[ECRIN standard requirements for good clinical practices-compliant data management in multinational clinical trials]. / Référentiel ECRIN pour la conformité aux bonnes pratiques de gestion des données des essais cliniques multinationaux.

CONTEXT: Clinical studies involve an increasing amount of data collection and management. However, there is no specific quality standard sufficiently practical, in free access, and open for data management and the underlying IT-infrastructure in academic units. European Clinical Research Infrastructures Network (ECRIN) published standard requirements for certified data management units. We present a French version of these standards. METHODS: A group of experts produced the standards, by consensus. The first version was revised after two pilot audits for data centre certification were performed. RESULTS: The revised version includes 21 lists of five to ten standards, in three groups: information technologies, data management (DM) and "general". CONCLUSIONS: These standards offer a clear description of DM and IT requirements for clinical studies. Initially created for ECRIN certification purposes, they offer a very useful reference for academic DM structures.

Assessment of Spontaneous Retinal Arterial Pulsations in Acute Central Retinal Vein Occlusions.

Central retinal vein occlusion (CRVO) is a common retinal disease. Recent works mentioned spontaneous retinal arterial pulsations (SRAPs) as a feature of some CRVOs. This is a retrospective study on patients presenting with CRVO who were followed up for at least 6 months. The objective was to identify SRAP in the acute phase of the disease and determine their relationship with patients' characteristics and visual prognosis. A 10-second infrared film centered on the optic disc was recorded within a month of the onset of symptoms, and SRAPs were detected in two-thirds of the cases. Patients with SRAP were significantly younger than those without SRAP. Mean central macular thickness was significantly higher in the absence of SRAP, which was translated into a more severe macular edema; however, this difference faded with time. BCVA tended to be higher in the presence of SRAP at the 6-month follow-up when adjusted to baseline. This study demonstrates that SRAPs are a frequent finding, easily detected by infrared fundus video recording, and associated with a younger age and lesser macular edema.

Nutritional Status Deterioration Occurs Frequently During Children's ICU Stay.

OBJECTIVES: Malnutrition and faltering growth at PICU admission have been related to suboptimal outcomes. However, little is known about nutritional status deterioration during PICU stay, as critical illness is characterized by a profound and complex metabolism shift, which affects energy requirements and protein turnover. We aim to describe faltering growth occurrence during PICU stay. DESIGN: Single-center prospective observational study. SETTING: Twenty-three-bed general PICU, Lyon, France. PATIENTS: All critically ill children 0-18 years old with length of stay longer than 5 days were included (September 2013-December 2015). INTERVENTIONS: Weight and height/length were measured at admission, and weight was monitored during PICU stay, in order to calculate body mass index for age z score. Faltering growth was defined as body mass index z score decline over PICU stay. Children admitted during the first year of the study and who presented with faltering growth were followed after PICU discharge for 3 months. MEASUREMENTS AND MAIN RESULTS: We analyzed 579 admissions. Of them, 10.2% presented a body mass index z score decline greater than 1 SD and 27.8% greater than 0.5. Admission severity risk scores and prolonged PICU stay accounted for 4% of the variability in nutritional status deterioration. Follow-up of post-PICU discharge nutritional status showed recovery within 3 months in most patients. CONCLUSIONS: Nutritional deterioration is frequent and often intense in critically ill children with length of stay greater than 5 days. Future research should focus on how targeted nutritional therapies can minimize PICU faltering growth and improve post-PICU rehabilitation.

Effect and Safety of Morphine Use in Acute Anterior ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Morphine is commonly used to treat chest pain during myocardial infarction, but its effect on cardiovascular outcome has never been directly evaluated. The aim of this study was to examine the effect and safety of morphine in patients with acute anterior ST-segment elevation myocardial infarction followed up for 1 year. METHODS AND RESULTS: We used the database of the CIRCUS (Does Cyclosporine Improve Outcome in ST Elevation Myocardial Infarction Patients) trial, which included 969 patients with anterior ST-segment elevation myocardial infarction, admitted for primary percutaneous coronary intervention. Two groups were defined according to use of morphine preceding coronary angiography. The composite primary outcome was the combined incidence of major adverse cardiovascular events, including cardiovascular death, heart failure, cardiogenic shock, myocardial infarction, unstable angina, and stroke during 1 year. A total of 554 (57.1%) patients received morphine at first medical contact. Both groups, with and without morphine treatment, were comparable with respect to demographic and periprocedural characteristics. There was no significant difference in major adverse cardiovascular events between patients who received morphine compared with those who did not (26.2% versus 22.0%, respectively; P=0.15). The all-cause mortality was 5.3% in the morphine group versus 5.8% in the no-morphine group (P=0.89). There was no difference between groups in infarct size as assessed by the creatine kinase peak after primary percutaneous coronary intervention (4023±118 versus 3903±149 IU/L; P=0.52). CONCLUSIONS: In anterior ST-segment elevation myocardial infarction patients treated by primary percutaneous coronary intervention, morphine was used in half of patients during initial management and was not associated with a significant increase in major adverse cardiovascular events at 1 year.

Measles virus infection of human keratinocytes: Possible link between measles and atopic dermatitis.

BACKGROUND: Measles virus (MV) infection is marked with a skin rash in the acute phase of the disease, which pathogenesis remains poorly understood. Moreover, the association between measles and progression of skin diseases, such as atopic dermatitis (AD), is still elusive. OBJECTIVE: We have thus analysed the susceptibility of human keratinocytes to MV infection and explore the potential relationship between MV vaccination and the pathogenesis the AD. METHODS: We performed immunovirological characterisation of MV infection in human keratinocytes and then tested the effect of live attenuated measles vaccine on the progression of AD in adult patients, in a prospective, double-blind study. RESULTS: We showed that both human primary keratinocytes and the keratinocyte cell line HaCaT express MV receptors and could be infected by MV. The infection significantly modulated the expression of several keratinocyte-produced cytokines, known to be implicated in the pathogenesis of inflammatory allergic diseases, including AD. We then analysed the relationship between exposure to MV by vaccination and the progression of AD in 20 adults during six weeks. We found a significant decrease in CCL26 and thymic stromal lymphopoietin (TSLP) mRNA in biopsies from acute lesions of vaccinated patients, suggesting MV-induced modulation of skin cytokine expression. Clinical analysis revealed a transient improvement of SCORAD index in vaccinated compared to placebo-treated patients, two weeks after vaccination. CONCLUSIONS: Altogether, these results clearly demonstrate that keratinocytes are susceptible to MV infection, which could consequently modulate their cytokine production, resulting with a beneficial effect in the progression of AD. This study provides thus a proof of concept for the vaccination therapy in AD and may open new avenues for the development of novel strategies in the treatment of this allergic disease.

Pre-PCI angiographic TIMI flow in the culprit coronary artery influences infarct size and microvascular obstruction in STEMI patients.

OBJECTIVE: The influence of initial-thrombolysis in myocardial infarction (i-TIMI) coronary flow in the culprit coronary artery on myocardial infarct and microvascular obstruction (MVO) size is unclear. We assessed the impact on infarct size of i-TIMI flow in the culprit coronary artery, as well as on MVO incidence and size, by contrast-enhanced cardiac magnetic resonance (ce-CMR). METHODS: In a prospective, multicenter study, pre-percutaneous coronary intervention (PCI) coronary occlusion was defined by an i-TIMI flow ≤1, and patency was defined by an i-TIMI flow ≥2. Infarct size, as well as MVO presence and size, were measured on ce-CMR 72h after admission. RESULTS: A total of 140 patients presenting with ST-elevated myocardial infarction referred for primary PCI were included. There was no significant difference in final post-PCI TIMI flow between the groups (2.95±0.02 vs. 2.97±0.02, respectively; p=0.44). In the i-TIMI flow ≤1 group, infarct size was significantly larger (32±17g vs. 21±17g, respectively; p=0.002), MVO was significantly more frequent (74% vs. 53%, respectively; p=0.012), and MVO size was significantly larger [1.3 IQR (0; 7.1) vs. 0 IQR (0; 1.6)], compared to in the i-TIMI ≥2 patient group. CONCLUSION: Initial angiographic TIMI flow in the culprit coronary artery prior to any PCI predicted final infarct size and MVO size: the better was the i-TIMI flow, the smaller were the infarct and MVO size.

Influence of cardiovascular risk factors on infarct size and interaction with mechanical ischaemic postconditioning in ST-elevation myocardial infarction.

OBJECTIVE: Previous studies have shown that mechanical postconditioning (PostC) significantly reduces infarct size (IS) in patients with acute myocardial infarction. Our objective was to assess the influence of traditional cardiovascular (CV) risk factors on IS and their interaction with ischaemic PostC in patients with acute ST-elevation myocardial infarction (STEMI). METHODS: The study population was constituted from the clinical database pooling of four previously published PostC prospective, multicentre, randomised, open-label controlled trials with identical inclusion criteria. Patients with STEMI, presenting within 12 h of symptoms onset referred for percutaneous coronary intervention, were included. Mechanical ischaemic PostC was performed by four repeated cycles of inflation-deflation of the angioplasty balloon within 1 min of reflow, while the control group underwent no intervention. IS was assessed by measuring total creatine kinase release over 72 h. RESULTS: 173 patients, aged 58±12 years, 76% males, 48% anterior infarct were included (82 in the PostC group, 91 in the control group). IS was significantly reduced in the PostC compared to the control group (71.7±41.6 vs 88.2±54.5×10(3) arbitrary units; p=0.027). After adjustment for abnormally contracting segments, older patients had smaller IS and smokers had larger IS. Gender, diabetes, hypertension, dyslipidemia and obesity did not have any significant effect on IS. Multivariate regression analysis showed that none of the traditional risk factors had a significant impact on the cardioprotective effect of mechanical ischaemic PostC. CONCLUSIONS: The present analysis suggests that the cardioprotective effect of mechanical PostC is not influenced by traditional CV risk factors that are prevalent in patients with STEMI.

A sensitive fluorigenic substrate for selective in vitro and in vivo assay of leukotriene A4 hydrolase activity.

Leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc-dependent metalloprotease bearing both an epoxide hydrolase, producing the pro-inflammatory LTB4 leukotriene, and an aminopeptidase activity, whose physiological relevance has long been ignored. Distinct substrates are commonly used for each activity, although none is completely satisfactory; LTA4, substrate for the hydrolase activity, is unstable and inactivates the enzyme, whereas aminoacids ß-naphthylamide and para-nitroanilide, used as aminopeptidase substrates, are poor and nonselective. Based on the three-dimensional structure of LTA4H, we describe a new, specific, and high-affinity fluorigenic substrate, PL553 [L-(4-benzoyl)phenylalanyl-ß-naphthylamide], with both in vitro and in vivo applications. PL553 possesses a catalytic efficiency (k(cat)/K(m)) of 3.8±0.5×104 M⁻¹ s⁻¹ using human recombinant LTA4H and a limit of detection and quantification of less than 1 to 2 ng. The PL553 assay was validated by measuring the inhibitory potency of known LTA4H inhibitors and used to characterize new specific amino-phosphinic inhibitors. The LTA4H inhibition measured with PL553 in mouse tissues, after intravenous administration of inhibitors, was also correlated with a reduction in LTB4 levels. This authenticates the assay as the first allowing the easy measurement of endogenous LTA4H activity and in vitro specific screening of new LTA4H inhibitors.

The IDEAL study : towards personalized drug treatment of hypertension.

OBJECTIVE: To identify markers (phenotypic, genetic, or environmental) of blood pressure (BP) response profiles to angiotensin converting enzyme inhibitors (ACEIs) and diuretics. METHODS: IDEAL was a crossover (two active and two wash out phases), double-blind, placebo-controlled trial. Eligible patients were untreated hypertensive, aged 25 to 70. After two visits, patients were randomized to one of four sequences. The main outcome was BP differences between the active treatment and placebo. RESULTS: One hundred and twenty-four patients were randomised: mean age 53, men 65%, family history of hypertension 60%. Average BP fall at each visit before randomisation was about 2% of the initial level reflecting both a regression to the mean and a placebo effect. CONCLUSION: The results are expected to improve knowledge in drug's mechanisms of action and pathophysiology of hypertension, and to help in personalizing treatment. The estimation of BP responses to each drug in standardized conditions provided a benefit to each participant.

[Is there a benefit to continue pap smear screening for cervical cancer after 65 years of age? A retrospective study on 53,644 women]. / Existe-t-il un intérêt à poursuivre les frottis de dépistage du cancer du col utérin après 65 ans ? Étude rétrospective sur 53 644 femmes.

BACKGROUND: One third of cervical cancers are discovered after age 65. French guidelines allow women to cease having cervical pap smears at age 65, providing they have had a minimum of two consecutive negative smears. AIM: To study the frequency of pathological smears in the group of women aged over 65 with a normal and sufficient cytological follow-up, according to the guidelines. To analyze the smear results and the former follow-up of this population to determine whether there is an interest to continue the smear screening after age 65. METHODS: This is a retrospective multicenter study based on collecting data from three pathology laboratories of the region Rhone-Alpes. We study a population of women 65 and older with smears that have been made between 2004 and 2008. RESULTS: Precancerous lesions and cervical cancer can be discovered after age 65 despite an adequate former follow-up. The rate of these women for having a pathological smear is 14,2‰, including 1,2‰ with cytological abnormalities in favour of cancer. CONCLUSION: These results show that there is interest to continue the smear tests after age 65 at least, while considering medical and financial issues of a reasonable screening strategy.

Thyroglobulin measurement in fine-needle aspirates of lymph nodes in patients with differentiated thyroid cancer: a simple definition of the threshold value, with emphasis on potential pitfalls of the method.

BACKGROUND: Thyroglobulin measurements in fine-needle aspirate (FNA-Tg) is an accurate method for the diagnosis of lymph node metastasis in differentiated thyroid carcinoma. The goal of this study is to determine the most appropriate diagnostic threshold value for FNA-Tg. METHODS: Ultrasound-guided fine-needle aspiration-cytology (FNA-C) and FNA-Tg were performed on suspicious lymph nodes in 114 consecutive patients with thyroid cancer prior to thyroidectomy (n=13) or during follow-up (n=93), and in 16 control subjects. Functional sensitivity of the thyroglobulin assay was 0.7 ng/mL. Sensitivity and specificity of FNA-Tg and FNA-C were determined for different cut-off values within a range of 0.69-1.34 nanogram/punction (ng/p) using receiver operating characteristic curve analysis. RESULTS: The FNA-Tg cut-off value of 0.93 ng/p offers the best diagnostic performances: 94.2% sensitivity, 97.8% specificity. FNA-C showed 100% specificity in diagnostic samples, but low sensitivity of 71% due primarily to inadequate samples. Combining FNA-C and FNA-Tg resulted in 98% sensitivity and 100% specificity. CONCLUSIONS: A unique threshold of 0.93 ng/p gives high sensitivity and specificity, even in non-thyroidectomized patients. However, since false negative results may be observed in poorly differentiated thyroid cancer, FNA-C should remain combined to FNA-Tg.