Jean-Baptiste Beuscart

Dietary CML-enriched protein induces functional arterial aging in a RAGE-dependent manner in mice.

SCOPE Advanced glycation end-products (AGEs) are endogenously produced and are present in food. N(ε)-carboxymethyllysine (CML) is an endothelial activator via the receptor for AGEs (RAGEs) and is a major dietary AGE. This work investigated the effects of a CML-enriched diet and RAGE involvement in aortic aging in mice. METHODS AND RESULTS After 9 months of a control diet or CML-enriched diets (50, 100, or 200 μg(CML)/g of food), endothelium-dependent relaxation, RAGE, vascular cell adhesion molecule-1, and sirtuin-1 expression, pulse wave velocity and elastin disruption were measured in aortas of wild-type or RAGE(-/-) male C57BL/6 mice. Compared to the control diet, endothelium-dependent relaxation was reduced in the wild-type mice fed the CML-enriched diet (200 μg(CML)/g) (66.8 ± 12.26 vs. 94.3 ± 2.6%, p < 0.01). RAGE and vascular cell adhesion molecule-1 (p < 0.05) expression were increased in the aortic wall. RAGE(-/-) mice were protected against CML-enriched diet-induced endothelial dysfunction. Compared to control diet, the CML-enriched diet (200 μg(CML)/g) increased the aortic pulse wave velocity (86.6 ± 41.1 vs. 251.4 ± 41.1 cm/s, p < 0.05) in wild-type animals. Elastin disruption was found to a greater extent in the CML-fed mice (p < 0.05). RAGE(-/-) mice fed the CML-enriched diet were protected from aortic stiffening. CONCLUSION Chronic CML ingestion induced endothelial dysfunction, arterial stiffness and aging in a RAGE-dependent manner.

Potentially inappropriate medications (PIMs) and anticholinergic levels in the elderly: A population based study in a French region

Prescriptions of PIMs and anticholinergic drugs lead to adverse events and hospitalizations in the elderly. The objective of this study was to determine the prevalence of PIMs and prescriptions with a high anticholinergic effect in a French region. All prescriptions dispensed at community pharmacies in patients aged 75 and older between January 1 and March 31, 2012 were extracted from French Health Insurance information System - Nord-Pas-de-Calais Region for patients affiliated to the Social Security. Prescription of PIMs was defined according to the Laroche list. The anticholinergic score for each prescription was calculated using the Anticholinergic Drug Scale (ADS). 65.6% (n=207,979) of people aged over 75 years, living in the Nord-Pas-de-Calais Region were included, of which 4.5% (n=9284) living in nursing homes. Patients received an average of 8.3 drugs over the 3-month study period. In 32.6% (n=67,863) of patients, at least one PMI was prescribed. According to the ADS, 10.0% (n=20,978) of patients in the general population and 24.0% (n=2231) of patients living in nursing homes was exposed to a prescription with a high or very high anticholinergic score (ADS≥3). Hydroxyzine prescribed in 51.4% (n=10,792) of them ranked first among drugs most often reported. In conclusion, PMIs and anticholinergic drugs were commonly prescribed in elderly living in the Nord-Pas-de-Calais Region. Improving the quality of prescriptions in the elderly appears necessary.

A systematic review of the outcomes reported in trials of medication review in older patients: the need for a core outcome set.

Aim Medication review has been advocated as one of the measures to tackle the challenge of polypharmacy in older patients, yet there is no consensus on how best to evaluate its efficacy. This study aimed to assess outcome reporting in trials of medication review in older patients. Methods Randomized controlled trials (RCTs), prospective studies and RCT protocols involving medication review performed in patients aged 65 years or older in any setting of care were identified from: (1) a recent systematic review; (2) RCT registries of ongoing studies; (3) the Cochrane library. The type, definition, and frequency of all outcomes reported were extracted independently by two researchers. Results Forty‐seven RCTs or prospective published studies and 32 RCT protocols were identified. A total of 327 distinct outcomes were identified in the 47 published studies. Only one fifth (21%) of the studies evaluated the impact of medication reviews on adverse events such as drug reactions or drug‐related hospital admissions. Most of the outcomes were related to medication use (n = 114, 35%) and healthcare use (n = 74, 23%). Very few outcomes were patient‐related (n = 24, 7%). A total of 248 distinct outcomes were identified in the 32 RCT protocols. Overall, the number of outcomes and the number and type of health domains covered by the outcomes varied largely. Conclusion Outcome reporting from RCTs concerning medication review in older patients is heterogeneous. This review highlights the need for a standardized core outcome set for medication review in older patients, to improve outcome reporting and evidence synthesis.

Overestimation of the probability of death on peritoneal dialysis by the Kaplan-Meier method: advantages of a competing risks approach

BackgroundIn survival analysis, patients on peritoneal dialysis are confronted with three different outcomes: transfer to hemodialysis, renal transplantation, or death. The Kaplan-Meier method takes into account one event only, so whether it adequately considers these different risks is questionable. The more recent competing risks method has been shown to be more appropriate in analyzing such situations.MethodsWe compared the estimations obtained by the Kaplan-Meier method and the competing risks method (namely the Kalbfleisch and Prentice approach), in 383 consecutive incident peritoneal dialysis patients. By means of simulations, we then compared the Kaplan-Meier estimations obtained in two virtual centers where patients had exactly the same probability of death. The only difference between these two virtual centers was whether renal transplantation was available or not.ResultsAt five years, 107 (27.9%) patients had died, 109 (28.4%) had been transferred to hemodialysis, 91 (23.8%) had been transplanted, and 37 (9.7%) were still alive on peritoneal dialysis; before five years, 39 (10.2%) patients were censored alive on peritoneal dialysis. The five-year probabilities estimated by the Kaplan-Meier and the competing risks methods were respectively: death: 50% versus 30%; transfer to hemodialysis: 59% versus 32%; renal transplantation: 39% versus 26%; event-free survival: 12% versus 12%. The sum of the Kaplan-Meier estimations exceeded 100%, implying that patients could experience more than one event, death and transplantation for example, which is impossible. In the simulations, the probability of death estimated by the Kaplan-Meier method increased as the probability of renal transplantation increased, although the probability of death actually remained constant.ConclusionThe competing risks method appears more appropriate than the Kaplan-Meier method for estimating the probability of events in peritoneal dialysis in the context of univariable survival analysis.

Proposal and evaluation of FASDIM, a Fast And Simple De-Identification Method for unstructured free-text clinical records.

PURPOSE Medical free-text records enable to get rich information about the patients, but often need to be de-identified by removing the Protected Health Information (PHI), each time the identification of the patient is not mandatory. Pattern matching techniques require pre-defined dictionaries, and machine learning techniques require an extensive training set. Methods exist in French, but either bring weak results or are not freely available. The objective is to define and evaluate FASDIM, a Fast And Simple De-Identification Method for French medical free-text records. METHODS FASDIM consists in removing all the words that are not present in the authorized word list, and in removing all the numbers except those that match a list of protection patterns. The corresponding lists are incremented in the course of the iterations of the method. For the evaluation, the workload is estimated in the course of records de-identification. The efficiency of the de-identification is assessed by independent medical experts on 508 discharge letters that are randomly selected and de-identified by FASDIM. Finally, the letters are encoded after and before de-identification according to 3 terminologies (ATC, ICD10, CCAM) and the codes are compared. RESULTS The construction of the list of authorized words is progressive: 12h for the first 7000 letters, 16 additional hours for 20,000 additional letters. The Recall (proportion of removed Protected Health Information, PHI) is 98.1%, the Precision (proportion of PHI within the removed token) is 79.6% and the F-measure (harmonic mean) is 87.9%. In average 30.6 terminology codes are encoded per letter, and 99.02% of those codes are preserved despite the de-identification. CONCLUSION FASDIM gets good results in French and is freely available. It is easy to implement and does not require any predefined dictionary.

Competing-risk analysis of death and dialysis initiation among elderly (≥80 years) newly referred to nephrologists: a French prospective study

BackgroundReasons underlying dialysis decision-making in Octogenarians and Nonagenarians have not been further explored in prospective studies.MethodsThis regional, multicentre, non-interventional and prospective study was aimed to describe characteristics and quality of life (QoL) of elderly (≥80 years of age) with advanced chronic kidney disease (stage 3b-5 CKD) newly referred to nephrologists. Predictive factors of death and dialysis initiation were also assessed using competing-risk analyses.ResultsAll 155 included patients had an estimated glomerular filtration rate (eGFR) below 45 ml/min/1.73 m2. Most patients had a non anaemic haemoglobin level (Hb) with no iron deficiency, and normal calcium and phosphate levels. They were well-fed and had a normal cognitive function and a good QoL. The 3-year probabilities of death and dialysis initiation reached 27% and 11%, respectively. The leading causes of death were cardiovascular (32%), cachexia (18%), cancer (9%), infection (3%), trauma (3%), dementia (3%), and unknown (32%). The reasons for dialysis initiation were based on uncontrolled biological abnormalities, such as hyperkalemia or acidosis (71%), uncontrolled digestive disorders (35%), uncontrolled pulmonary or peripheral oedema (29%), and uncontrolled malnutrition (12%). No patients with acute congestive heart failure or cancer initiated dialysis. Predictors of death found in both multivariate regression models (Cox and Fine & Gray) included acute congestive heart failure, age, any walking impairment and Hb <10 g/dL. Regarding dialysis initiation, eGFR <23 mL/min/1.73 m2 was the only predictor found in the Cox multivariate regression model whereas eGFR <23 mL/min/1.73 m2 and diastolic blood pressure were both independently associated with dialysis initiation in the Fine & Gray analysis. Such findings suggested that death and dialysis were independent events.ConclusionsOctogenarians and Nonagenarians newly referred to nephrologists by general practitioners were highly selected patients, without any symptoms of the common geriatric syndrome. In this population, nephrologists’ dialysis decision was based exclusively on uremic criteria.

Systematic skin examination in an acute geriatric unit: skin cancer prevalence

Ageing is a determining factor in skin cancer, but the incidence and prevalence of skin cancer in elderly patients are not known.

Anti-sRAGE autoimmunity in obesity: Downturn after bariatric surgery is independent of previous diabetic status

AIM Morbid obesity increases the risk of cardiovascular disease (CVD). The receptor for advanced glycation end-products (RAGE) is implicated in proinflammatory processes that underlie CVD. Its soluble form (sRAGE) has been proposed as a vascular biomarker. Recently, anti-sRAGE autoantibodies were described and found to be increased in diseases where RAGE is overexpressed. This study aimed to investigate serum levels of anti-sRAGE autoantibodies in morbidly obese patients. METHODS After exclusion based on specific criteria, 150 subjects (50 normoglycemics, 50 glucose-intolerants and 50 diabetics) were randomly recruited from a cohort of 750 obese patients (ABOS). Serum sRAGE and anti-sRAGE autoantibodies were measured before bariatric surgery. Sixty-nine patients were followed for up to 1year after gastric bypass, and their levels of sRAGE and anti-sRAGE autoantibodies measured. The control group consisted of healthy blood donors. RESULTS Compared with controls, baseline levels of sRAGE and anti-sRAGE autoantibodies were significantly higher in all obese patients independently of glucose regulation (P<0.001). At 1year after gastric bypass, sRAGE and anti-sRAGE were decreased (P<0.001). The decrease in anti-sRAGE autoantibodies was correlated with an increase in high-density lipoprotein (HDL; P=0.02). CONCLUSION Independently of previous diabetic status, morbid obesity increases sRAGE and anti-sRAGE levels. Weight loss after gastric bypass is followed by a decrease in both titres. The decrease in anti-sRAGE correlates with an increase in HDL.

Acrylamide induces accelerated endothelial aging in a human cell model

Acrylamide (AAM) has been recently discovered in food as a Maillard reaction product. AAM and glycidamide (GA), its metabolite, have been described as probably carcinogenic to humans. It is widely established that senescence and carcinogenicity are closely related. In vitro, endothelial aging is characterized by replicative senescence in which primary cells in culture lose their ability to divide. Our objective was to assess the effects of AAM and GA on human endothelial cell senescence. Human umbilical vein endothelial cells (HUVECs) cultured in vitro were used as model. HUVECs were cultured over 3 months with AAM or GA (1, 10 or 100 μM) until growth arrest. To analyze senescence, β-galactosidase activity and telomere length of HUVECs were measured by cytometry and semi-quantitative PCR, respectively. At all tested concentrations, AAM or GA reduced cell population doubling compared to the control condition (p < 0.001). β-galactosidase activity in endothelial cells was increased when exposed to AAM (≥10 μM) or GA (≥1 μM) (p < 0.05). AAM (≥10 μM) or GA (100 μM) accelerated telomere shortening in HUVECs (p < 0.05). In conclusion, in vitro chronic exposure to AAM or GA at low concentrations induces accelerated senescence. This result suggests that an exposure to AAM might contribute to endothelial aging.

Adverse drug events with hyperkalaemia during inpatient stays: evaluation of an automated method for retrospective detection in hospital databases

BackgroundAdverse drug reactions and adverse drug events (ADEs) are major public health issues. Many different prospective tools for the automated detection of ADEs in hospital databases have been developed and evaluated. The objective of the present study was to evaluate an automated method for the retrospective detection of ADEs with hyperkalaemia during inpatient stays.MethodsWe used a set of complex detection rules to take account of the patient’s clinical and biological context and the chronological relationship between the causes and the expected outcome. The dataset consisted of 3,444 inpatient stays in a French general hospital. An automated review was performed for all data and the results were compared with those of an expert chart review. The complex detection rules’ analytical quality was evaluated for ADEs.ResultsIn terms of recall, 89.5% of ADEs with hyperkalaemia “with or without an abnormal symptom” were automatically identified (including all three serious ADEs). In terms of precision, 63.7% of the automatically identified ADEs with hyperkalaemia were true ADEs.ConclusionsThe use of context-sensitive rules appears to improve the automated detection of ADEs with hyperkalaemia. This type of tool may have an important role in pharmacoepidemiology via the routine analysis of large inter-hospital databases.