 900°C and one time at 950°C for 24 h in an oxygen atmosphere with intermediate grindings. The second synthesis method was very similar to the first one, but with NiF 2 (99 % Aldrich) as precursor for fluorine. The following molar mixture was prepared: 0.55 Li 2 CO 3 / 0.1 NiF 2 / 0.2825 NiO / 0.3825 MnO 2 / 0.045 Co 3 O 4 , and then calcinated three times in a gold crucible at 950°C for 24 h in an oxygen atmosphere with intermediate grindings.

Powder X-ray diffraction (XRD) analyses were performed using a Siemens D5000 diffractometer equipped with a graphite diffracted beam monochromator and Cu Kα radiation. The diffraction patterns were collected in the 5 -120° (2θ) range using steps of 0.02° (2θ) with a constant counting time of 8 s and analysed using the Fullprof program and the Le Bail method (refinement of the background, profile and cell parameters only). The profile was described using a pseudo-Voigt function.

In order to confirm the chemical composition of the various samples, lithium and transition metal ions were titrated using ICP measurements (using a Thermo Iris Intrepid II XP spectrometer). Fluorine and transition metal ions were also titrated using electron microprobe (CAMECA SX 100 spectrometer).

Powders were pressed into pellets (13 mm in diameter) and metallized by gold -palladium plasma deposition. The analysis area was (15 x 15) µm 2 with 1 µm depth, the accuracy being around 1-2 at.%. Finally, the average oxidation state Materials were characterized by 7

Results and discussion

The X-ray diffraction patterns of the "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 " materials obtained using solid state reactions, with LiF or NiF 2 as fluorine precursor, are compared in Fig. 1 to that of "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop" obtained as described in [24] by combination of coprecipitation and solid state reactions and using LiF as fluorine precursor. α-NaFeO 2 type layered phases were obtained with all the diffraction peaks indexed in the R-3m space group. For the two new materials, neither LiF nor NiF 2 were detected by XRD analyses whereas a secondary (minor) layered phase could be detected (highlighted by arrows in Fig. 1). In comparison, for the "Li 7 Li and 19 F MAS NMR to be present as a thin deposit on the particle surface of A comparison of the cell parameters (a hex , c hex and volume) determined for "Li [24], a broad signal from the probe that contains PTFE in non-spinning parts.

These 7 Li and 19 F NMR spectra therefore allow us to conclude that fluorine was not incorporated into these layered oxide materials synthesized by solid state reaction using either LiF or NiF 2 as fluorine precursor, despite changes in structural parameters with increasing fluorine content. Fluorine is again present as a thin deposit of LiF, not detected by XRD. The feature in the NMR spectra that allows us to conclude for the immediate proximity of LiF from the surface of the layered oxide is the striking difference in the line shape (spinning sidebands envelope) for the 7 interesting to characterize the morphology and electrochemical performances of these materials proven to be LiF-"coated" and not fluorine substituted, and to compare these results with those reported in literature for materials announced to be Li 1+x M 1-x O 2-z F z .

The Scanning Electron Microscopy micrographs obtained for the three samples are given in Fig. 5. The primary particles of the two materials "Li Altogether, although LiF appears not to be in the form of a uniform film at the surface of the materials, the proximity with the material can be considered as similar in all cases. Since this distribution of distances governs the global lineshape of the Li and F MAS NMR spectra, this leads to similar lineshapes for the three compounds. NMR analyses, that -irrespective of the synthesis method used -LiF-"coated" layered oxide materials were obtained, the active mass was corrected from its LiF content for the electrochemical tests. The reversible capacity obtained in first discharge is rather good for the four samples, but significantly larger for the bare sample (175 mAh.g -1 vs. 150 to 160 mAh.g -1 for the LiF-"coated" samples). Larger irreversible capacity is also observed for the LiF-"coated" materials (30 -50 mAh.g -1 ) compared to that obtained for the bare material (16 mAh.g -1 ). The polarization measured between charge and discharge curves is also significantly more important for "Li These first electrochemical results suggest thus that presence of LiF would improve the stability of the capacity during cycling -as also reported in literature for materials announced to be Li 1+x M 1-x O 2-z F z materials -and that the modification of the composition and structure of the active material is thus not essential to have this impact on its electrochemical performances in lithium cells. In fact, as already reported for instance for metal-oxide coated materials

[15], although SEM micrographs have shown discontinuous small particles or platelets on grain boundaries, the modification of its surface by the presence of LiF probably modifies locally the composition of the material/electrolyte interface and can also be beneficial to a better cyclability during cycling, for instance through a minimization of the electrolyte degradation at its surface.

From a general point of view, changes in the interface nature could also affect thermal stability of the positive electrode in the charged state. This will be discussed in the case of the LiF-"coated" materials in a forthcoming paper [32].

Conclusion

"Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 " materials were prepared with LiF or NiF 2 as fluorine precursors using a one-step solid state method. These synthesis methods were reported in literature to lead to the formation of fluorinesubstituted layered oxides. In fact, 7 Li and 19 materials obtained with a two-step coprecipitation and solid state synthesis reported earlier [24]). Changes in cell parameters with increasing fluorine content were observed for these samples obtained by solid state reaction: combining X-ray diffraction, chemical and NMR analyses it was possible to discriminate between actual fluorine substitution for oxygen and heterogeneity in the transition metal ions distribution, this latter being at the origin of those changes in cell parameters. This LiF coating was shown to be present as small particles or "sheets" in some grain boundaries (30 nm in diameter or in thickness, respectively): interestingly, although different synthesis methods and fluorine precursors were used, the proximity of LiF with the paramagnetic material can thus be considered as similar in all cases, explaining the similar lineshapes of the 7 Li and 19 F MAS NMR spectra for the three compounds.

LiF is not present as a continuous layer covering the particles surface.

Nevertheless, improved cycling stability was observed for these LiF-"coated" materials, at least during a few cycles in the [2 -4.5 V] potential window at the C/20 rate, showing that surface modification (without substitution and thus bulk modification) can be sufficient to improve the cyclability.

  Croguennec et al. (corresponding author: L. Croguennec) Submitted to Journal of the Electrochemical Society -4constituted a uniform layer on the whole surface of the material, since this was not characterized) [24]. However, several synthesis methods were reported in literature to form these fluorine-substituted layered oxide materials, such as combination of coprecipitation and solid state reactions [18-19, 25-26], solid state reaction only [14, 27], sol-gel synthesis [20, 28] and spray drying process [23]. Although LiF was the main fluorine precursor reported, NH 4 F [19, 29], NiF 2 [30] and NaF [31] were also used. In this paper, we report on one-step solid state reactions to obtain "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 " materials, with LiF or NiF 2 as fluorine precursor, that are assumed in literature to lead to the formation of Li 1+x (Ni y Mn y Co 1-2y ) 1-x O 2-z F z materials via direct fluorination. We aim at determining if fluorine substitution for oxygen is actual or not in this case, or if only a mixture of a parasitic fluorine-containing compound with Li(Ni 0.425 Mn 0.425 Co 0.15 )O 2 is obtained as for the materials synthesized according to a two-step synthesis with fluorine addition only in the second step we recently studied.

  NiO and MnO 2 were obtained from the decomposition of Ni(NO 3 ) 2 •6H 2 O and Mn(NO 3 ) 2 •4H 2 O at 450°C during 15 h, whereas Co 3 O 4 was obtained from the decomposition of CoCO 3 at 400°C during 12 h in oxygen atmosphere. These oxide materials are highly reactive because of their small particle sizes Croguennec et al. (corresponding author: L. Croguennec) Submitted to Journal of the Electrochemical Society -5 -(~ 150 nm and ~30 nm for NiO/MnO 2 and Co 3 O 4 , respectively) and large specific area. A ~ 10 g mixture of Li 2 CO 3 , LiF, NiO, MnO 2 and Co 3 O 4 was

  Croguennec et al. (corresponding author: L. Croguennec) Submitted to Journal of the Electrochemical Society -6of the transition metal ions was determined by iodometric titration. The samples were dissolved in a concentrated acidic solution with an excess of KI and the produced iodide I 3 -ions were titrated with a Na 2 S 2 O 3 solution.

Li(

  Ni 0.425 Mn 0.425 Co 0.15 )O 2 . The chemical composition of the three samples was analyzed combining elemental and redox titrations, as well as electron microprobe analyses. As reported in Tab. 1, the experimental average composition of the powders was found to be in really good agreement with the nominal compositions. The larger discrepancy observed for fluorine could come from an overlapping in Energy Dispersive X-ray spectrometry (EDX) analyses between peaks characteristic in energy of F, Au (coming from metallization) and Co, and not only from an Croguennec et al. (corresponding author: L. Croguennec) Submitted to Journal of the Electrochemical Society -8actual fluorine loss during the thermal treatment at high temperature. Redox titration showed as expected for the three materials an average oxidation state (oxid. state) close to 3 for the transition metal ions. As shown in Fig. 2 with the results of the electron microprobe analyses, the transition metal ions distribution is homogeneous in "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop" whereas that of fluorine appears significantly more heterogeneous. Electron microprobe analyses revealed also that the transition metal and fluorine ions are heterogeneously distributed in the two new samples obtained by solid state reactions: as shown in Fig. 2b-c, a manganese-rich phase (bright areas) is formed next to the main layered oxide phase. All these results, and especially the heterogeneous distribution of fluorine as in "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop", thus suggest the formation of an LiF / Li(Ni 0.425 Mn 0.425 Co 0.15 )O 2 mixture rather than effective fluorine substitution for oxygen in the two new Li(Ni 0.425 Mn 0.425 Co 0.15 )O 2 materials as well.

1 (Fig. 3 and. 4 ,

 134 Croguennec et al. (corresponding author: L. Croguennec) Submitted to Journal of the Electrochemical Society -9observed earlier no changes in structural parameters for a series of coprecipitated materials which were finally shown to be non-sucessfully substituted [24]. Note that for the two materials obtained by solid state reactions, the secondary phases detected, which are manganese-rich after electron microprobe analyses, have smaller a hex and larger c hex cell parameters than the major phase. In our opinion, changes in cell parameters with increasing fluorine content are not by themselves proofs for effective fluorine substitution for oxygen in these layered oxide materials, especially because careful analyses using combination of X-ray diffraction and electron microprobe have shown heterogeneity in the transition metal and fluoride ions distribution at the crystallites' scale. Indeed, changes in composition (Li/M and Ni/Mn/Co ratios) due to this heterogeneity for these layered oxides would induce also cell parameters modifications. At this step, the question remains thus open: is there really any fluorine substitution for oxygen in these compounds? Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop" [24], MAS NMR spectroscopy analyses allow discriminating between presence of fluorine in a paramagnetic layered oxide material (large shift expected for the NMR signal due to transfer of electron spin density from the transition metals to fluorine) and presence of fluorine in a diamagnetic material such as LiF (small shift expected). As shown in Figfor the two materials obtained by solid state reaction the 7 Li and 19 F NMR spectra reveal LiF signals separated into narrow spinning sidebands (-1.4 ppm in 7 Li resonance and -204 ppm in 19 F resonance), similar in relative magnitude and in shape to those of "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop". The chemical shifts of these 7 Li and in "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -ss LiF" and "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -ss NiF 2 " but present as LiF; their shape shows that this LiF is present -as it was shown previously for "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop" -as a thin deposit at the surface of the layered oxide with a similar thickness for the three samples; finally, their magnitude shows that the amount of LiF is similar for the three samples in good agreement with similar nominal fluorine amount. In addition to the LiF signal, the very broad signal in Fig. 3 (not separated into spinning sidebands) corresponds to Li in the layered oxide material; its width (~ 600 ppm) results from dipolar interactions with the electron spins of nickel and manganese and its (Fermi contact) shift around 250 ppm is due to the transfer of some electron spin density from the transition metals to lithium. An other signal, with its isotropic position at ~ 410 ppm, separated into spinning side bands and negligible in relative magnitude, corresponds most probably to Li in the secondary manganese-rich layered material detected by XRD and confirms the heterogeneous cation distribution. In 19 F resonance, Fig. 4 also shows, as discussed previously for "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop" in reference

Fig. 6

 6 Fig. 6 gives changes in voltage versus capacity during the first 10 galvanostatic charge / discharge cycles performed between 2 and 4.5 V (vs. Li + /Li) at C/20 rate in lithium cells using LiF-"coated" samples as positive electrode materials, in comparison with that obtained for the bare Li(Ni 0.425 Mn 0.425 Co 0.15 )O 2 material. Since we have demonstrated, especially by

1 . 1 (

 11 Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2ss NiF 2 " (250 mV vs. 180 mV for the others). Nevertheless, the LiF-"coated" samples show better stability of their capacity during cycling in non-optimized laboratory lithium cells, with less than 6 % of capacity loss after 10 cycles, Croguennec et al. (corresponding author: L. Croguennec) Submitted to Journal of the Electrochemical Society -13whereas the bare Li(Ni 0.425 Mn 0.425 Co 0.15 )O 2 material loses more than 13 % of its capacity after 10 cycles between 2 and 4.5 V (vs. Li + /Li).

F

  MAS NMR analyses revealed the presence of fluorine as a thin LiF deposit at the surface of the Li(Ni 0.425 Mn 0.425 Co 0.15 )O 2 particles and thus showed that fluorine-substituted Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 materials were not obtained (like for Croguennec et al. (corresponding author: L. Croguennec) Submitted to Journal of the Electrochemical Society -14 -

Figure 1 : 9 O 1 . 8 F 0. 2 "

 19182 Figure 1: XRD patterns of the "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 " samples prepared by combination of coprecipitation and solid state reactions (cop) or solid state reactions only (ss), using LiF or NiF 2 as fluorine precursor (a). Enlargements given in the 36-38.5° and 42.5-45.5° 2θ angular ranges (b).

1 ( 1 (Fig. 2 :

 112 Fig. 2: Electron microprobe analyses of the "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 " samples obtained using combination of coprecipitation and solid state reactions (cop) with LiF as fluorine precursor (a), and solid state reactions only (ss) with LiF (b) or NiF 2 (c) as fluorine precursors.

Figure 3 : 7 Figure 4 : 19 FFig. 5 : 1 (Figure 6 :

 37419516 Figure 3: 7 Li MAS NMR spectra of "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 " materials synthesized by combination of coprecipitation and solid state reactions (cop) or solid state reactions only (ss) using LiF or NiF 2 as fluorine precursors. The spectra intensity is scaled to the sample mass except for the LiF reference.

1 )"L i 1 . 1 (

 111 Ni 0.425 Mn 0.425 C o 0.15 ) 0.9 O 1.8 F 0.2 -ss L iF " "L i 1.1 (Ni 0.425 Mn 0.425 C o 0.15 0.9 O 1.8 F 0.2 -ss NiF 2 " " L i 1.1 (Ni 0.425 Mn 0.425 C o 0.15 ) 0.9 O 1.8 F 0.2 -cop" B are-L i(Ni 0.425 Mn 0.425 C o 0.15 )O 2 -cop D 1 = 158 mAh.g -1 D 10 = 157 mAh.g -1 C irrevers ible = 41 mAh.g -1 P olarisation : ~ 180 mV D 1 = 150 mAh.g -1 D 10 = 142 mAh.g -1 C irrevers ible = 49 mAh.g -1 P olarisation : ~ 250 mV D 1 = 173 mAh.g -1 D 10 = 153 mAh.g -1 C irrevers ible = 16 mAh.g -1 P olarisation : ~ 180 mV D 1 = 153 mAh.g -1 D 10 = 142 mAh.g -1 C irrevers ible = 30 mAh.g -1 P olarisation : ~ 180 mV

  1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -ss LiF" and "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -ss NiF 2 " with those already reported for Li(Ni 0.425 Mn 0.425 Co 0.15 )O 2 in "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop" is given in Tab. 2 . Considering the major phases, the cell parameters were found larger

	than	those	determined	for	Li(Ni 0.425 Mn 0.425 Co 0.15 )O 2	in
	"Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop". These results are in very good
	agreement with changes in lattice parameters reported in literature for layered

Li(Ni,Mn,Co)O 2 materials as a function of their fluorine content and taken as a proof for effective substitution [14,17,19, 26-27, 30]. On the contrary, we

  Li and 19 F signals in the LiF standard compared to Croguennec et al. (corresponding author: L. Croguennec) Submitted to Journal of the Electrochemical Society -11those in the materials. Indeed, for both nuclei, the larger global width (number of spinning sidebands) for the "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 " samples than for the LiF standard indicates that LiF is very close to the electronic spins

	of the layered oxide, which lead to a through space dipolar interaction and to a
	broadening of the NMR signals.
	Combination of X-ray diffraction, chemical analyses and 7 Li and 19 F
	MAS NMR spectroscopy has thus revealed that fluorine substitution for oxygen
	does not occur in "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 " samples, despite the use
	of different synthesis methods or fluorine precursors assumed in literature to
	lead to the formation of Li 1+x M 1-x O 2-z F z materials. Nevertheless, it was found

  Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -ss LiF" and as formless grains of 15 to 50 nm in diameter for "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -ss NiF 2 ".

	Croguennec et al. (corresponding author: L. Croguennec)		-12 -
	Submitted to Journal of the Electrochemical Society
	for "
	1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 " synthesized by solid state reaction are as
	expected larger in size (more than 700 nm in diameter) and distributed more
	heterogeneously	in	comparison	with	those	observed	for
	"Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop" (~ 300 nm in diameter), indeed they
	were obtained after longer thermal treatments at higher temperature. The
	micrographs show the presence of small particles or "sheets" (assumed to be
	LiF as confirmed by analyses using Auger electron spectroscopy under etching

-not shown here) in the grain boundaries. LiF would thus be present in some grain boundaries, as small particles of 30 nm in diameter for "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop", as "sheets" of 30 nm in thickness

Table 1 : Results of the chemical and redox analyses for the samples of target composition "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 "; these results were obtained by iodometric and ICP titrations as well as analyses.

 1 Li/M) th. = 1.22; (Ni/Mn) th. = 1; (Co/Mn) th. = 0.35) Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop" i.e. LiF-coated Li(Ni 0.425 Mn 0.425 Co 0.15 )O 2 Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -ss NiF 2 " 2.97 Croguennec et al. (corresponding author: L. Croguennec) Submitted to Journal of the Electrochemical Society

	Material	Oxid. state	ICP analyses ((Microprobe analyses ((F/M) th. = 0.22)
			(Li/M) exp.	(Ni/Mn) exp.	(Co/Mn) exp.	(F/M) exp.
		3.02	1.26	1.02	0.35	0.15
	"Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -ss LiF"	2.98	1.19	1.01	0.34	0.14
	"1.16	1.05	0.35	0.14

"

Table 2 : Cell parameters determined for the "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 " samples by the refinement of their X-ray diffraction data by the Full Pattern Matching method (or Le Bail method).

 2 "Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -cop" i.e. LiF-coated Li(Ni 0.425 Mn 0.425 Co 0.15 )O 2 Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -ss LiF" Li 1.1 (Ni 0.425 Mn 0.425 Co 0.15 ) 0.9 O 1.8 F 0.2 -ss NiF 2 "

	Material	Phases	a hex (Å)	c hex (Å)	V (Å 3 )	R wp (%)
		1 [24]	2.8785(2)	14.281(2)	102.48(2)	13.0
	1* "2	2.8823(2) 2.8654(2)	14.293(1) 14.319(1)	102.83(2) 101.81(2)	12.9
	1* "2	2.8836(3) 2.8686(3)	14.292(3) 14.322(3)	102.92(3) 102.06(3)	29.7
	(*) Major phase

Note that for a given map, the lighter the grey is, the larger the amount of the element.Furthermore, no quantitative comparison can be done between different maps. Each map is characterized by its own scale in grey levels (concentrations).

Li NMR MAS

Acknowledgements: the authors thank O. Jan (Saft), C. Denage (ICMCB) and L. Raison (ICMCB) for their technical assistance, Pr A. Lecerf (INSA, Rennes, France) and Dr S. Levasseur (Umicore, Olen, Belgium) for fruitful discussions and Région Aquitaine and Saft for their financial support.