Obesity related to metabolic syndrome: comparison of obesity indicators in an older french population.

OBJECTIVES: Metabolic syndrome (MS) represents a cluster of metabolic abnormalities. Insulin resistance is a major component of the syndrome. We analyze in this study the relationship between body fat composition and MS in comparison to usual obesity indicators in an older adult population. DESIGN: The PROgnostic indicator OF cardiovascular and cerebrovascular events (PROOF) study is a prospective longitudinal community cohort study among the inhabitants of Saint-Etienne, France. METHODS: The study is a cohort study of 1011 subjects, mean age 65.6 ± 0.8 years old at inclusion, recruited from the electoral list of the town in 2000. Among them, 806 subjects realized a Dual-energy X-ray absorptiometry (DXA) used to evaluate body fat and lean mass repartition. We evaluate biological metabolic parameters according to usual techniques. The indices of obesity were calculated according to standard formula. MS presence and its components were simultaneously evaluated. RESULTS: All obesity parameters were significantly higher (p < 0.0001) in subjects suffering metabolic syndrome as compared to those without. Body fat index (BFI) presented a stronger correlation to total fat mass, trunk fat mass and body adiposity index (BAI). The correlations between body indices and metabolic components showed that body mass index (BMI) and waist circumference were more strongly associated with BFI as compared to BAI and total fat mass. According to logistic regression analysis, only the waist-hip ratio (WHR) demonstrated a significant association with MS severity (p < 0.0001). CONCLUSIONS: Among the obesity indices, BFI and BAI represented the best indicators to characterize global obesity while WHR only is highly predictive of metabolic syndrome presence and severity. The BAI indicator is an alternative for measuring obesity. Comparison of long-term impact of such markers on cardiovascular morbidity and mortality is now questioned.

A specific technique of immunolabelling of urinary small extracellular vesicle biomarkers for the diagnostic of renal cancer.

Small extracellular vesicles (EVs) are characterized by the membrane expression of CD63, CD81 and CD9 tetraspanins. Their size is inferior to 200 nm. They share the same characteristics as the native cells and are found in human fluids. Specific membrane protein biomarkers expressed on small EV are useful for the diagnosis of tumoural pathologies. Clear cell renal cell carcinoma (CCRCC) is diagnosed by imaging examinations and/or tissue biopsy. Carbonic anhydrase IX (CAIX) is a powerful biomarker of CCRCC. The detection of CAIX on small EV from the urine of patients could constitute a liquid biopsy for CCRCC. We have set up a specific protocol for the preparation, the immunostaining characterization and the transmission electron microscopy observation of small EVs isolated from the urine of CCRCC patients. The background labelling was significantly reduced. We successfully detected biomarkers on urinary small EVs from CCRCC patients. This technique could be extended with antibodies directed against other EV biomarkers for the detection and the monitoring of cancer diseases.

The Acti-Pair program helps men with prostate cancer increase physical activity with peer support: a mixed method pilot study.

Background: Although the health benefits of physical activity (PA) are recognized, prostate cancer patients do not follow PA recommendations. Barriers to PA, whether physical, environmental or organizational, are known. Furthermore, even when these barriers are overcome, this achievement is not systematically accompanied by lifestyle change. Many strategies have shown to be effective in increasing patient adherence to PA. This study aims to assess the feasibility and the viability of the Acti-Pair program which combines three strategies: peer support, a personalized and realistic PA project, and support from health and adapted physical activity professionals in a local context. Methods and analysis: We conducted a pilot study utilizing a mixed qualitative and quantitative methodology, employing feasibility and viability assessments. Quantitative assessments included recruitment, retention adherence rates, process and potential effectiveness (PA and motivation) indicators; while qualitative methods were used to evaluate the program's practicality, suitability and usefulness. Indicators of potential effectiveness were assessed before and after the intervention using a Wilcoxon test for matched data. Qualitative data were collected through semistructured interviews conducted by two researchers with various program stakeholders. The study lasted for 3 years. Results: Twenty-four patients were recruited over a 25-month period. Forty-two percent of patients completed the program 3 months after the beginning. We recruited 14 peers and trained nine peers over a 10-month period. The program was coordinated extensively by adapted PA professionals, while health professionals were involved in recruiting patients and peers. Self-reporting of moderate to vigorous PA was increased after the Acti-Pair program initiation [42.86 (30.76) at baseline to 53.29 (50.73)]. Intrinsic motivation significantly increased after participation in the Acti-Pair program [1.76 (1.32) before the intervention vs. 2.91 (1.13) after the intervention]. The key player to support the Acti-Pair program in the field has been the PA support system. The main challenge has been the difficulty of health professionals in promoting PA. Discussion: This pilot study has shown that the Acti-Pair program is feasible and viable. It will allow us to extend the peer support intervention to other contexts and assess the effectiveness of this intervention and its generalization.

Management of Long COVID-The CoviMouv' Pilot Study: Importance of Adapted Physical Activity for Prolonged Symptoms Following SARS-CoV2 Infection.

Context: After a COVID-19 infection, some patients have persistent symptoms, the most common is fatigue. To prevent it from becoming chronic (post-COVID-19 syndrome), early management before 3 months could be useful. Exercise and education are recommended. Objective: To assess fatigue in patients with prolonged symptoms after COVID-19 infection and who received a mixed program of remote adapted physical activity and therapeutic education. The secondary objective was to evaluate the efficacy and safety of this training method thanks to aerobic and anaerobic parameters. Methods: "CoviMouv': From Coaching in Visual to Mouv in real" is a nonrandomized controlled pilot study. Patients in telerehabilitation followed 12 remote exercise sessions and 3 therapeutic education workshops. Patients on traditional rehabilitation followed their program with a community-based physiotherapist. Results: Fatigue was reduced after the one-month intervention in both groups (p = 0.010). The majority of aerobic parameters were significantly improved, e.g., maximal oxygen uptake (p = 0.005), walking distance (p = 0.019) or hyperventilation values (p = 0.035). The anaerobic parameter was not improved (p = 0.400). No adverse event was declared. Discussion: Telerehabilitation is a good alternative when a face-to-face program is not possible. This care at an early stage of the disease could help prevent the chronicity of post-COVID-19 symptoms and the installation of vicious circles of physical deconditioning. A larger study would be necessary.

Resistance Training of Inspiratory Muscles After Coronary Artery Disease May Improve Obstructive Sleep Apnea in Outpatient Cardiac Rehabilitation: RICAOS Study.

Background: Obstructive sleep apnea (OSA) affects 5% of the adult population and its prevalence is up to 13 times higher in coronary artery disease (CAD) patients. However, OSA in this population is less symptomatic, leading to lower adherence to positive airway pressure (CPAP). While oropharyngeal exercise showed a significant decrease in apnea-hypopnea index (AHI) in patients with moderate OSA, there have been no studies testing the impact of specific inspiratory muscle training (IMT) for these patients. The aim of our study was to assess the effectiveness of IMT on AHI reduction in CAD patients with moderate OSA. Methods: We included patients with CAD involved in a cardiac rehabilitation program and presenting an AHI between 15 and 30. Patients were randomized in a 1:1 allocation to a control group (CTL - classic training) or an IMT group (classic training + IMT). IMT consisted in 60 deep inspirations a day, 6 days a week, into a resistive load device set at 70% of the maximum inspiratory pressure (MIP). After 6 weeks, we compared AHI, neck circumference, Epworth Sleepiness Scale, Pittsburgh Sleep Quality index, and quality of life with the 12-item Short Form Survey before and after rehabilitation. Results: We studied 45 patient (60 ± 9 y, BMI = 27 ± 6 kg.m-2). The IMT group (n = 22) significantly improved MIP ( p < 0.05) and had a significant decrease in AHI by 25% (-6.5 ± 9.5, p = 0.02). In the CTL group (n = 23), AHI decreased only by 3.5% (-0.7 ± 13.1; p = 0.29). Between groups, we found a significant improvement in MIP ( p = 0.003) and neck circumference ( p = 0.01) in favor of the IMT group. However, we did not find any significant improvement of AHI in the IMT group compared to CTL ( p = 0.09). Conclusion: A specific IMT during cardiac rehabilitation contributes to reduce significantly AHI in CAD patients with moderate OSA. Magnitude of the decrease in OSA severity could be enhanced according to implementation of specific IMT in this population.

Platelet transmission electron microscopy for the assessment of poor biological response to antiplatelet agent: pilot descriptive and prospective study - ELECTROSTROKE.

INTRODUCTION: Ischaemic stroke is the leading cause of adult disability. Thus, a strategy based on an efficient antiplatelet therapy has been developed. The monitoring of antiplatelet therapy is now limited to high risk and poor prognosis patients. Indeed, the biological monitoring of the antiplatelet therapy with available platelet function assays do not provide a global integrative approach. Platelet transmission electron microscopy, recently validated for assessing distinct ultrastructural abnormalities is a reliable morphological platelet structural analysis tool which could be used to collect all the ultrastructural platelet characteristics and assess the degree of activation of platelets. METHODS AND ANALYSIS: Our pilot prospective and descriptive study will include 50 consecutive patients hospitalized for an ischaemic stroke. We expect to identify ultrastructural characteristics that will be correlated with the degree of platelet activation to guide clinicians in decision making regarding the antiplatelet therapy strategy. ETHICS AND DISSEMINATION: The French Ethics Committee (comité de protection des personnes d'Ile-de-France VII) approved the information notice that will be given to participants and the protocol of this trial (protocol No 21-031).The results of the trial will be disseminated through scientific publications. TRIAL REGISTRATION NUMBER: NCT05004233.

Long-Term Clinical and Psychiatric Complications of Young Adults Cured of a Pediatric Bone Tumor Diagnosed Between 1987 and 1999 in Rhône: Alpes Region (France).

Purpose: The 5-year survival for children diagnosed with cancer is ∼85%. The constant increase in survival curves is evidence of therapeutic optimization. Clinical and psychological complications are rarely analyzed simultaneously in the literature for pediatric malignant bone tumors. We aimed to describe different clinical and psychiatric sequelae and to evaluate the quality of life (QoL) of adults followed for a pediatric bone tumor. Methods: The Association of the Childhood Cancer Registry in Rhône-Alpes Region has coordinated two long-term follow-up studies designed to evaluate complications of childhood cancer. Only bone tumors are analyzed. Patients were given a self-questionnaire, followed by a clinical consultation then a psychological interview. Results: Twenty-five patients were studied. The mean age at diagnosis was 11.3 years. The median follow-up time was 20.7 years. Of the patients, 66.7% had at least one psychiatric disorder versus 31.9% in the general population (p = 0.0006). Comparing with the general population, 47.6% have at least one mood disorder (p < 0.001), 52.4% have at least one anxiety disorder (p = 0.0035), and 28.6% have an addiction (p < 0.0001). The mean number of clinical sequelae per patient was 3.12. Ninety-six percent of the patients studied had at least one clinical sequela. The overall QoL score was 59.7 with a physical score of 60.5 and a mental score of 52.9. All domains considered were lower for these patients. Conclusion: It is essential to offer psychological support from the time of diagnosis to limit the risk of developing an addiction. Clinical Trial numbers: NCT01531478 and NCT02675166.

Prevention of Atrial Fibrillation After Atrial Flutter Ablation With Ramipril (from the PREFACE Study).

The clinical efficacy of the inhibitors of the renin-angiotensin-aldosterone system (RAAS) as an upstream therapy for atrial fibrillation (AF) prevention is controversial. No study has itemized so far the role of RAAS inhibitors in AF prevention after atrial flutter (AFL) ablation. This trial aims to investigate the effect of ramipril compared with placebo on AF occurrence in patients hospitalized for AFL ablation without structural heart disease. The Prevention of Atrial Fibrillation by Inhibition Conversion Enzyme (ICE) After Radiofrequency Ablation of Atrial Flutter (PREFACE) trial was a prospective, multicenter, randomized, double-blind, double-dummy trial depicting the AF occurrence during a 12-month follow-up as the primary end point. A total of 198 patients hospitalized for AFL ablation were enrolled in the trial and randomized to placebo or ramipril 5 mg/day. Patients were followed up during 1 year after AFL ablation using 1-week Holter electrocardiogram at 3, 6, 9, and 12 months. The intention-to-treat population encompassed 97 patients in the ramipril group and 101 patients in the placebo group. The primary end point, such as AF occurrence during the 1-year follow-up, was not different between the 2 groups (p = 0.96). Secondary end points, including the occurrence of supraventricular arrhythmia (p = 0.50), heart failure, stroke, and death, were not different between the 2 groups. Safety outcome parameters, including serious adverse events leading to treatment disruption (p = 0.10), hypotension, impairment of renal function, and elevated serum potassium level, also were not different between the 2 groups. In conclusion, RAAS inhibition using ramipril does not reduce AF occurrence in patients facing AFL ablation during the 1-year follow-up.

Insulin Resistance and Type 2 Diabetes in Asymptomatic Obstructive Sleep Apnea: Results of the PROOF Cohort Study After 7 Years of Follow-Up.

The aim of the study was to assess potential associations between obstructive sleep apnea (OSA) and the occurrence of diabetes mellitus and insulin resistance in the elderly. Nondiabetic volunteers (n = 549) with undiagnosed or untreated asymptomatic OSA (66.2+/-1 years at the inclusion) were evaluated as an ancillary study of the PROOF cohort study (n = 1,011). After 7 years follow-up, 494 subjects underwent assessment of fasting insulin and glucose levels. OSA was defined by an apnea-hypopnea index (AHI) of ≥15/h using polygraphy. Diabetes mellitus was defined by a fasting glucose ≥ 1.26 g/L and/or when requiring pharmacological treatment, while insulin resistance corresponded to HOMA-IR ≥ 2. Asymptomatic OSA subjects (men or women) did not display increased risk of incident diabetes (2.8 vs. 3.9%, p = 0.51). However, there was a greater frequency of insulin resistance in subjects with severe OSA (AHI > 30) [OR 2.21; 95% CI (1.22-4.02); p = 0.009]. Furthermore, multiple logistic regression showed that triglycerides levels [OR 1.61; 95% CI (1.10-2.36); p = 0.01] and fasting glycaemia [OR 4.69; 95% CI (1.12-192.78); p = 0.04], but not AHI or oxyhemoglobin desaturation index were independently associated with higher rate of insulin resistance. The deleterious metabolic effect of asymptomatic OSA in the population may be indirectly mediated via perturbations in lipids, and is particularly likely to become manifest in severe apneic subjects with higher glycemic levels.

Presence of Urinary Exosomes for Liquid Biopsy of Clear Cell Renal Cell Carcinoma: Protocol for a Pilot Feasibility Study.

BACKGROUND: Approximately 70%-80% of kidney cancers are clear cell renal cell carcinomas (CCRCCs). Patient management is based on imaging (abdominal ultrasound and computerized tomography), surgical excision of the tumor, and pathological analysis. A tissue biopsy is therefore necessary to confirm the diagnosis and avoid unnecessary nephrectomy. For metastatic cancers, a tissue biopsy is essential for establishing the targeted therapy. This biopsy of tumor material is invasive and painful. Other techniques such as liquid biopsy would help reduce the need for tissue biopsy. The development of a simple biological test for diagnosis is essential. CA9 is a powerful marker for the diagnosis of CCRCC. Exosomes have become a major source of liquid biopsy because they carry tumor proteins, RNA, and lipids. Urine is the most convenient biological liquid for exosome sampling. OBJECTIVE: The aim of this study (PEP-C study) is mainly to determine whether it is possible to detect urinary exosomal CA9 for the molecular diagnosis of CCRCC. METHODS: This study will include 60 patients with CCRCC and 40 noncancer patients. Exosomes will be isolated from urine samples and exosomal CA9 will be detected by transmission electron microscopy, flow cytometry, and reverse transcription-quantitative polymerase chain reaction. RESULTS: This study is currently underway with funding support from the CHU Saint-Etienne of France. CONCLUSIONS: We expect to demonstrate that urinary tumor exosomes could be a novel liquid biopsy to diagnose CCRCC and to guide clinicians in treatment decision-making. TRIAL REGISTRATION: ClinicalTrials.gov NCT04053855; https://clinicaltrials.gov/ct2/show/NCT04053855. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/24423.

Personalized Massive Open Online Course for Childhood Cancer Survivors: Behind the Scenes.

BACKGROUND: Today, in France, it is estimated that 1 in 850 people aged between 20 and 45 years has been treated for childhood cancer, which equals 40,000 to 50,000 people. As late effects of the cancer and its treatment affect a large number of childhood cancer survivors (CCS) and only 30% of them benefit from an efficient long-term follow-up care for prevention, early detection, and treatment of late effects, health education of CCS represents a challenge of public health. OBJECTIVES: Massive open online courses (MOOCs) are a recent innovative addition to the online learning landscape. This entertaining and practical tool could easily allow a deployment at a national level and make reliable information available for all the CCS in the country, wherever they live. METHODS: The MOOC team brings together a large range of specialists involved in the long-term follow-up care, but also associations of CCS, video producers, a communication consultant, a pedagogical designer, a cartoonist and a musician. We have designed three modules addressing transversal issues (lifestyle, importance of psychological support, risks of fertility problems) and eight modules covering organ-specific problems. Detailed data on childhood cancer treatments received were used to allocate the specific modules to each participant. RESULTS: This paper presents the design of the MOOC entitled "Childhood Cancer, Living Well, After," and how its feasibility and its impact on CCS knowledge will be measured. The MOOC about long-term follow-up after childhood cancer, divided into 11 modules, involved 130 participants in its process, and resulted in a 170-minute film. The feasibility study included 98 CCS (31 males vs. 67 females; p < 0.0001). CONCLUSION: Such personalized, free, and online courses with an online forum and a possible psychologist consultation based on unique characteristics and needs of each survivor population could improve adherence to long-term follow-up without alarming them unnecessarily.

PHILEOS (haemoPHILia and ostEoporOSis) Study: protocol of a multicentre prospective case-control study.

INTRODUCTION: Two meta-analyses showed lower bone mineral density (BMD) in patients with haemophilia (haemophilia type and severity were often not specified) compared with healthy controls. This finding could be related to reduced mobility and sedentary lifestyle, and/or hepatitis C or HIV infection. The aim of this study is to determine osteoporosis prevalence in patients with haemophilia classified in function of the disease type (A or B) and severity, and to evaluate the potential role of regular prophylactic factor replacement (early vs delayed initiation) in preserving or restoring BMD. METHODS AND ANALYSIS: The haemoPHILia and ostEoporOSis Study is a prospective, controlled, multicentre study that will include patients in France (13 haemophilia treatment centres), Belgium (1 centre) and Romania (1 centre). In total, 240 patients with haemophilia and 240 matched healthy controls will be recruited (1:1). The primary objective is to determine osteoporosis prevalence in patients with severe haemophilia A and B (HA and HB) without prophylaxis, compared with healthy controls. Secondary outcomes include: prevalence of osteoporosis and osteopenia in patients with mild, moderate and severe HA or HB with prophylaxis (grouped in function of their age at prophylaxis initiation), compared with healthy subjects; BMD in patients with HA and HB of comparable severity; correlation between BMD and basal factor VIII/IX levels and thrombin potential; and quantification of plasmatic markers of bone remodelling (formation and resorption) in patients with haemophilia. ETHICS AND DISSEMINATION: The protocol was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2019-A03358-49). The results of this study will be actively disseminated through scientific publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04384341.

Monitoring of biological response to clopidogrel after treatment for non-cardioembolic ischemic stroke or transient ischemic attack.

BACKGROUND AND PURPOSE: Biological response to clopidogrel prescribed after a non-cardioembolic ischemic stroke or transient ischemic attack (TIA) has been little studied. The aim of our study (AAPIX) was to assess this response and investigate the agreement between different biological assays in revealing poor responders. METHODS: Patients hospitalized following a non-cardioembolic ischemic stroke or transient ischemic attack (TIA) and prescribed clopidogrel were consecutively included from September 2013 to November 2015 in the Stroke Center of Saint-Etienne Hospital. Blood was drawn after 5 to 8 days of standard-dose clopidogrel. Light transmission aggregometry (LTA) and flow cytometric assays, using vasodilator-stimulated phosphoprotein [VASP] and CD62P, were accomplished for all patients. Transmission electron microscopy (TEM) was performed for a poor clopidogrel-responder and for a patient with discordant platelet assay results (platelet reactivity index (PRI) >50% and maximum platelet aggregation <70%), after activation with adenosine diphosphate (ADP) 10 µM. RESULTS: 72 patients were included. According to LTA, VASP assay and CD62P test results, 65%, 71% and 0% of patients, respectively, had a low response to clopidogrel, indicating poor agreement between these assays. Images of ADP-activated platelet samples from a patient manifesting a low response to clopidogrel and from a patient with discordant platelet assay results showed an ultrastructural pattern typical of activation and a state of slight activation, respectively. CONCLUSIONS: Platelet function results obtained using different assays for patients having experienced a non-cardioembolic ischemic stroke or TIA were discordant. Transmission electron microscopy could be useful in certain clinical contexts when platelet function assay results disagree.

Dysautonomia in Childhood Cancer Survivors: A Widely Underestimated Risk.

PURPOSE: Survival rate of childhood cancers is now reaching 80% overall. However, early or late complications related to surgery, chemotherapy, and radiotherapy remain at a high rate and greatly increase the risk of late mortality. The objective of this study is to assess the autonomic nervous system (ANS) activity, measured through heart rate variability indices in childhood cancer survivors compared with healthy controls. METHODS: This prospective study included 51 long-term childhood cancer survivors diagnosed before 15 years of age between 1987 and 1992 and controlled for age and sex with healthy volunteers. RESULTS: We observed a significant increase in spontaneous heart rate (beats per minute) (67 ± 10 vs. 60 ± 10, p = 0.001), and all the studied parameters showed a significantly altered ANS activity in cases compared with healthy controls. In both groups, the main cofactors of dysautonomia (tobacco, drugs, cannabis, estro-progestative pills, alcohol, limited physical activity) were analyzed without any significant difference. The effect of cancer treatments received was not analyzed due to the small number of participants. CONCLUSION: The results showed a significant ANS dysfunction in childhood cancer survivors compared with healthy controls and suggested the value of autonomic screening to underscore and possibly quantify the effect of the cancer treatments in a larger cohort. This evaluation could lead to the recommendation to increase physical activity, the most efficient way known to improve ANS activity, as already shown in other pathologies (breast cancer).

Role of platelet α2-adrenoreceptor in biological low response to Clopidogrel for patients with non cardioembolic ischemic stroke or transient ischemic attack.

BACKGROUND AND PURPOSE: Low biological response to Clopidogrel prescribed after non cardioembolic ischemic stroke or transient ischemic attack (TIA) is a major clinical problem and could explain the recurrence of vascular events. Platelet α2-adrenoreceptors are involved in the high residual platelet reactivity in stable coronary artery disease patients on dual antiplatelet therapy. In the present study we investigated the impact of platelet α2-adrenoreceptors on ADP-induced platelet aggregation and on ADP-induced platelet membrane CD62P (P-selectin) expression, a marker of platelet activation on blood samples from patients hospitalized at the acute phase of a non cardioembolic ischemic stroke or TIA. METHODS: 72 consecutive patients were prospectively recruited over the course of two years in a monocentric study. Patients received a daily 75 mg-dose of Clopidogrel. ADP-induced platelet aggregation was measured alone, with low dose epinephrine or with atipamezole, a selective α blocker of α2-adrenoreceptors, by Light Transmittance Aggregometry (LTA). Platelet membrane expression of P-selectin was measured by flow cytometry with either ADP alone or combined with epinephrine. RESULTS: Epinephrine at low dose stimulated ADP-induced platelet membrane expression of CD62P whereas Atipamezole significantly inhibited 10 µM ADP-induced platelet aggregation. CONCLUSIONS: Our study showed the role of platelet α2-adrenoreceptors in biological low response to Clopidogrel for patients hospitalized for a non-cardioembolic ischemic stroke or TIA. Atipamezole could improve the status of biological response to Clopidogrel.

Leukoaraiosis and ambulatory blood pressure load in a healthy elderly cohort study: the PROOF study.

BACKGROUND: Old age and hypertension are consistently reported to be the main risk factors of leukoaraiosis. The association between white matter lesions (WMLs) and other cardiovascular risk factors (CVRF) remains controversial. We evaluated the association between CVRF and WMLs in a cohort study and determined the blood pressure variables that could predict WML severity. METHODS: 830 subjects (65+/-1 years of age, 60% women) from the PROOF study, with a reliable ABPM and brain MRI, were included. The exclusion criteria included prior myocardial infarction, stroke, heart failure, atrial fibrillation, type 1 diabetes mellitus, and pacing. White matter changes on MRI were defined as hyperintensities >5mm on FLAIR images. We used the total degree of WML (range: 0-30) by adding the region-specific scores of both hemispheres. RESULTS: Linear regression analyses demonstrated a significant relationship between total leukoaraiosis score and 24h systolic blood pressure (SBP), 24h diastolic BP, daytime SBP and DBP and nighttime SBP. No significant relationship was found between leukoaraiosis score and clinical SBP, clinical DBP, or nocturnal DIP. There was also no significant relationship between leukoaraiosis and other recognized cardiovascular risk factors. Based on a ROC curve analysis, we identified the optimal threshold separating high-risk WML patients for a mean 24h SBP above 123 mmHg (p<0.05). CONCLUSIONS: Even moderate increases in 24h SBP promote arteriolar fragility of the cerebral white matter in a population aged 65. The prognostic implications of such abnormalities in asymptomatic and moderate cardiovascular risk populations remain to be evaluated.

Relation of central fat mass to obstructive sleep apnea in the elderly.

STUDY OBJECTIVES: Obesity is a recognized risk factor for obstructive sleep apnea syndrome (OSAS). We evaluated whether total trunk and central fat mass (CFM) is associated with OSAS in elderly subjects. DESIGN: Cross-sectional. SETTING: Body composition assessment by dual-energy X-ray absorbsiometry (DEXA). PARTICIPANTS: 749 volunteers aged 67.2 ± 0.8 years (59.4% women). INTERVENTION: All participants underwent evaluation of their body composition by DEXA in parallel with clinical and polygraphic assessments. The presence of OSAS was defined by an apnea plus hypopnea index (AHI) ≥ 15. MEASUREMENTS AND RESULTS: A total of 44.8% of the population had an AHI < 15, and 55.2% presented OSAS. OSAS subjects were more frequently overweight and had a higher total trunk fat mass and central fat mass (CFM). Correlation analyses revealed that body mass index (r = 0.27, P < 0.001), neck circumference (r = 0.35, P < 0.001), and CFM (r = 0.23, P < 0.001) were significantly related to AHI. Logistic regression analysis indicated that in mild OSAS cases (> 15AHI < 30), BMI (OR: 1.10; 95% CI: 1.03-1.18; P = 0.008), and male gender (OR: 1.49; 95% CI: 1.05-2.12, P = 0.03) were key factors explaining an AHI between 15 and 30. In severe cases (AHI > 30), male gender (OR: 3.65; 95% CI: 2.40-5.55; P < 0.001) and CFM (OR: 1.10; 95% CI: 1.03-1.19; P = 0.009) were significant independent predictors of OSAS. CLINICAL TRIAL REGISTRATION: NCT 00759304 and NCT 00766584. CONCLUSIONS: Although central fat mass plays a role in the occurrence of severe OSAS in men older than 65 years of age, its low discriminative sensitivity in mild OSAS cases does not warrant systematic use of DEXA for the diagnosis of OSAS.

Investigation of drug-drug interactions between clopidogrel and fluoxetine.

Drug-drug interactions may contribute to the variability of the response of clopidogrel. Several hypotheses have been proposed concerning the potential modification of clopidogrel pharmacokinetics and pharmacodynamics by fluoxetine. This open-label crossover study assessed the effect of fluoxetine on the pharmacological activity of clopidogrel in healthy volunteers. Eight healthy male volunteers received a single 600-mg loading dose of clopidogrel followed by 20 mg of fluoxetine on 4 days and then 20 mg of fluoxetine plus 600 mg of clopidogrel on the fifth day. Eleven blood samples were withdrawn after clopidogrel administration to determine plasma concentrations of clopidogrel active metabolite (CAM) and platelet function. Platelet aggregation was measured by light transmittance aggregometry (LTA) and platelet reactivity index by flow cytometric vasodilator-stimulated phosphoprotein (VASP) analysis. The areas under the curve and maximum plasma concentrations of CAM were, respectively, 20.6 and 25.3% lower after co-administration of fluoxetine compared with administration of clopidogrel alone. The percentage maximum platelet aggregation values in the presence of 5 µM and 10 µM adenosine diphosphate, measured by LTA, were, respectively, 13.9 and 22.4% lower after fluoxetine co-administration. The platelet reactivity index measured by the flow cytometric VASP method was 36.8% lower when clopidogrel was administered in conjunction with fluoxetine.

A semi-mechanistic absorption model to evaluate drug-drug interaction with dabigatran: application with clarithromycin.

AIM: The aim of this study was to develop a PK/PD model to assess drug-drug interactions between dabigatran and P-gp modulators, using the example of clarithromycin, a strong inhibitor of P-gp. METHODS: Ten healthy male volunteers were randomized to receive in the first treatment period a single 300 mg dose of dabigatran etexilate (DE) and in the second treatment period 500 mg clarithromycin twice daily during 3 days and then 300 mg DE plus 500 mg clarithromycin on the fourth day, or the same treatments in the reverse sequence. Dabigatran plasma concentration and ecarin clotting time (ECT) were measured on 11 blood samples. Models were built using a non-linear mixed effect modelling approach. RESULTS: The best PK model was based on an inverse Gaussian absorption process with two compartments. The relationship between dabigatran concentration and ECT was implemented as a linear function. No continuous covariate was associated with a significant decrease in the objective function. The concomitant administration of clarithromycin induced a significant change only in DE bioavailability, which increased from 6.5% to 10.1% in the presence of clarithromycin. Clarithromycin increased peak concentration and AUC by 60.2% and 49.1% respectively. CONCLUSION: The model proposed effectively describes the complex PK of dabigatran and takes into account drug-drug interactions with P-gp activity modulators, such as clarithromycin.