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Inflammatory labyrinthitis is defined as a fluctuant vestibulo-cochlear syndrome associated with an impairment of the blood-labyrinthine barrier (BLB) on delayed FLAIR MRI sequences. Systemic and intratympanic corticosteroids are the gold standard treatment but their effect is frequently insufficient. The objective is here to determine whether infliximab could be of value in the treatment of bilateral inflammatory labyrinthitis. A retrospective monocentric study was conducted between January 2013 and December 2021. All patients included in the study were affected with a bilateral vestibulo-cochlear syndrome associated with bilateral blood-labyrinthine barrier impairment. Patients were administered infliximab at the dose of 5 mg/kg every 6 weeks for 6 months. Audiometry, MRI with delayed FLAIR sequences on the labyrinth, and corticosteroid doses still required were assessed both before and after treatment with infliximab was completed. Pure-tone average (PTA) was the primary outcome. The secondary outcomes were the speech recognition threshold (SRT), the Dizziness Handicap Inventory (DHI) score, and the corticosteroid (CS) dose. A total of nine patients including five men and four women were enrolled in the study. Thirteen ears were analyzed. After a 6-month period of treatment, the mean PTA (54 ± 24 db versus 66 ± 22 db; p = 0.027), SRT (54 ± 37 db versus 66 ± 32 db; p = 0.041) and DHI score (27 ± 15 versus 9 ± 2; p = 0.032) significantly improved. After the 6-month treatment period, the mean CS dose decreased from 38 ± 33 to 6 ± 5 mg/day (p = 0.003). We conclude that infliximab substantially improves the vestibulo-cochlear function in patients with bilateral inflammatory labyrinthitis and could be of value in corticosteroid-dependent cases.

BACKGROUND: Clinical presentation and risk factors of death in COVID-19 in oldest adults have not been well characterized. OBJECTIVES: To describe clinical features and outcome of COVID-19 in patients older than 85 years and study risk factors for mortality. DESIGN: Prospective cohort. PARTICIPANTS AND SETTING: Patients aged 85 years and older, admitted in noncritical care units at the University Hospital Lariboisiere Fernand-Widal (Paris, France) for confirmed severe acute respiratory syndrome coronavirus 2 infection were included and followed up for 21 days. MEASUREMENTS: Clinical and laboratory findings were collected. Cox survival analysis was performed to explore factors associated with death. RESULTS: From March 14 to April 11, 2020, 76 patients (median age = 90 (86-92) years; women = 55.3%) were admitted for confirmed COVID-19. Of the patients, 64.5% presented with three or more comorbidities. Most common symptoms were asthenia (76.3%), fever (75.0%) and confusion and delirium (71.1%). An initial fall was reported in 25.0% of cases, and digestive symptoms were reported in 22.4% of cases. COVID-19 was severe in 51.3% of cases, moderate in 32.9%, and mild in 15.8%. Complications included acute respiratory syndrome (28.9%), cardiac decompensation (14.5%), and hypotensive shock (9.0%). Fatality at 21 days was 28.9%, after a median course of disease of 13 (8-17) days. Males were overrepresented in nonsurvivors (68.2%). In survivors, median length of stay was 12 (9-19.5) days. Independent predictive factors of death were C-reactive protein level at admission and lymphocyte count at nadir. CONCLUSION: Specific clinical features, multiorgan injury, and high case fatality rate are observed in older adults with COVID-19. However, rapid diagnosis, appropriate care, and monitoring seem to improve prognosis.

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Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (r Pearson = 0.26; P = 10 −3 ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10 −4 ; p corrected = 0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (p empirical = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients’ genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.

Background: Increased knowledge of the pharmacokinetic characteristics of orally administered levothyroxine (L-T4) has improved individualization of dosing regimens. However, up to 40–45% of patients, depending on the leading cause of hypothyroidism, are still over- or, more often, undertreated. Unintentional non-adherence to L-T4 replacement therapy includes all situations of unintended drug–drug and drug–food interactions as well as fasting conditions that are not necessarily respected by patients. Results: In this specific context, the overall information concerning those factors with the potential to affect L-T4 absorption refers only to tablet formulation. Indeed, this is the reason why new non-tablet formulations of L-T4 were introduced some years ago. In this regard, the current literature review was designed to summarize pharmacokinetic, drug and food interactions and clinical data focusing on two new oral L-T4 formulations, i.e., liquid and soft-gel capsule in healthy volunteers and patients with primary hypothyroidism. The non-tablet L-T4 soft-gel capsules and solution have proven bioequivalence with the usual L-T4 tablet Princeps and generic formulations. Clinical studies have suggested higher performance of non-tablet formulations than tablet in those patients with suboptimal adherence. The impact of gastrointestinal conditions and variation of gastric pH was lower with either soft gel/solution than with tablets. In addition, the extent of drug–drug and drug–food interactions remains low and of uncertain clinical relevance. Conclusions: Pending further studies allowing one to extend the use of soft-gel/solution preparations in unselected patients, non-tablet L-T4 formulations should be considered as a first-line choice, especially in those patients with moderate-to-high potential of suboptimal tablet performance.

Background people suffering from substance use disorders (SUD) often die by suicide, so that the prevention of suicide attempts (SA) remains a top priority in this population. SA recurrence is common and is associated with suicide death, but this phenotype has been overlooked in SUD populations. Thus, we aimed at identifying the risk factors of SA recurrence in SUD, controlling for both gender and levels of exposure to addictive substances, including tobacco. Methods we consecutively recruited 433 treatment-seeking outpatients with either opiate or cocaine use disorder and assessed their lifetime history of addictive and suicidal symptoms by standardized questionnaires. They were reliably classified as never, single or recurrent (≥ 2) suicide attempters, whose characteristics were identified by multinomial regression, stratified by gender; and compared to our previous work on serious SA in order to identify common or different risk profiles. Results 86/140 (61%) suicide attempters reported recurrence. The mean number of SA was 3.1. Recurrence was independently associated with psychiatric hospitalization in both genders, with nicotine dependence in men and with sedative use disorders in women. Limitations psychiatric diagnoses were derived from the current medication regimen. Conclusion specific and possibly avoidable/treatable risk factors for the recurrence of SA in SUD have been identified for the first time, opening new avenues for research and prevention in this high-risk population. Apart from nicotine dependence, these risk factors were very similar to those of serious SA. Although this comparison is indirect for now, it suggests a common liability towards suicidal behavior.

Introduction La maladie de Behcet est une maladie inflammatoire idiopathique survenant habituellement avant l’âge de 50 ans chez des patients originaires du pourtour mediterraneen, Moyen Orient ou Extreme Orient [1] . L’atteinte neurologique, observee dans 5 a 59 % des cas, correspond le plus souvent a un tableau de meningoencephalite avec des lesions parenchymateuses inflammatoires mais des lesions pseudotumorales sont egalement rapportees [2] . Observation Une patiente senegalaise de 36 ans, sans antecedent, a ete adressee en medecine interne pour cephalees avec hemiparesie et paralysie faciale gauches apparues en 24 heures. L’IRM cerebrale montrait une volumineuse lesion capsulo-lenticulo-thalamique et du pedoncule cerebral a droite, en hypersignal FLAIR et rehaussee au gadolinium, avec compression du ventricule lateral droit. La ponction lombaire retrouvait une meningite lymphocytaire. Devant la presence d’ulcerations orales et genitales, de synovites interphalangiennes et d’une reaction de pathergie, et apres elimination d’un processus infectieux, le diagnostic de maladie de Behcet a ete retenu. Une corticotherapie par bolus intraveineux puis relais oral a ete initiee en association a du cyclophosphamide mensuel (1000 mg) et de l’aspirine. Apres 6 cures, on observait une regression des signes neurologiques et d’imagerie conduisant a un espacement des perfusions. Au moment de la 9e cure, la patiente presentait des troubles de la vigilance et une aphasie, avec une nouvelle lesion inflammatoire atteignant le pedoncule cerebral et le noyau lenticulaire gauches et comprimant le 3e ventricule a l’IRM, et de nouveau une meningite lymphocytaire. La biopsie cerebrale etant jugee trop dangereuse, la prise en charge a consiste en un nouveau traitement d’attaque par corticoides, associe a de l’infliximab et de la colchicine. L’evolution etait favorable jusqu’a une rupture de traitement par la patiente, et dix-huit mois plus tard une readmission pour ralentissement psychomoteur. Il existait alors une hypothermie (32 °C), une bradycardie (54/min) et une hypotension arterielle (100/52 mmHg), une absence de signe de localisation neurologique, et une thrombopenie a 55 000/mm3. La ponction lombaire et l’electro-encephalogramme etaient normaux et l’IRM cerebrale ne montrait que des anomalies sequellaires. Le PET-scanner cerebral retrouvait un hypometabolisme dans les regions hippocampiques et cingulaires. Apres elimination d’autres causes (hypothyroidie, insuffisance surrenalienne), l’hypothermie a ete rapportee a de probables sequelles cerebrales du neuro-Behcet impliquant le systeme limbique. L’utilisation d’une couverture chauffante et l’introduction de clonidine a permis une resolution durable de l’hypothermie avec normalisation de l’etat neurologique et des plaquettes. La colchicine et l’aspirine ont ete reintroduits pour le traitement au long cours de la maladie de Behcet. Discussion Les formes pseudotumorales de neuro-Behcet sont rares, et ont une expression clinique plus aigue et severe. Le traitement de premiere intention est souvent le cyclophosphamide associe a la corticotherapie, mais les anti-TNF alpha presentent un interet dans les formes refractaires [2] . L’atteinte IRM du neuro-Behcet concerne plutot le tronc cerebral pour les formes encephalitiques, et les regions capsulo-thalamiques pour les formes pseudotumorales, mais une etude a observe la presence d’un hypometabolisme significatif dans les regions parahippocampiques et cingulaires chez ces patients, par rapport a des sujets sains et des cas non neurologiques de Behcet, malgre l’absence de lesion observee a l’IRM [3] . La thermoregulation repose sur l’hypothalamus mais egalement sur le systeme limbique dont l’atteinte peut etre responsable d’hypothermie paroxystique. Par analogie avec le syndrome de Shapiro, l’introduction de clonidine a montre un benefice chez notre patiente. Conclusion Nous rapportons un cas rare de neuro-Behcet pseudotumoral responsable d’une hypothermie paroxystique sequellaire.

Introduction Une prevalence elevee d’embolie pulmonaire (EP) a ete decrit au cours de la COVID-19, avec une morbi-mortalite significative. L’objectif etait d’identifier des facteurs predictifs d’EP chez des patients atteints de COVID-19 severes hospitalises hors reanimation. Patients et methodes Au cours d’une etude retrospective multicentrique nationale francaise, nous avons inclus entre le 6 et le 28 avril 2020, les patients atteints de COVID-19 confirmee par RT-PCR, hospitalises en service de Medecine Interne ou de Pneumologie, avec un angioscanner thoracique realise au Service d’Accueil des Urgences pour suspicion d’EP. Les donnees de base, les traitements et l’evolution ont ete recueillies lors de l’admission et au dernier suivi disponible. Des modeles de regression uni et multivaries ont ete utilises pour identifier les facteurs predictifs associes au diagnostic d’EP confirmee. Resultats Au total, 88 patients (âge median [interquartile range IQR] de 68 ans [60-78]) ont ete analyses. Sur la base de l’angioscanner thoracique, une EP a ete confirmee chez 47 (53,4 %) patients, et refutee chez 41 autres. Un taux de D-dimeres ≥ 3000 ng/mL (Odds ratio OR = 8,2 [intervalle de confiance a 95 %] 1,3-74,2, sensibilite (Se) 0,84, specificite (Sp) 0,78, p = 0,03), un taux de leucocytes ≥ 12 G/L (OR = 29,5 [2,3-1221,2], Se 0,47, Sp 0,92, p = 0,02) et une ferritinemie ≥ 480 μg/L (OR = 17,0 [1,7-553,3], Se 0,96, Sp 0,44, p = 0,03) etaient associes au diagnostic d’EP de maniere independante. L’association d’un taux de D-dimeres ≥ 3000 ng/mL et d’un taux de leucocytes ≥ 12 G/L etait tres associes au diagnostic d’EP (OR = 21,4 [4,0-397,9], p = 0,004). Conclusion Le taux de leucocytes, de D-dimeres et la ferritinemie sont des biomarqueurs simples et facilement disponibles a l’admission pour predire le diagnostic d’embolie pulmonaire chez des patients atteints de COVID-19 hospitalises hors reanimation. Ces biomarqueurs pourraient integrer la demarche diagnostique d’embolie pulmonaire et a l’initiation rapide d’une anticoagulation curative au cours de la COVID-19, et pourraient inversement reduire le nombre d’angioscanner thoracique non necessaire.

Introduction La sarcoidose est une pathologie inflammatoire systemique d’etiologie inconnue et de presentation heterogene, dont le diagnostic repose sur un faisceau d’arguments du fait de l’absence de test specifique. L’objectif de cette etude etait d’evaluer la valeur du dosage du recepteur soluble de l’interleukine 2 (sIL2R), marqueur de l’activation lymphocytaire T, pour le diagnostic et l’evolutivite de la sarcoidose. Patients et methodes Cette etude prospective concernait tous les patients admis dans le service de medecine interne de l’Hopital Lariboisiere (APHP) avec une suspicion de sarcoidose ou une sarcoidose averee, entre novembre 2019 et decembre 2020. Les donnees recueillies etaient celles permettant le diagnostic de sarcoidose : atteintes cliniques, donnees biologiques incluant l’enzyme de conversion de l’angiotensine (ECA), donnees histologiques (presence d’un granulome sans necrose) ; ainsi que la presence de traitement. La maladie etait consideree active au diagnostic ou en presence de manifestations cliniques et paracliniques justifiant une adaptation therapeutique au decours du bilan. Le dosage du sIL2R etait realise au Centre Hospitalier Lyon Sud, avec un seuil de positivite a 1425 pg/mL. L’analyse statistique reposait sur la mesure de la sensibilite et de la specificite du dosage, et sur des tests statistiques univaries (Chi2). Resultats Cinquante-sept patients ont ete inclus dans l’etude, dont 32 femmes (56,1 %) avec un âge moyen de 46,4 ans (ecart-type 15,8 ans). Dans 28 sur 51 cas (49,1 %), il y avait un granulome objective sur biopsie. Un diagnostic de sarcoidose etait effectif chez 27 patients (47,4 %). Les principales manifestations etaient ganglionnaires (22 cas, 81,5 %) et pulmonaires (17 cas, 63 %), et 88,9 % presentaient du granulome (24 cas). Neuf patients (33,3 %) faisaient l’objet d’un diagnostic initial de sarcoidose, et la plupart des patients (16 soit 59,3 %) avaient une maladie active au moment du bilan. Quatorze patients etaient sous traitement (51,3 %) dont douze sous corticotherapie. Trente patients avaient un diagnostic differentiel : uveite idiopathique (n = 10), tuberculose (n = 6), lymphome (n = 2), autres (n = 12). Le taux moyen de sIL2R etait de 2494,9 pg/mL (ecart-type 3233,4 pg/mL), avec 51,9 % de positivite, chez les patients atteint de sarcoidose, contre 1679,4 pg/mL (ecart-type 1088,7 pg/mL) avec 50 % de positivite dans les autres diagnostics, sans difference significative (p = 0,9). Pour l’ECA, les taux moyens etaient respectivement de 77,7 UI/L (ecart-type 48,5 UI/L) et 36,3 UI/L (ecart-type 23,5 UI/L), les taux de positivite de 48,1 % et 8,7 % (p = 0,002). La specificite de l’ECA etait meilleure (91,3 % versus 50 %). Les taux seriques de sIL2R et d’ECA etaient plus souvent eleves en presence qu’en l’absence d’un granulome, quel qu’en soit le diagnostic (60,7 % versus 30,4 % ; p = 0,03 ; 48,1 % versus 10,5 % ; p = 0,007, respectivement). Chez les patients sarcoidosiques, le taux serique de sIL2R etait plus eleve chez les patients ayant une sarcoidose active que chez ceux ayant une sarcoidose quiescente (3424,9 versus 1142,1 pg/mL) de meme que le taux de positivite (75 % versus 18,2 % ; p = 0,004). Le taux de positivite de l’ECA etait de 62,5 % chez les patients ayant une sarcoidose active contre 27,3 % chez ceux ayant une sarcoidose quiescente (p = 0,07), avec des taux seriques respectivement de 91,8 UI/L et 57,2 UI/L. Pour les 16 patients atteints d’uveite, dont 6 atteints de sarcoidose (37,5 %), la sensibilite du dosage du sIL2R et de l’ECA etait respectivement a 66,7 % et 50 %. Discussion Dans notre serie, le dosage du sIL2R presentait une sensibilite faible pour le diagnostic de sarcoidose tout comme l’ECA meme si ce dernier presentait une meilleure specificite. Dans la litterature, les chiffres de sensibilite et specificite du sIL2R sont tres variables (respectivement 63-82 % et 57-100 %), et il pourrait y avoir une meilleure sensibilite dans le contexte d’uveite (82-98 %) [1] , tout comme dans notre etude. Chez les patients ayant une sarcoidose, les taux seriques de sIL2R sont significativement associes au degre d’activite, avec une meilleure correlation que l’ECA, comme cela est rapporte dans d’autres etudes [1] , [2] . Conclusion Le sIL2R ne semble pas etre suffisamment discriminant comme test diagnostique de sarcoidose mais semble etre un meilleur biomarqueur d’activite que l’ECA.

To assess tocilizumab (TCZ) efficacy associated to standard of care (SOC) compared to SOC alone in severe coronavirus associated disease 2019 (COVID-19) patients. In a matched case-control study from 3 French Hospital COVID-19 Departments, 27 patients with severe COVID-19 treated with TCZ and SOC were matched for baseline epidemiological and clinical features and compared to 27 severe COVID-19 patients treated with SOC alone. Baseline characteristics of the study population were comparable between groups. Eleven patients (20%) died. TCZ was not associated with clinical improvement as compared to SOC regarding oxygen-free status (44% vs 63%) and death (18.5% vs 22%), despite a higher decrease of the C-reactive protein at Day 7 (10.7 vs 52 mg/L; P 

Protein expression levels of drug-metabolizing enzymes and transporters in human jejunal tissues excised from morbidly obese subjects during gastric bypass surgery were evaluated using quantitative targeted absolute proteomics. Protein expression levels of 15 cytochrome P450 (CYP) enzymes, 10 UDP-glucuronosyltransferase (UGT) enzymes, and NADPH-P450 reductase (P450R) in microsomal fractions from 28 subjects and 49 transporters in plasma membrane fractions from 24 of the same subjects were determined using liquid chromatography-tandem mass spectrometry. Based on average values, UGT1A1, UGT2B15, UGT2B17, SGLT1, and GLUT2 exhibited high expression levels (over 10 fmol/μg protein), though UGT2B15 expression was detected at a high level in only one subject. CYP2C9, CYP2D6, CYP3A5, UGT1A6, P450R, ABCG2, GLUT5, PEPT1, MCT1, 4F2 cell-surface antigen heavy chain (4F2hc), LAT2, OSTα, and OSTβ showed intermediate levels (1-10 fmol/μg protein), and CYP1A1, CYP1A2, CYP1B1, CYP2C18, CYP2C19, CYP2J2, CYP3A7, CYP4A11, CYP51A1, UGT1A3, UGT1A4, UGT1A8, UGT2B4, ABCC1, ABCC4, ABCC5, ABCC6, ABCG8, TAUT, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OCTN1, CNT2, PCFT, MCT4, GLUT4, and SLC22A18 showed low levels (less than 1 fmol/μg protein). The greatest interindividual difference (364-fold) was detected for UGT2B17. However, differences in expression levels of other quantified UGTs (except UGT2B15 and UGT2B17), CYPs (except CYP1A1 and CYP3A5), and P450R, and all quantified transporters, were within 10-fold. Expression levels of CYP1A2 and GLUT4 were significantly correlated with body-mass index. The levels of 4F2hc showed significant gender differences. Smokers showed increased levels of UGT1A1 and UGT1A3. These findings provide a basis for understanding the changes in molecular mechanisms of jejunal metabolism and transport, as well as their interindividual variability, in morbidly obese patients.

Background and Objectives The burden of opiate dependence not only relies on somatic complications such as infectious diseases or acute intoxication but also on frequent psychiatric events such as major depressive disorder (MDD) and suicidal behavior (SB). Given the preclinical and clinical evidence regarding the associations between cannabinoid systems and both opiate dependence and psychiatric disorders, we chose to address whether one single nucleotide polymorphism (SNP) of the cannabinoid receptor type 1 gene (CNR1) named rs2023239 would be associated with lifetime MDD and SB in a population of opiate-dependent outpatients remitted under stable methadone treatment. Methods Sociodemographic and clinical data were included as independent factors in two logistic regression models aimed at predicting SB and MDD, respectively, performed with 85 Caucasian individuals. Results The minor C allele of rs2023239 showed an independent protective effect against lifetime MDD after adjustment for potential confounders. It was not associated with variables related to suicidal behavior. Conclusions and Scientific Significance Despite limitations due to the modest sample size, our results are consistent with previous research on the endocannabinoid system and suggest new leads for detecting subjects at risk of MDD, which remains insufficiently diagnosed and treated in patients suffering from severe addictive disorders. (Am J Addict 2015;XX:1 –8)

Aims Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients.

The clinical efficacy, safety, and acceptability of a new oral saliva equivalent (Novasial) administered four times daily in the treatment of xerostomia in various medical conditions was compared with that of oxygenated glycerol triester oral spray (Aequasyal) and a moisturizing spray (Biotene) in a 2-week, multicenter, randomized, crossover study. Assessment included patient-based evaluation of mouth dryness score (primary endpoint) with a visual analog scale (VAS), blinded assessment of the oral tissue condition by a four-point ordinal scale, and patient-based assessment of tolerability and acceptability.At day 14, Novasial decreased oral mouth dryness by 19.5%, (12.5 ± 22.6 mm, P.0001 versus baseline), versus 10% (6.6 ± 17.9 mm with Aequasyal, P.0001 versus Baseline; and P.0156 versus Novasial) and 13% (8.6 ± 18.9 mm) with Biotene (P.0001 versus baseline). The 50% decrease in the primary endpoint was not achieved, and the overall efficacy of Novasial and Aequasyal were similar with respect to xerostomia. Novasial was preferred to Aequasyal and Biotene in alleviating taste alteration and chewing difficulty. Treatment compliance was higher with Novasial (P = .0014 versus Aequasyal). The treatments improved the oral condition with equal efficacy and were safe and well tolerated (VAS 72-77 mm).Novasial was a safe, well-tolerated, and acceptable treatment in patients with xerostomia induced by various treatments or pathologic conditions.

International audience; The purpose of the present work was to study the change in morphine metabolic ratio in obese subjects before and after Roux-en-Y Gastric Bypass (RYGB) and to identify clinical and/or biological factors associated with this change. The pharmacokinetics (PK) of oral morphine (30mg), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was performed in patients before (n=25; mean BMI=43.2 (35.4-61.9)kg/m2), 7-15days (n=16) and 6 months after RYGB (n=19; mean BMI=32.3 (25.4-46.0)kg/m2). Morphine Cmax and AUC0-inf were significantly increased and morphine Tmax significantly shortened at 6 months after RYGB compared with preoperative data, indicating an important increase in the rate and extent of morphine absorption. The morphine metabolic ratio 0-inf M3G+M6G/Morphine, decreased significantly from the preoperative to 6 months postoperative period with an average of -26% (range -74%; +21%; p=0.004), but not in the immediate post-operative period. The change in morphine metabolic ratio was associated with a change in BMI, fat mass in kg, and triglyceride levels (rho=0.5, p≤0.04). The degree of change in several markers of low-grade inflammation, or the level of liver steatosis and fibrosis before surgery, was not associated with the change in morphine metabolic ratios. Our findings indicate that RYGB-induced weight loss significantly decreases morphine metabolic ratio, arguing for an effect of morbid obesity on glucuronidation. With glucuronide exposure at 6 months similar to preoperative values, a higher morphine AUC0-inf should encourage reducing morphine dosage in patients undergoing RYGB and chronically receiving immediate-release oral morphine.

Obesity and opioid use for chronic pain in obese individuals are both important public health concerns. The pharmacokinetics of oral morphine after Roux-en-Y gastric bypass (RYGB) are unknown. Therefore, we aimed to study the pharmacokinetics of oral morphine in morbidly obese patients before and after RYGB surgery, to identify the effects of RYGB and the subsequent reversal of morbid obesity on the pharmacokinetic parameters of morphine. The pharmacokinetics of oral morphine (30 mg) were studied in 30 obese patients before (Visit 1) and then 7–15 days (Visit 2) and 6 months (Visit 3) after RYGB. A population pharmacokinetic model was used to describe the time course of the plasma morphine concentration, to study the effect of RYGB on morphine pharmacokinetics and to estimate inter-patient variability. The oral morphine time to maximum plasma concentration (t max) was twofold lower and maximum plasma concentration (C max) was 1.7 times higher at Visit 2, and t max was 7.5 times lower and C max 3.3 times higher at Visit 3 than at Visit 1. The mean oral morphine area under the plasma concentration–time curve (AUC) increased significantly (1.55-fold) between Visits 1 and 3. Changes in body mass index (BMI) after RYGB were clearly associated with decreased apparent oral morphine clearance and apparent central and peripheral morphine volumes of distribution. None of the other anthropometric parameters explained the inter-subject variability in morphine exposure better than BMI. RYGB and the BMI reduction that followed it dramatically increased the rate of morphine absorption and slightly increased morphine exposure. The dose of immediate-release forms of morphine may be divided in obese patients after RYGB to prevent adverse events due to early and high morphine plasma peaks.

Background Many drugs increase the duration of the QT interval of patients, potentially leading to harmful effects such as polymorphic ventricular arrhythmias. Most of these drugs do so by inhibiting the rapid component IKr of the delayed rectifier potassium current IK. Methadone is the most prescribed heroin maintenance treatment and is known to inhibit the cardiac potassium channel hERG, which recapitulates IKr. In order to evaluate if any polymorphism of potassium channels’ genes could explain some of the “idiosyncratic” QT prolongations observed in patients treated with methadone, we tested the association between KCNE1 , KCNE2 , and KCNH2 polymorphism and the QT interval prolongation in those patients, controlling for other variables associated with a decrease of the repolarizing reserve. Methods A cohort of 82 patients treated with stable dosage of methadone (mean dosage 65 mg/d) for at least three months was genotyped for five polymorphisms in KCNE1 , KCNE2 and KCNH2 genes and had their corrected QT (QTc) assessed. Results The mean QTc interval was 415 ± 34 ms. In a linear regression model, longer QTc interval was associated with methadone dosage and with one genetic factor. Each copy of a Lys allele at codon 897 of KCNH2 , the gene that encodes the cardiac potassium voltage-gated channel hERG, was associated with a 15.4 ms longer QTc (95% CI [4.6–26.2]; p = 0.001). Conclusion KCNH2 genotyping may be relevant in the analysis of cumulative risk factors for QT prolongation in patients on methadone maintenance treatment.

Resume Objectifs Plusieurs indicateurs ont mis en evidence une performance francaise insuffisante dans la conduite d’essais cliniques, en partie liee a une formation des investigateurs et une organisation des sites insuffisantes et heterogenes. Un groupe multidisciplinaire a construit une formation de futurs formateurs a l’investigation clinique. Nous decrivons ici le referentiel elabore par le groupe sur l’organisation des sites investigateurs. Resultats Le groupe de travail incluait des personnes impliquees dans la recherche clinique d’origine academique, industrielle, autorite de sante, liberale, ou consultants independants. Des methodes et outils permettant une bonne organisation du site investigateur ont ete developpes. Conclusion Les outils proposes sont axes sur la connaissance par les investigateurs de leurs responsabilites, de leur environnement a l’hopital ou en ville, de l’analyse de la faisabilite, de methodes actives de recrutement des patients. Ils devraient permettre une meilleure organisation des sites investigateurs, pour de meilleures performances dans la conduite des etudes cliniques.

Aim We aimed to evaluate changes in venous physiologic parameters with aging in healthy volunteers. Methods Sixty subjects (29 women, 31 men, mean age 63.1 ± 4.4, 24 subjects aged over 75 years) with no history of deep venous thromboembolism, venous insufficiency, deep venous thrombosis, peripheral arteriopathy, lower limb edema, atrial fibrillation or acute medical condition within the last 7 days were enrolled. Subjects remained in the supine position for 15 min before and during data acquisition. Mercury strain gauge was put around the calf and connected to the EC6 plethysmograph. We measured the venous parameters by inflating the collecting cuff up to 50 mmHg pressure for 4 min. The data were implemented in the NIVP3 software to measure compliance, maximum venous outflow (MVO) and half-emptying time (T1/2). Results The venous capacitance, compliance and MVO significantly decreased with age ( P = 0.023, P = 0.01 and P = 0.02, respectively, ANOVA) while T1/2 increased with age ( P = 0.02, ANOVA). There was a negative correlation between age and respectively, compliance (rs = −0.21, P = 0.01) and MVO (rs = −0.25, P = 0.0003), and a positive correlation between T1/2 and age (rs = 0.14, P = 0.0003). Using logistic regression analysis, calf circumference ( P = 0.0001), venous capacitance ( P = 0.012) and MVO ( P = 0.033) were the only variables independently associated to age. Conclusion Using a sensitive, non-invasive, painless, reproducible and easily repeatable computerized method, we successfully forecasted changes of venous physiological parameters over age and provided valuable information in the field of physiological aging.

Guidelines recommend routine universal HIV testing in adults to reduce the pool of infected patients unaware of their status, without specific recommendations concerning the method. We compared acceptability and feasibility of HIV testing by ELISA tests or rapid tests from finger-stick whole blood.Prospective randomized multi-center study comparing acceptability and feasibility of routine universal HIV testing by ELISA tests, with a charge, subsequently reimbursed by Social Security for affiliated patients, or rapid tests from finger-stick whole blood, without any charge from the patients or the general practitioner for the study. A single investigator performed all interventions. After consent, all adults (18-70 years old) consulting their general practitioner in Paris, France, unaware of their status, were enrolled. Testing was performed immediately for the patients in the rapid test arm; a prescription was given for testing in a lab for the patients in the ELISA arm. The primary endpoint was acceptability of each method. The secondary endpoint was feasibility of each method, assessed one month after the consultation.Two hundred and seventy patients were enrolled: 133 patients in the ELISA arm, 137 in the rapid test arm. Acceptability of the rapid test (92%) was higher than that of the ELISA (63.9%), P0.0001. Feasibility of the rapid test (100%) was higher than that of the ELISA (50.5%), P0.0001. A center effect was shown concerning feasibility of ELISA but not concerning feasibility of rapid tests.Rapid testing from finger-stick whole blood is more acceptable and feasible than ELISA for routine universal HIV testing. A larger use of rapid tests, ideally free of charge, by general practitioners could reduce the pool of infected patients unaware of their status.

Aim: To report changes in the quality of sleep after drinking an evening cup of either caffeinated or decaffeinated coffee, in healthy subjects in everyday life. Methods: Sixty-three healthy men and women, who considered themselves to be caffeine sensitive were included in a double-blind, cross-over trial, randomised to receive either caffeinated coffee containing 90 mg of caffeine, or, as control, a dose of decaffeinated coffee containing 4.5 mg caffeine, taken after dinner. The primary outcome measure was the degree of sleep disturbance, scored on a visual analogue scale, ranging from 0 (excellent sleep) to 100 (very disturbed sleep). Ancillary criteria were patients' reported estimate of sleep latency, and how often the subjects reported waking. Results: Mean age of subjects was 30.5 ± 12 years. The quality of sleep was significantly worse with caffeinated (mean 30.8 ± 22.7) than with decaffeinated coffee (mean 19.5 ± 16.9), P = 0.001. Caffeinated coffee also significantly increased the sleep latency (mean difference 17 ± 31 minutes, P

OBJECTIVES Early evaluation of direct home discharge (DHD) after hospitalization of elderly patients is important to organize discharge planning quickly. Many scores, scales, and indices have been developed to improve discharge planning. Is clinical judgment better than functional status, comorbidity, or cognitive function scales in predicting DHD of elderly patients after hospitalization? METHODS Ninety-seven patients, aged 75 years or older, admitted from the emergency department to an internal medicine department in a French teaching hospital between December 1, 2006 and May 1, 2007, were enrolled prospectively in the study. Demographic, clinical, and laboratory characteristics and functional status, comorbidity, and cognitive function scales were determined. The primary outcome was the percentage of correct discharge prediction made by junior and senior doctors within the first 48 hours upon admission. Univariate analysis and logistic regression were assessed to determine predictive variables of patients' discharge. RESULTS Junior and senior doctors obtained correct prediction in 74.2% and 73.2% of cases, respectively (P > 0.99). Activities of daily living, instrumental activities of daily living, and duration of hospitalization were predictive of DHD (95% confidence interval [CI] -6.1 to 0.2, P = 0.037; 95% CI -2.1 to 9.9, P = 0.003; 95% CI -3 to 9.1, P = 0.0001, respectively) in the univariate analysis. Instrumental activities of daily living was an independent predictive variable of patients' discharge in a logistic regression. No difference between clinical evaluation and the use of an independent predictive variable regarding the prediction of DHD was found. CONCLUSIONS Early clinical evaluation is as effective as the use of functional status scales to predict DHD of hospitalized elderly patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Increased INR was previously observed in patients treated with warfarin and amoxicillin/clavulanic acid (amoxiclav) combination. To date, no prospective study has yet evaluated the effect of amoxiclav on INR in patients on warfarin therapy and consequently, there are no clear-cut conclusions or clear recommendations for clinicians. WHAT THIS PAPER ADDS • We provided the first systematic prospective evaluation of the interaction between amoxiclav and warfarin and found that amoxiclav did not modify INR in patients treated with stable warfarin therapy in the absence of any infectious or inflammatory syndrome, suggesting that the previously observed INR increase in these patients may not be attributable to a drug–drug interaction. AIMS To investigate whether an interaction exists between amoxicillin/clavulanic acid (amoxiclav) and warfarin in patients treated with stable oral anticoagulant therapy. METHODS In a double-blind, cross-over, placebo-controlled study, 12 patients on stable warfarin therapy, received a 7 day amoxiclav regimen or placebo. RESULTS The mean maximum increase in INR observed was 0.22 ± 0.3 with amoxiclav vs. 0.24 ± 0.6 with placebo (P= 0.94). The day 7–day 1 factor II, R(–) and S(–) warfarin plasma concentrations were similar during the amoxiclav and placebo study periods (P= 0.81, P= 0.45, P= 0.75, respectively). CONCLUSION Amoxiclav did not modify anticoagulation in patients treated with stable warfarin therapy and without infection.

Morbidly obese patients are at significantly elevated risk of postsurgery complications and merit closer monitoring by health care professionals after bariatric surgery. It is now recognized that genetic factors influence individual patient’s response to drug used in anesthesia and analgesia. Among the many drug administered by anesthetists, we focused in this pilot study on morphine, since morphine patient-controlled anesthesia in obese patients undergoing gastric bypass surgery is frequently prescribed. We examined the allelic frequency of three polymorphisms involved in morphine pharmacodynamics and pharmacokinetics in patients with body mass index (BMI) >40. One hundred and nine morbidly obese patients (BMI = 49.1 ± 7.7 kg/m²) were genotyped for three polymorphisms c.A118G of mu opioid receptor (OPRM1), c.C3435T of the P-glycoprotein gene (ABCB1), and p.Val158Met of catechol-O-methyltransferase gene (COMT). Allelic frequencies were 118G—0.22, C3435—0.55, and 158Met—0.5 in our whole population and 0.23, 0.5, and 0.47 in Caucasian population. Allelic frequencies did not differ according to gender. Mean BMI did no differ according to the allelic variant. OPRM1118G allele was more frequent in our population than in most previously described European populations. Since the concept of “personalized medicine” promises to individualize therapeutics and optimize medical treatment in term of efficacy and safety, especially when prescribing drugs with a narrow therapeutic index such as morphine, further clinical studies examining the clinical consequences of the OPRM1 c.A118G polymorphism in patients undergoing gastric bypass surgery are needed.

Morphine is an analgesic drug used to treat acute and chronic pain. Obesity is frequently associated with pain of various origins (e.g. arthritis, fibromyalgia, cancer), which increases the need for analgesic drugs. Obesity changes drug pharmacokinetics, and for certain drugs, specific modalities of prescription have been proposed for obese patients. However, scant data are available regarding the pharmacokinetics and pharmacodynamics of morphine in obesity. Prescription of morphine depends on pain relief but the occurrence of respiratory adverse effects correlates with obesity, and is not currently taken into account. Variations in the volume of distribution, elimination half-life and oral clearance of morphine, as well as recent advances in the respective roles of drug-metabolizing enzymes, catechol-O-methyltransferase and the mu opioid receptor in morphine pharmacokinetics and pharmacodynamics, may contribute to differences between obese and non-obese patients. In addition, drug-drug interactions may alter the disposition of morphine and its glucuronide metabolites, which may either increase the risk of adverse effects or reduce drug efficacy.

We report the first case of granulomatous mastitis due to Corynebacterium kroppenstedtii linked to strongly impaired neutrophil responses to Nod2 agonist and a single nucleotide polymorphism within the NOD2 gene (SNP13 [Leu1007fsinsC]) in a heterozygous state. These findings provided the first demonstration of impaired Nod2 function associated with corynebacterial infection.

Drug-drug interactions (DDIs) contribute significantly to the incidence of adverse drug reactions. Important advances in the knowledge of human drug-metabolizing enzymes have fueled the integration of in vitro drug metabolism and clinical DDIs studies for use in drug development programs and in the clinical setting. The activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein are critical determinant of drug clearance, interindividual variability in drug disposition and clinical efficacy, and appears to be involved in the mechanism of numerous clinically relevant DDIs. Cell-based in vitro models are being increasingly applied in elucidating the pharmacokinetic profile of drug candidates during the preclinical steps of drug development. Human liver, intestinal samples and recombinant human CYP3A4 are now readily available as in vitro screening tools to predict the potential for in vivo DDIs. Although it is easy to determine in vitro metabolic DDIs, the interpretation and extrapolation of in vitro interaction data to in vivo situations requires a good understanding of pharmacokinetic principles. Clinicians and pharmacokineticists should recognize that in vitro models may not be clinically relevant in all situations. In the current article, research will be presented on drug metabolism and DDIs along with examples illustrating the utility of specific in vitro or in vivo approaches. In addition, the impact and clinical relevance of complexities such as dosing-route dependent effects, multi-site kinetics of drug-metabolizing enzymes and non-CYP determinants of metabolic clearance will be addressed.

Resume Objectifs Les inhibiteurs de la pompe a protons (IPP) sont la 3e classe de medicaments la plus couteuse pour l’assurance-maladie (plus d’un milliard d’euros soit 5,7 % des depenses pharmaceutiques de ville, dont 50 % dans le reflux gastro-œsophagien [RGO]). Methodes L’observatoire Thales (1 200 medecins generalistes [MG] informatises en reseau, representatifs pour l’âge, le sexe, la distribution geographique) a recueilli les donnees de consultation des patients de 20 ans et plus, ayant consulte au moins une fois en 2005 pour RGO symptomatique sans signe de gravite. Resultats En 2005, 122 571 patients (âge moyen : 56 ans, 45 % d’hommes [sexe ratio 0,8], 2,6 consultations annuelles en moyenne pour le RGO) satisfaisaient les criteres de selection (effectif extrapole a la France entiere de 5,7 millions de personnes soit 13 % de la population adulte ayant consulte un MG dans l’annee). Les IPP etaient prescrits en premiere ligne de traitement du RGO dans 84 % des consultations. L’omeprazole, princeps ou generique, etait majoritairement prescrit (79 %) a dose pleine (20 mg), alors que les autres molecules (lansoprazole, pantoprazole, rabeprazole et esomeprazole) l’etaient a demi-dose (64 %). Les couts extrapoles annuels des IPP rembourses dans cette indication etaient de 465 millions d’euros (M€) avec un taux de remboursement de 73 %. L’omeprazole princeps representait 11 % du cout total rembourse. Un remplacement complet de l’omeprazole princeps par son generique permettrait une economie de 18,35 M€ (−4,3 % des depenses remboursees). Le changement pour d’autres IPP a demi-dose aurait permis une economie supplementaire de 2,6 (avec le lasoprazole) a 13,2 M€ (avec le pantoprazole). Conclusion Une economie substantielle sur les depenses pharmaceutiques remboursees dans le RGO non complique pourrait etre realisee par des changements respectant les recommandations de pratique clinique.

Aim: Methadone maintenance treatment is characterized by large interindividual dose variability. The aim of this study was to evaluate whether DNA methylations are associated with daily dose of methadone. Materials & methods: Subjects stabilized at high (n = 12) or low (n = 12) methadone doses were selected from two independent cohorts (French and Swiss). DNA methylation patterns were analyzed using HumanMethylation450 BeadChips. Results: In total, 584 differentially methylated sites were identified in the French cohort corresponding to 352 genes. Of these, 26 were replicated in the Swiss cohort. The methylation status of 13 genes varied similarly in both cohorts and calcium signaling pathway was significantly enriched. Conclusion: Our results indicate that differentially methylated sites are associated with methadone daily dose and give insights into the molecular pathways underlying this interindividual dose variability.

The objective of our work was to study the association between the jejunal expression levels of P-gp, MRP2, MRP3, UGT2B7, CYP3A4, the ABCB1 c.3435CT polymorphism, and several obesity-associated biomarkers, as well as oral morphine and glucuronides pharmacokinetics in a population of morbidly obese subjects. The pharmacokinetics of oral morphine (30 mg) and its glucuronides was performed in obese patients candidate to bariatric surgery. A fragment of jejunal mucosa was preserved during surgery. Subjects were genotyped for the ABCB1 single nucleotide polymorphism (SNP) c.3435CT. The subjects were 6 males and 23 females, with a mean body mass index of 44.8 (35.4-61.9) kg/m(2). The metabolic ratios AUC0-inf M3G/morphine and AUC0-inf M6G/morphine were highly correlated (rs = 0.8, p0.0001) and were 73.2 ± 24.6 (34.7-137.7) and 10.9 ± 4.1 (3.8-20.6). The pharmacokinetic parameters of morphine and its glucuronides were not associated with the jejunal contents of P-gp, CYP3A4, MRP2, and MRP3. The jejunal content of UGT2B7 was positively associated with morphine AUC0-inf (rs = 0.4, p = 0.03). Adiponectin was inversely correlated with morphine Cmax (rs = -0.44, p = 0.03). None of the factors studied was associated with morphine metabolic ratios. The interindividual variability in the jejunal content of drug transporters and metabolizing enzymes, the ABCB1 gene polymorphism, and the low-grade inflammation did not explain the variability in morphine and glucuronide exposure. High morphine metabolic ratio argued for an increased morphine glucuronidation in morbidly obese patients.

To evaluate the ability of two graphologists and two practising internists not trained in graphology to differentiate letters written by subjects who have attempted to commit suicide by self-poisoning and healthy volunteers, we performed a maximal blind controlled study vs. healthy volunteers. Forty fully recovered patients who had attempted to commit suicide and 40 healthy volunteers wrote and signed a short letter or story not related to the parasuicide or their mental health status. The evaluators classified the 80 letters as 'suicide' or 'no suicide' in an intention-to-treat analysis. Letters expressing sadness were subsequently excluded for a per-protocol analysis. Correct diagnosis of suicide and of healthy controls was made in, respectively, 32 of 40 and 33 of 40 letters by the graphologists and in 27 of 40 and 34 of 40 letters by the internists. After the exclusion of 12 letters expressing sadness, the sensitivity, specificity, positive predictive value and negative predictive value were, respectively, 73, 88, 81 and 82% for the graphologists and 53, 89, 80 and 71% for the internists. Both classified the letters with significantly more effectiveness than chance (p < 0.001) with no statistically significant difference between the two groups of evaluators. We concluded that graphological analysis is able to differentiate letters written by patients who attempt suicide from those written by healthy controls. This technique shows an acceptable degree of accuracy and could therefore become an additional discharge or decision-making tool in Psychiatry or Internal Medicine.

Xerostomia is a subjective sensation of mouth dryness that may frequently occur in older patients.To compare the clinical efficacy and acceptability of a new oxygenated glycerol triester (OGT) oral spray taken five times daily with that of a commercially available saliva substitute Saliveze in the treatment of xerostomia.Forty-one institutionalised patients (28 women, 13 men; mean age 84 +/- 7 years) were randomly assigned to receive either OGT or Saliveze in a 2-week, randomised, parallel-group study. Clinical assessment of xerostomia included evaluation of mouth dryness using a self-rated, 10cm long visual analogue scale (VAS), objective assessment of oral tissue condition using a four-point ordinal scale and subjective assessment of symptoms of xerostomia using dichotomous responses to a questionnaire. The primary endpoint was the day (D) 14 patient-based mouth dryness score measured on a self-rated VAS.At D14, OGT resulted in significantly greater efficacy with respect to mouth dryness (mean between-treatment difference 2.1 +/- 0.1, 95% CI 1.9, 2.3; p = 0.001), swallowing difficulty (1.8 +/- 0.3, 95% CI 1.5, 2.1; p = 0.001), speech difficulty (1.1 +/- 0.2, 95% CI 1.0, 2.4; p = 0.04) and overall sensation of symptom relief (2.7 +/- 1.2, 95% CI 1.9, 3.8; p = 0.001). Objective assessment of oral tissues also showed significantly better improvement with OGT spray with respect to dryness (p = 0.01), stickiness (p = 0.005) and dullness (p = 0.001) of oral mucosa; severity of mucositis (p = 0.01); and thickening of the tongue (p = 0.03). A significant difference in taste acceptability was also noted in favour of OGT (1.4 +/- 0.6, 95% CI 1.2, 1.9; p = 0.04).OGT lubricant oral spray was superior to Saliveze in improving xerostomia and oral tissue condition in older institutionalised patients.