Papers by Olivier LANTIERI
HAL (Le Centre pour la Communication Scientifique Directe), Mar 22, 2011
Diabetologia, Dec 6, 2012
Aims/hypothesis MODY is believed to be caused by at least 13 different genes. Five rare mutations... more Aims/hypothesis MODY is believed to be caused by at least 13 different genes. Five rare mutations at the BLK locus, including only one non-synonymous p.A71T variant, were reported to segregate with diabetes in three MODY families. The p.A71T mutation was shown to abolish the enhancing effect of BLK on insulin content and secretion from pancreatic beta cell lines. Here, we reassessed the contribution of BLK to MODY and tested the effect of BLK-p.A71T on type 2 diabetes risk and variations in related traits. Methods BLK was sequenced in 64 unelucidated MODY samples. The BLK-p.A71T variant was genotyped in a Electronic supplementary material The online version of this article
To date, only two replicated loci, LPA and PALMD, have been identified as causal genes for calcif... more To date, only two replicated loci, LPA and PALMD, have been identified as causal genes for calcific aortic valve stenosis (CAVS) using genome-wide and transcriptome-wide association study (TWAS). To identify additional susceptibility genes for CAVS, we performed a GWAS meta-analysis totaling 5,115 cases and 354,072 controls of European descent. Four loci achieved genome-wide significance, including two new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating an eQTL study of 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Association results at the genome-wide scale showed genetic correlation with coronary artery disease and cardiovascular risk factors. Our study highlights three new loci implicating inflammation, mineralization and blood vessel integrity in CAVS pathogenesis and supports shar...
The Lancet. Neurology, Nov 1, 2017
Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe menta... more Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10(-8)) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restl...
Thrombosis and Haemostasis, 2011
SummaryIt was the objective of this study to investigate the relation between vitronectin and pla... more SummaryIt was the objective of this study to investigate the relation between vitronectin and plasminogen activator inhibitor (PAI)-1 plasma levels with nine-year incidences of the metabolic syndrome (MetS) and of type 2 diabetes mellitus (T2DM). Baseline plasma concentrations of vitronectin and PAI-1 were measured in 627 healthy participants from the prospective D.E.S.I.R. cohort who subsequently developed MetS (n=487) and T2DM (n=182) over a nine-year follow-up (42 presented both) and who were matched with two healthy control subjects each by use of a nested case-control design. Parameters composing the MetS explained about 20% of plasma vitronectin levels. An increase of one standard deviation of vitronectin was associated with increased risks of both the MetS (odds ratio [OR] = 1.21 [1.07 – 1.37], p = 0.003) and T2DM (OR = 1.24 [1.01 – 1.53], p = 0.045). Corresponding ORs for PAI-1 levels were 1.46 [1.27 – 1.68] (p < 10−4) and 1.40 [1.14 – 1.72] (p = 0.0012). However, the eff...
Journal of Nutrition Health & Aging, Jun 21, 2020
Objectives: To propose a simple frailty screening tool able to identify frailty profiles. Design:... more Objectives: To propose a simple frailty screening tool able to identify frailty profiles. Design: Crosssectional observational study. Setting: Participants were recruited in 3 different clinical settings: a primary care outpatient clinic (RURAL population, N=591), a geriatric day clinic (DAY-CLINIC population, N=76) and healthy volunteers (URBAN population, N=147). Participants: A total of 817 older adults (>70 years old) living at home were included. Intervention: A 9-item questionnaire (Lorraine Frailty Profiling Screening Scale, LoFProSS), constructed by an experts' working group, was administered to participants by health professionals. Measurements: A Multiple Correspondence Analysis (MCA) followed by a hierarchical clustering of the results of the MCA performed in each population was conducted to identify participant profiles based on their answers to LoFProSS. A response pattern algorithm was resultantly identified in the RURAL (main) population and subsequently applied to the URBAN and DAY-CLINIC populations and, in these populations, the two classification methods were compared. Finally, clinically-relevant profiles were generated and compared for their ability to similarly classify subjects. Results: The response pattern differed between the 3 sub-populations for all 9 items, revealing significant intergroup differences (1.2±1.4 positive responses for URBAN vs. 2.1±1.3 for RURAL vs. 3.1±2.1 for DAY-CLINIC, all p<0.05). Five clusters were highlighted in the main RURAL population: "non-frail", "hospitalizations", "physical problems", "social isolation" and "behavioral", with similar clusters highlighted in the remaining two populations. Identification of the response pattern algorithm in the RURAL population yielded a second classification approach, with 83% of tested participants classified in the same cluster using the 2 different approaches. Three clinically-relevant profiles ("non-frail" profile, "physical frailty and diseases" profile and "cognitive-psychological frailty" profile) were subsequently generated from the 5 clusters. A similar double classification approach as above was applied to these 3 profiles revealing a very high percentage (95.6%) of similar profile classifications using both methods. Conclusion: The present results demonstrate the ability of LoFProSS to highlight 3 frailty-related profiles, in a consistent manner, among different older populations living at home. Such scale could represent an added value as a simple frailty screening tool for accelerated and better-targeted investigations and interventions.
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Presse Medicale, Mar 9, 2013
Objectives: To study the reproducibility and validity of a French self-administered questionnaire... more Objectives: To study the reproducibility and validity of a French self-administered questionnaire (NAQAPNNS) evaluating the adequation of a subject with the French national nutrition and health program recommendations. Methods: The reproducibility was estimated by weighted kappa in 48 subjects working in the administrative departments of the head office of the Institut Inter Régional pour la Santé in Tours aged from 21 to 63 years who filled the questionnaire NAQAPNNS twice with a two weeks interval. The validity was assessed in 524 hyperglycaemic subjects (fasting plasma glucose between 1.10g/l and 1.25g/l) aged from 25 to 70 years against a seven-day dietary recall using the Kruskall-Wallis test. Agreement between self-administration of the questionnaire and dietetic interview was evaluated by weighted kappa. Results: The reproducibility was "good" (kappa≥0.67) except for recommendations on breads, cereals, potatoes and legumes (kappa=0.50) and sweetened foods consumption (kappa=0.54) which showed only "satisfactory" reproducibility. For each recommendation, subjects who reached it had dietary intakes closer to dietary references intakes (P<0.03). The agreement between self-administration and dietetic interview was "good" (kappa≥0.63) except for recommendations on added fats (kappa=0.41) and salt (kappa=0.50) consumption which were only "satisfactory". Discussion: The NAQAPNNS questionnaire is a consistent and reproducible tool to evaluate adequation of a subject with French national nutritional recommendations. Conclusion: The self-administered questionnaire NAQAPNNS can be used in clinical practice or in epidemiological studies to detect subjects with a food imbalance and needing specific care.
Digestive and Liver Disease, Aug 1, 2012
Immunochemical faecal occult blood tests perform as well with either one or two samples, and bett... more Immunochemical faecal occult blood tests perform as well with either one or two samples, and better than guaiac tests with 6 samples. Clarifying relationship between tests&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; performance, bleeding pattern and observation level. The data of 32,225 average-risk subjects who performed both Hemoccult II (guaiac) and Magstream (immunochemical) tests were re-analysed by varying the cutoff and number of samples of Magstream. The identical performances obtained using one or two samples of Magstream (lower cutoff for one sample) at the population level were explained by opposite patterns of bleeding according to the presence of advanced neoplasias. They translated into discrepancy at the individual level: for example a 60% increase in sensitivity and 20% in specificity observed with one (39ng Hb/ml cutoff) or two samples (63ng Hb/ml cutoff) Magstream compared with Hemoccult II meant that 28.5% of the subjects testing positive with one sample (18.0% in subjects with advanced neoplasias) would have been considered negative by using two samples of Magstream at a higher cutoff (and reciprocal). The identical performance of immunochemical tests using one or two samples (different cutoff), explained by opposite pattern of bleeding according to advanced neoplasias is true only at the population level, the appropriate level for mass screening.
Background: The superiority of several immunochemical fecal occult blood tests (I-FOBT) over guai... more Background: The superiority of several immunochemical fecal occult blood tests (I-FOBT) over guaiac-based tests in colorectal cancer screening is now established. The aim of this study was to compare the analytical performance of 3 quantitative I-FOBTs.Methods: Stool samples from 10 healthy volunteers, initially I-FOBT negative, supplemented with human blood, were used to compare reproducibility and stability of measurement at varying storage temperatures (4°C, 10°C, 20°C, and 30°C) and durations before test analysis (1 to 10 days) for 3 I-FOBTs (New Hemtube/Magstream HT, OC-Auto sampling bottle3/OC-Sensor DIANA, and FOB Gold/SENTiFOB). Concentrations ranging from 0 to 350 μg Hb/g of feces were evaluated.Results: The measurement reproducibility of OC-Sensor was superior to Magstream and far superior to FOB Gold. For all tests, variability was essentially related to sampling. Detected hemoglobin (Hb) levels were substantially lower for all tests at temperatures above 20°C. At 20°C, this loss in concentration was less important with OC-Sensor (significant 1.7% daily decrease vs. 7.4% for Magstream and 7.8% for FOB Gold). At 30°C, daily loss was 8.6% with OC-Sensor, whereas after 24 hours, only 30% of the original Hb was detected with FOB Gold, compared to 70% with Magstream. No Hb was detected on day 5 for the latter 2 tests.Conclusions: About reproducibility and temperature stability, OC-Sensor performed better than Magstream and far better that FOB Gold.Impact: Independently of the chosen test, the delay between sampling and test processing should be reduced, the maximal admissible delay depending on ambient temperature. Cancer Epidemiol Biomarkers Prev; 20(7); 1492–501. ©2011 AACR.
Background: The superiority of several immunochemical fecal occult blood tests (I-FOBT) over guai... more Background: The superiority of several immunochemical fecal occult blood tests (I-FOBT) over guaiac-based tests in colorectal cancer screening is now established. The aim of this study was to compare the analytical performance of 3 quantitative I-FOBTs.Methods: Stool samples from 10 healthy volunteers, initially I-FOBT negative, supplemented with human blood, were used to compare reproducibility and stability of measurement at varying storage temperatures (4°C, 10°C, 20°C, and 30°C) and durations before test analysis (1 to 10 days) for 3 I-FOBTs (New Hemtube/Magstream HT, OC-Auto sampling bottle3/OC-Sensor DIANA, and FOB Gold/SENTiFOB). Concentrations ranging from 0 to 350 μg Hb/g of feces were evaluated.Results: The measurement reproducibility of OC-Sensor was superior to Magstream and far superior to FOB Gold. For all tests, variability was essentially related to sampling. Detected hemoglobin (Hb) levels were substantially lower for all tests at temperatures above 20°C. At 20°C, t...
Diabetologia, Aug 14, 2013
Aims/hypothesis. The relation between insulin secretion and the incidence of hypertension has not... more Aims/hypothesis. The relation between insulin secretion and the incidence of hypertension has not been well characterized. We hypothesised that both a parental history of diabetes and the TCF7L2 polymorphism, which increases susceptibility todiabetesbecause of impaired beta cell function, are associated with incident hypertension. We assessed in a separate cohort whether low insulin secretion is related to incident hypertension. Methods Nine-year incident hypertensionwas studied in 2391 normotensive participants from the D.E.S.I.R. cohort.The relation between insulin secretion and 3-year incident hypertension was investigated in 1047 non-diabetic, normotensive individuals from the RISC cohort. Insulin secretion during an OGTT was expressed in relation to the degree of insulin resistance, as assessed by a hyperinsulinemic-euglycemic clamp. Results In the D.E.S.I.R. cohort, a parental history of diabetes and the TCF7L2 at-risk variant were both associated with hypertension incidence at year-9, independently of waist, blood pressure, fasting glucose, insulin levels and the HOMA-IR at inclusion (p=0.02 for parental history, p=0.006 for TCF7L2). In the RISC cohort, a lower insulin secretion rate during the OGTT at baseline was associated with both higher blood pressure and a greater risk of hypertension at year-3. This inverse correlationbetween the insulin secretion rate and incident hypertension persisted after controlling for baseline insulin resistance, glycaemia and blood pressureat baseline (p=0.007). Conclusions/interpretationParental history of diabetes, the TCF7L2polymorphism and a reduced insulin secretion rate were consistently associated with incident hypertension. A low insulin secretion rate may be a new risk factor for incident hypertension, beyond insulin resistance.
Diabetologia, Mar 19, 2013
Aims/hypothesis We previously identified the G6PC2 locus as a strong determinant of fasting plasm... more Aims/hypothesis We previously identified the G6PC2 locus as a strong determinant of fasting plasma glucose (FPG) and showed that a common G6PC2 intronic single nucleotide polymorphism (SNP) (rs560887) and two common G6PC2 promoter SNPs (rs573225 and rs13431652) are highly associated with FPG. However, these promoter SNPs have complex effects on G6PC2 fusion gene expression, and our data suggested that only rs13431652 is a potentially causative SNP. Here we examine the effect of rs560887 on G6PC2 pre-mRNA splicing and the contribution of an additional common G6PC2 promoter SNP, rs2232316, to the association signal. Methods Minigene analyses were used to characterise the effect of rs560887 on G6PC2 pre-mRNA splicing. Fusion gene and gel retardation analyses characterised the effect of rs2232316 on G6PC2 promoter activity and transcription factor binding. The genetic association of rs2232316 with D. A. Baerenwald, A. Bonnefond and N. Bouatia-Naji contributed equally to this study.
Diabetes, Jul 9, 2010
OBJECTIVE-Genome-wide association studies have identified a single nucleotide polymorphism (SNP),... more OBJECTIVE-Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs560887, located in a G6PC2 intron that is highly correlated with variations in fasting plasma glucose (FPG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. This study examines the contribution of two G6PC2 promoter SNPs, rs13431652 and rs573225, to the association signal. RESEARCH DESIGN AND METHODS-We genotyped 9,532 normal FPG participants (FPG Ͻ6.1 mmol/l) for three G6PC2 SNPs, rs13431652 (distal promoter), rs573225 (proximal promoter), rs560887 (3rd intron). We used regression analyses adjusted for age, sex, and BMI to assess the association with FPG and haplotype analyses to assess comparative SNP contributions. Fusion gene and gel retardation analyses characterized the effect of rs13431652 and rs573225 on G6PC2 promoter activity and transcription factor binding. RESULTS-Genetic analyses provide evidence for a strong contribution of the promoter SNPs to FPG variability at the G6PC2 locus (rs13431652:  ϭ 0.075, P ϭ 3.6 ϫ 10 Ϫ35 ; rs573225  ϭ 0.073 P ϭ 3.6 ϫ 10 Ϫ34), in addition to rs560887 ( ϭ 0.071, P ϭ 1.2 ϫ 10 Ϫ31). The rs13431652-A and rs573225-A alleles promote increased NF-Y and Foxa2 binding, respectively. The rs13431652-A allele is associated with increased FPG and elevated promoter activity, consistent with the function of G6PC2 in pancreatic islets. In contrast, the rs573225-A allele is associated with elevated FPG but reduced promoter activity. CONCLUSIONS-Genetic and in situ functional data support a potential role for rs13431652, but not rs573225, as a causative SNP linking G6PC2 to variations in FPG, though a causative role for rs573225 in vivo cannot be ruled out.
Diabetologia, Jun 4, 2014
International Journal of Obesity, Oct 23, 2012
Obesity is the major determinant of type 2 diabetes (T2D), presumably through its effect on insul... more Obesity is the major determinant of type 2 diabetes (T2D), presumably through its effect on insulin resistance. Genomewide association studies reported many single-nucleotide polymorphisms (SNPs) that increase obesity risk and body mass index (BMI), but their impact on T2D-related traits and risk is unclear. OBJECTIVE: We aimed at analyzing the effect of 24 obesity risk alleles, separately and in combination, on variation of both insulin resistance and b-cell dysfunction, and on T2D risk. DESIGN: We genotyped 24 obesity-associated SNPs and calculated an obesity genotype score (sum of the obesity risk alleles per individual). We analyzed the contribution of each SNP and this score to the variation of four metabolic indices: homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of the pancreatic b-cell function (HOMA-B), insulin sensitivity index (ISI) and insulinogenic index (II) (in up to 8050 nondiabetic French individuals) and to T2D risk (in 2077 T2D cases and 3085 controls). RESULTS: We found a highly significant effect of the obesity genotype score on increased insulin resistance adjusted for age and gender (b ¼ 0.02; P-value ¼ 7.16 Â 10 À 9 for HOMA-IR). Individually, we identified nominal or significant association between increased insulin resistance and risk alleles in FAIM2, FTO, GNPDA2, MC4R, NPC1, PTER and SH2B1. Most signals, including the obesity genotype score and FTO SNP, were also associated with increased b-cell function (b ¼ 0.01; P-value ¼ 1.05 Â 10 À 6 and b ¼ 0.04; P-value ¼ 3.45 Â 10 À 4 , respectively). In our T2D case-control study, only the obesity genotype score and the well-known FTO locus significantly contributed to T2D risk (OR ¼ 1.03; P-value ¼ 9.99 Â 10 À 3 and OR ¼ 1.15; P-value ¼ 9.46 Â 10 À 4 , respectively). Adjustment for BMI abolished all significant associations. CONCLUSIONS: Genetic predisposition to obesity contributes to increased insulin resistance and to its compensation through increased b-cell function, and weakly increases the T2D risk. These associations are mediated by BMI.
Journal of Clinical Pathology, Oct 29, 2013
Aims To determine full blood count (FBC) normal reference values for adults. Methods FBC normal v... more Aims To determine full blood count (FBC) normal reference values for adults. Methods FBC normal values for healthy adults were defined, after establishing preanalytical conditions, in a population of 33 258 subjects, 19 612 men and 13 646 women. The values were established after excluding from this population all people having conditions liable to modify, directly or indirectly, FBC parameters. Results Results for values of standard parameters are provided in detail for each parameter, by sex and by age group from 16 to 69 years of age. In addition, we present FBC values from a population of 339 subjects aged over 69 years with no comorbidities. Conclusions These normal values are proposed for use in everyday practice. They make it possible to distinguish, without ambiguity, a normal situation from a pathological situation. Moreover, they might be used over all mainland France.
The Journal of Clinical Endocrinology and Metabolism, Dec 1, 2014
Context: Vasopressin plays a central role in water homeostasis but it has also been recognized to... more Context: Vasopressin plays a central role in water homeostasis but it has also been recognized to be associated with adverse effects in several chronic diseases. Recently, copeptin has been increasingly used as a surrogate for vasopressin, as they are co-secreted, and copeptin is easier to measure. However, the relationship between plasma concentrations of copeptin (P cop) and vasopressin (P vp) has only been studied in relatively small numbers of selected people. Objective: This study sought to evaluate the relationship between P vp and P cop in a communitybased population and in people with chronic kidney disease (CKD). Design, Setting, and Participants: P vp , P cop , and urinary osmolarity (U osm) were compared in 500 participants of the DESIR study, and in 83 ambulatory people with CKD. Results: Median [interquartile range] of P cop and P vp in the DESIR study were 4.13 [3.58] pmol/L and 0.92 [1.93] pmol/L, respectively. Log-transformed P cop and P vp concentrations correlated significantly and positively (r ϭ 0.686, P Ͻ .001) and they correlated inversely with estimated U osm (P Ͻ .001). Copeptin explained only approximately half of the vasopressin variation. In CKD, P cop and P vp both increased with decreasing estimated glomerular filtration rate (eGFR), but P cop increased much faster than P vp. The P cop /P vp ratios in the lower and upper quintile groups of eGFR were 14.3 [18.3] and 5.3 [4.5], P Ͻ .001, respectively. Conclusions: This study in a normal population, the largest ever with measurements of both peptides, shows that copeptin and vasopressin concentrations correlated well. But their relationship is distorted in CKD, suggesting that the peptide clearances differ when the renal function is impaired.
Diabetes Care, Nov 14, 2011
OBJECTIVEdWater intake alters vasopressin secretion. Recent findings reveal an independent associ... more OBJECTIVEdWater intake alters vasopressin secretion. Recent findings reveal an independent association between plasma copeptin, a surrogate for vasopressin, and risk of diabetes. RESEARCH DESIGN AND METHODSdParticipants were 3,615 middle-aged men and women, with normal baseline fasting glycemia (FG), who were recruited in a 9-year follow-up study. Odds ratios (ORs) and 95% CIs for the incidence of hyperglycemia (FG $6.1 mmol/L or treatment for diabetes) were calculated according to daily water intake classes based on a selfadministered questionnaire. RESULTSdDuring follow-up, there were 565 incident cases of hyperglycemia. After adjustment for confounding factors, ORs (95% CIs) for hyperglycemia associated with classes of water intake (,0.5 L, n = 677; 0.5 to ,1.0 L, n = 1,754; and .1.0 L, n = 1,184) were 1.00, 0.68 (0.52-0.89), and 0.79 (0.59-1.05), respectively (P = 0.016). CONCLUSIONSdSelf-reported water intake was inversely and independently associated with the risk of developing hyperglycemia.
Nature Genetics, Jan 29, 2012
Genome-wide association studies revealed that common non-coding variants in MTNR1B (encoding mela... more Genome-wide association studies revealed that common non-coding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT 2) increase type 2 diabetes (T2D) risk 1,2. Although the strongest association signal was highly significant (P<10 −20), its contribution to T2D risk was modest (odds ratio, OR~1.10-1.15) 1-3. We performed large-scale exon resequencing in 7,632 Europeans including 2,186 T2D patients and identified 40 non-synonymous variants, including 36 very rare variants (minor allele frequency, MAF<0.1%) associated with T2D (OR=3.31[1.78;6.18] 95%); P=1.64×10 −4. A four-tier functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF<1%); four were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial or total loss-of-function variants, but not the neutral ones, contributed to T2D (OR=5.67[2.17;14.82] 95% ; P=4.09×10 −4). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (N cases =8,153/N controls =10,100; OR=3.88[1.49;10.07] 95% ; P=5.37×10 −3). This study establishes a firm functional link between MTNR1B and T2D risk. Disruption of central and peripheral circadian rhythms, including the pancreatic clock, may lead to metabolic disorders and type 2 diabetes (T2D) 4, 5. The neurohormone melatonin (MLT) is mainly secreted from the pineal gland in a circadian pattern with higher levels being observed during the night. MLT targets two high-affinity G protein-coupled receptors (GPCRs): melatonin receptor 1A (also known as MT 1 , encoded by MTNR1A) and MT 2 (encoded by MTNR1B) that modulate both G i protein/adenylyl cyclase and ERK1/2 pathways 6, 7. Genome-wide association studies (GWAS) recently revealed an association Bonnefond et al.
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Papers by Olivier LANTIERI