Université Nantes Angers Le Mans

BACKGROUND: Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. We evaluated the effect of early application of prone positioning on outcomes in patients with severe ARDS. METHODS: In this multicenter, prospective, randomized, controlled trial, we randomly assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (FiO2) of less than 150 mm Hg, with an FiO2 of at least 0.6, a positive end-expiratory pressure of at least 5 cm of water, and a tidal volume close to 6 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died from any cause within 28 days after inclusion. RESULTS: A total of 237 patients were assigned to the prone group, and 229 patients were assigned to the supine group. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P<0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P<0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67). The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group. CONCLUSIONS: In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique National 2006 and 2010 of the French Ministry of Health; PROSEVA ClinicalTrials.gov number, NCT00527813.).

UNLABELLED: Several animal studies have emphasized the role of gut microbiota in nonalcoholic fatty liver disease (NAFLD). However, data about gut dysbiosis in human NAFLD remain scarce in the literature, especially studies including the whole spectrum of NAFLD lesions. We aimed to evaluate the association between gut dysbiosis and severe NAFLD lesions, that is, nonalcoholic steatohepatitis (NASH) and fibrosis, in a well-characterized population of adult NAFLD. Fifty-seven patients with biopsy-proven NAFLD were enrolled. Taxonomic composition of gut microbiota was determined using 16S ribosomal RNA gene sequencing of stool samples. Thirty patients had F0/F1 fibrosis stage at liver biopsy (10 with NASH), and 27 patients had significant F≥2 fibrosis (25 with NASH). Bacteroides abundance was significantly increased in NASH and F≥2 patients, whereas Prevotella abundance was decreased. Ruminococcus abundance was significantly higher in F≥2 patients. By multivariate analysis, Bacteroides abundance was independently associated with NASH and Ruminococcus with F≥2 fibrosis. Stratification according to the abundance of these two bacteria generated three patient subgroups with increasing severity of NAFLD lesions. Based on imputed metagenomic profiles, Kyoto Encyclopedia of Genes and Genomes pathways significantly related to NASH and fibrosis F≥2 were mostly related to carbohydrate, lipid, and amino acid metabolism. CONCLUSION: NAFLD severity associates with gut dysbiosis and a shift in metabolic function of the gut microbiota. We identified Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis. Thus, gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre-/probiotics therapies.

MAXENT is now a common species distribution modeling (SDM) tool used by conservation practitioners for predicting the distribution of a species from a set of records and environmental predictors. However, datasets of species occurrence used to train the model are often biased in the geographical space because of unequal sampling effort across the study area. This bias may be a source of strong inaccuracy in the resulting model and could lead to incorrect predictions. Although a number of sampling bias correction methods have been proposed, there is no consensual guideline to account for it. We compared here the performance of five methods of bias correction on three datasets of species occurrence: one "virtual" derived from a land cover map, and two actual datasets for a turtle (Chrysemys picta) and a salamander (Plethodon cylindraceus). We subjected these datasets to four types of sampling biases corresponding to potential types of empirical biases. We applied five correction methods to the biased samples and compared the outputs of distribution models to unbiased datasets to assess the overall correction performance of each method. The results revealed that the ability of methods to correct the initial sampling bias varied greatly depending on bias type, bias intensity and species. However, the simple systematic sampling of records consistently ranked among the best performing across the range of conditions tested, whereas other methods performed more poorly in most cases. The strong effect of initial conditions on correction performance highlights the need for further research to develop a step-by-step guideline to account for sampling bias. However, this method seems to be the most efficient in correcting sampling bias and should be advised in most cases.

BACKGROUND & AIMS: Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-δ. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with nonalcoholic steatohepatitis (NASH). METHODS: Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n = 93), elafibranor 120 mg (n = 91), or placebo (n = 92) each day for 52 weeks at sites in Europe and the United States. Clinical and laboratory evaluations were performed every 2 months during this 1-year period. Liver biopsies were then collected and patients were assessed 3 months later. The primary outcome was resolution of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver disease activity score. RESULTS: In intention-to-treat analysis, there was no significant difference between the elafibranor and placebo groups in the protocol-defined primary outcome. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranor group vs the placebo group (19% vs 12%; odds ratio = 2.31; 95% confidence interval: 1.02-5.24; P = .045), based on a post-hoc analysis for the modified definition. In post-hoc analyses of patients with nonalcoholic fatty liver disease activity score ≥4 (n = 234), elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; odds ratio = 3.16; 95% confidence interval: 1.22-8.13; P = .018) and the modified definitions (19% vs 9%; odds ratio = 3.52; 95% confidence interval: 1.32-9.40; P = .013). Patients with NASH resolution after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resolution (mean reduction of 0.65 ± 0.61 in responders for the primary outcome vs an increase of 0.10 ± 0.98 in nonresponders; P < .001). Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group vs the placebo group. Elafibranor was well tolerated and did not cause weight gain or cardiac events, but did produce a mild, reversible increase in serum creatinine (effect size vs placebo: increase of 4.31 ± 1.19 μmol/L; P < .001). CONCLUSIONS: A post-hoc analysis of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat analysis and in patients with moderate or severe NASH. However, the predefined end point was not met in the intention to treat population. Elafibranor was well tolerated and improved patients' cardiometabolic risk profile. ClinicalTrials.gov number: NCT01694849.

Biofilms are widespread in nature and constitute an important strategy implemented by microorganisms to survive in sometimes harsh environmental conditions. They can be beneficial or have a negative impact particularly when formed in industrial settings or on medical devices. As such, research into the formation and elimination of biofilms is important for many disciplines. Several new methodologies have been recently developed for, or adapted to, biofilm studies that have contributed to deeper knowledge on biofilm physiology, structure and composition. In this review, traditional and cutting-edge methods to study biofilm biomass, viability, structure, composition and physiology are addressed. Moreover, as there is a lack of consensus among the diversity of techniques used to grow and study biofilms. This review intends to remedy this, by giving a critical perspective, highlighting the advantages and limitations of several methods. Accordingly, this review aims at helping scientists in finding the most appropriate and up-to-date methods to study their biofilms.

IMPORTANCE: D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients. OBJECTIVE: To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE. DESIGN, SETTINGS, AND PATIENTS: A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013. INTERVENTIONS: All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period. MAIN OUTCOMES AND MEASURES: The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result. RESULTS: Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings. CONCLUSIONS AND RELEVANCE: Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01134068.

Despite current recommendations on the management of pre-operative anaemia, there is no pragmatic guidance for the diagnosis and management of anaemia and iron deficiency in surgical patients. A number of experienced researchers and clinicians took part in an expert workshop and developed the following consensus statement. After presentation of our own research data and local policies and procedures, appropriate relevant literature was reviewed and discussed. We developed a series of best-practice and evidence-based statements to advise on patient care with respect to anaemia and iron deficiency in the peri-operative period. These statements include: a diagnostic approach for anaemia and iron deficiency in surgical patients; identification of patients appropriate for treatment; and advice on practical management and follow-up. We urge anaesthetists and peri-operative physicians to embrace these recommendations, and hospital administrators to enable implementation of these concepts by allocating adequate resources.

Butyrate is a natural substance present in biological liquids and tissues. The present paper aims to give an update on the biological role of butyrate in mammals, when it is naturally produced by the gastrointestinal microbiota or orally ingested as a feed additive. Recent data concerning butyrate production delivery as well as absorption by the colonocytes are reported. Butyrate cannot be detected in the peripheral blood, which indicates fast metabolism in the gut wall and/or in the liver. In physiological conditions, the increase in performance in animals could be explained by the increased nutrient digestibility, the stimulation of the digestive enzyme secretions, a modification of intestinal luminal microbiota and an improvement of the epithelial integrity and defence systems. In the digestive tract, butyrate can act directly (upper gastrointestinal tract or hindgut) or indirectly (small intestine) on tissue development and repair. Direct trophic effects have been demonstrated mainly by cell proliferation studies, indicating a faster renewal of necrotic areas. Indirect actions of butyrate are believed to involve the hormono-neuro-immuno system. Butyrate has also been implicated in down-regulation of bacteria virulence, both by direct effects on virulence gene expression and by acting on cell proliferation of the host cells. In animal production, butyrate is a helpful feed additive, especially when ingested soon after birth, as it enhances performance and controls gut health disorders caused by bacterial pathogens. Such effects could be considered for new applications in human nutrition.

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) has become a major public health issue. The goal of this study was to assess the clinical use of liver stiffness measurement (LSM) evaluated by supersonic shear imaging (SSI), FibroScan, and acoustic radiation force impulse (ARFI) in a cohort of NAFLD patients who underwent liver biopsy. A total of 291 NAFLD patients were prospectively enrolled from November 2011 to February 2015 at 2 French university hospitals. LSM was assessed by SSI, FibroScan (M probe), and ARFI within two weeks prior to liver biopsy. Calculations of the area under the receiver operating curve (AUROC) were performed and compared for the staging of liver fibrosis. AUROC for SSI, FibroScan, and ARFI were 0.86, 0.82, and 0.77 for diagnoses of ≥F2; 0.89, 0.86, and 0.84 for ≥F3; and 0.88, 0.87, and 0.84 for F4, respectively. SSI had a higher accuracy than ARFI for diagnoses of significant fibrosis (≥F2) (P = 0.004). Clinical factors related to obesity such as body mass index ≥ 30 kg/m(2) , waist circumference ≥102 cm or increased parietal wall thickness were associated with LSM failures when using SSI or FibroScan and with unreliable results when using ARFI. In univariate analysis, FibroScan values were slightly correlated with NAFLD activity score and steatosis (R = 0.28 and 0.22, respectively), whereas SSI and ARFI were not; however, these components of NAFLD did not affect LSM results in multivariate analysis. The cutoff values for SSI and FibroScan for staging fibrosis with a sensitivity ≥90% were very close: 6.3/6.2 kPa for ≥F2, 8.3/8.2 kPa for ≥F3, and 10.5/9.5 kPa for F4. CONCLUSION: Although obesity is associated with an increase in LSM failure, the studied techniques and especially SSI provide high value for the diagnosis of liver fibrosis in NAFLD patients. (Hepatology 2016;63:1817-1827).

Superparamagnetic ferrite nanoparticles (MFe 2 O 4, where M = Fe, Co, Mn) were synthesized through a novel one-step aqueous coprecipitation method based on the use of a new type of alkaline agent: the alkanolamines isopropanolamine and diisopropanolamine. The role played by the bases on the particles’ size, chemical composition, and magnetic properties was investigated and compared directly with the effect of the traditional inorganic base NaOH. The novel MFe 2 O 4 nanomaterials exhibited high colloidal stability, particle sizes in the range of 4–12 nm, and superparamagnetic properties. More remarkably, they presented smaller particle sizes (up to 6 times) and enhanced saturation magnetization (up to 1.3 times) relative to those prepared with NaOH. Furthermore, the nanomaterials exhibited improved magnetic properties when compared with nanoferrites of similar size synthesized by coprecipitation with other bases or by other methods reported in the literature. The alkanolamines were responsible for these achievements by acting both as alkaline agents and as complexing agents that controlled the particle size during the synthesis process and improved the spin rearrangement at the surface (thinner magnetic “dead” layers). These results open new horizons for the design of water-dispersible MFe 2 O 4 nanoparticles with tuned properties through a versatile and easily scalable coprecipitation route.

RATIONALE: Many patients with severe acute respiratory distress syndrome (ARDS) caused by influenza A(H1N1) infection receive extracorporeal membrane oxygenation (ECMO) as a rescue therapy. OBJECTIVES: To analyze factors associated with death in ECMO-treated patients and the influence of ECMO on intensive care unit (ICU) mortality. METHODS: Data from patients admitted for H1N1-associated ARDS to French ICUs were prospectively collected from 2009 to 2011 through the national REVA registry. We analyzed factors associated with in-ICU death in ECMO recipients, and the potential benefit of ECMO using a propensity score-matched (1:1) cohort analysis. MEASUREMENTS AND MAIN RESULTS: A total of 123 patients received ECMO. By multivariate analysis, increasing values of age, lactate, and plateau pressure under ECMO were associated with death. Of 103 patients receiving ECMO during the first week of mechanical ventilation, 52 could be matched to non-ECMO patients of comparable severity, using a one-to-one matching and using control subjects only once. Mortality did not differ between the two matched cohorts (odds ratio, 1.48; 95% confidence interval, 0.68-3.23; P = 0.32). Interestingly, the 51 ECMO patients who could not be matched were younger, had lower Pa(o(2))/Fi(o(2)) ratio, had higher plateau pressure, but also had a lower ICU mortality rate than the 52 matched ECMO patients (22% vs. 50%; P < 0.01). CONCLUSIONS: Under ECMO, an ultraprotective ventilation strategy minimizing plateau pressure may be required to improve outcome. When patients with severe influenza A(H1N1)-related ARDS treated with ECMO were compared with conventionally treated patients, no difference in mortality rates existed. The unmatched, severely hypoxemic, and younger ECMO-treated patients had, however, a lower mortality.

This paper proposes a new algorithm for automatic crack detection from 2D pavement images. It strongly relies on the localization of minimal paths within each image, a path being a series of neighboring pixels and its score being the sum of their intensities. The originality of the approach stems from the proposed way to select a set of minimal paths and the two postprocessing steps introduced to improve the quality of the detection. Such an approach is a natural way to take account of both the photometric and geometric characteristics of pavement images. An intensive validation is performed on both synthetic and real images (from five different acquisition systems), with comparisons to five existing methods. The proposed algorithm provides very robust and precise results in a wide range of situations, in a fully unsupervised manner, which is beyond the current state of the art.

IMPORTANCE: Although retrievable inferior vena cava filters are frequently used in addition to anticoagulation in patients with acute venous thromboembolism, their benefit-risk ratio is unclear. OBJECTIVE: To evaluate the efficacy and safety of retrievable vena cava filters plus anticoagulation vs anticoagulation alone for preventing pulmonary embolism recurrence in patients presenting with acute pulmonary embolism and a high risk of recurrence. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, blinded end point trial (PREPIC2) with 6-month follow-up conducted from August 2006 to January 2013. Hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity were assigned to retrievable inferior vena cava filter implantation plus anticoagulation (filter group; n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers. INTERVENTIONS: Full-dose anticoagulation for at least 6 months in all patients. Insertion of a retrievable inferior vena cava filter in patients randomized to the filter group. Filter retrieval was planned at 3 months from placement. MAIN OUTCOMES AND MEASURES: Primary efficacy outcome was symptomatic recurrent pulmonary embolism at 3 months. Secondary outcomes were recurrent pulmonary embolism at 6 months, symptomatic deep vein thrombosis, major bleeding, death at 3 and 6 months, and filter complications. RESULTS: In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group (relative risk with filter, 2.00 [95% CI, 0.51-7.89]; P = .50). Results were similar at 6 months. No difference was observed between the 2 groups regarding the other outcomes. Filter thrombosis occurred in 3 patients. CONCLUSIONS AND RELEVANCE: Among hospitalized patients with severe acute pulmonary embolism, the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent pulmonary embolism at 3 months. These findings do not support the use of this type of filter in patients who can be treated with anticoagulation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00457158.

Purpose This paper provides a structured literature review of sustainability in purchasing and supply management, moving beyond the traditional environmental and social sustainability. The paper reviews the concept of sustainability at three levels of inter‐organizational analysis – i.e. dyad, supply chain and network. The paper distils the nature and scope of existing research and synthesizes measures used to research sustainability across organizational boundaries. Design/methodology/approach This literature review systematically analyzes existing literature. In particular, the review focuses on definitions and measures of sustainable purchasing and supply management to obtain an accurate view of current research. Findings This paper uncovers two distinct trends in the type of research carried out. First, internal or dyadic issues are in focus and second, a tendency to deal with environmental, as opposed to social, sustainability. Despite the need to look beyond the dyad given the risks associated with the extended network, few studies do so in any of the sustainability dimensions. Research limitations/implications This review is limited by the method employed focusing on definitions and measures. Although the review considers supply chain and network research, it does so purely from a purchasing perspective, thus excluding issues such as logistics and transport. Practical implications The paper identifies areas open to future research and provides practical insights into how sustainable purchasing and supply are measured. It also synthesizes existing measures of sustainability at different levels and organizes these into a taxonomy. Originality/value The paper examines studies across multiple levels of analysis and integrates multiple fields of knowledge to show how research on sustainability in purchasing and supply is structured.

Brugada syndrome is a genetic disease associated with sudden cardiac death that is characterized by ventricular fibrillation and right precordial ST segment elevation on ECG. Loss-of-function mutations in SCN5A, which encodes the predominant cardiac sodium channel alpha subunit NaV1.5, can cause Brugada syndrome and cardiac conduction disease. However, SCN5A mutations are not detected in the majority of patients with these syndromes, suggesting that other genes can cause or modify presentation of these disorders. Here, we investigated SCN1B, which encodes the function-modifying sodium channel beta1 subunit, in 282 probands with Brugada syndrome and in 44 patients with conduction disease, none of whom had SCN5A mutations. We identified 3 mutations segregating with arrhythmia in 3 kindreds. Two of these mutations were located in a newly described alternately processed transcript, beta1B. Both the canonical and alternately processed transcripts were expressed in the human heart and were expressed to a greater degree in Purkinje fibers than in heart muscle, consistent with the clinical presentation of conduction disease. Sodium current was lower when NaV1.5 was coexpressed with mutant beta1 or beta1B subunits than when it was coexpressed with WT subunits. These findings implicate SCN1B as a disease gene for human arrhythmia susceptibility.

With the constant increase in poultry meat consumption worldwide and the large variety of poultry meat products and consumer demand, ensuring the microbial safety of poultry carcasses and cuts is essential. In the present review, we address the bacterial contamination of poultry meat from the slaughtering steps to the use-by-date of the products. The different contamination sources are identified. The contaminants occurring in poultry meat cuts and their behavior toward sanitizing treatments or various storage conditions are discussed. A list of the main pathogenic bacteria of concern for the consumer and those responsible for spoilage and waste of poultry meat is established.

BACKGROUND: Drug patch tests (PTs) can reproduce delayed hypersensitivity to drugs and entail a moderate re-exposure of patients to offending drugs. OBJECTIVES: To determine the value of PTs for identifying the responsible drug in severe cutaneous adverse drug reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). METHODS: In a multicentre study, PTs were conducted on patients referred for DRESS, AGEP or SJS/TEN within 1 year of their SCAR. All drugs administered in the 2 months prior to and the week following the onset of the SCAR were tested. RESULTS: Among the 134 patients included (48 male, 86 female; mean age 51·7 years), positive drug PTs were obtained for 24 different drugs. These included positive tests for 64% (46/72) of patients with DRESS, 58% (26/45) of those with AGEP and 24% (4/17) of those with SJS/TEN, with only one relapse of AGEP. The value of PTs depended on the type of drug and the type of SCAR (e.g. carbamazepine was positive in 11/13 DRESS cases but none of the five SJS/TEN cases). PTs were frequently positive for beta lactams (22 cases), pristinamycin (11 cases) and in DRESS with pump proton inhibitors (five cases), but were usually negative for allopurinol and salazopyrin. Of 18 patients with DRESS, eight had virus reactivation and positive PTs. In DRESS, multiple drug reactivity was frequent (18% of cases), with patients remaining sensitized many years later. CONCLUSIONS: PTs are useful and safe for identifying agents inducing SCAR.

BACKGROUND Critically ill neonates are at high risk for adverse neurologic sequelae, but the bedside evaluation of a neonate's neurologic status, especially cortical functioning, is extremely limited. In such circumstances, continuous video EEG provides particularly useful information about brain function and can identify electroencephalographic seizures without clinical correlate (Clancy et al., 1988; Murray et al., 2008). For these reasons, continuous video EEG monitoring is a useful tool in the intensive care nursery. The American Clinical Neurophysiology Society has recently produced guidelines regarding methods and indications for continuous EEG monitoring in neonates (Shellhaas et al., 2011). A challenge in EEG monitoring of neonates is to understand the clinical significance of various EEG patterns. In the adult population in intensive care unit, there has been extensive debate, for example, regarding the importance of fluctuating rhythmic patterns (Hirsch et al., 2004; Oddo et al., 2009; Orta et al., 2009; Vespa et al., 1999). The American Clinical Neurophysiology Society Critical Care Monitoring Committee has generated standardized terminology of rhythmic EEG patterns in the critically ill to facilitate multicenter collaborations to determine whether these patterns have clinical significance (Hirsch et al., 2005). Neonates have distinctive EEG patterns that necessitate separate terminology. This document is the consensus of experts to establish standardized neonatal EEG nomenclature aimed at improving consistency and facilitating collaborative research. Where evidence exists to support a particular definition, it is noted. For terms with historically variable definitions, alternative nomenclature is referenced but a single definition is proposed. We anticipate that future revisions will incorporate feedback and emerging research building on this initial effort. Many of the studies on which these criteria are based used routine-length EEG recordings, and in this limited context, values such as acceptable duration of interburst intervals have been offered. However, greater variability may be expected in recordings of longer duration. It is hoped that this document provides groundwork for collaboration to determine the clinical significance of various EEG patterns in continuous monitoring of the critically ill neonate. DETAILS TO BE REPORTED Characterization of a 24-hour period of continuous video EEG recording should include the following (Table 1). Documentation of the patient’s postmenstrual age (PMA = gestational age, measured from the time of the last menstrual period + chronological age) at the time of recording (Engle, 2004) (We use the term PMA in accordance with the American Academy of Pediatrics policy statement on age terminology in the perinatal period. However, we recognize that historically, many seminal investigations of EEG ontogeny calculated gestational age from the time of conception rather than the last menstrual period. This has been traditionally termed conceptional age (CA). The LMP occurs approximately 2 weeks before conception.). a) Term = 37 up to 44 weeks of PMA b) Preterm = less than 37 weeks of PMA c) Post term = 44 to 48 weeks of PMA Documentation of neuroactive medications at the time of recording. This includes sedatives, hypnotics, anxiolytics, general anesthesia, and antiepileptic drugs. An ideal report would also document when these medications are administered during the recording. Documentation of the depth and duration of hypothermia during the recording, and whether it is spontaneous or induced. An ideal report would also document the clinical changes that have the potential to impact cerebral function. These would include sudden hemodynamic instability, rapid changes in respiratory function, or cardiorespiratory failure. Documentation of the number of hours of recording that cannot be interpreted as a result of technical problems. Detailed characterization of the background EEG features during the first hour of recording. Presence or absence of state changes must be included. Characterization of 1 hour of background recording within each 24-hour period of EEG monitoring. Characterization of additional epochs of background when there are relevant changes. Relevant changes include evidence for not only the increasing encephalopathy but also the new development of episodic state changes. Documentation of seizure onset, seizure burden, and seizure resolution. When present, specific note should also be made of the beginning and end of status epilepticus. TABLE 1: Details to Include in Daily EEG ReportThe normal neonatal EEG evolves as the brain matures, reflecting both antenatal and postnatal experiences. All else being equal, two healthy infants with the same PMA should have very similar appearing EEG recordings. There should be no visible differences between an EEG recorded from a 5-week chronological age infant born at 35 weeks of estimated gestational age (PMA = 40 weeks) compared with a 1-week chronological age baby born at 39 weeks EGA (PMA is also 40 weeks). However, in contrast to the older child or adult, the age difference of a few weeks can cause visible changes in normal EEG features. The following text proposes nomenclature to describe normal and abnormal features of the EEG in the preterm and term infants. Where relevant, it refers to the specific PMA at which various features are seen. We focus specifically on normal state changes, background features, graphoelements (or named neonatal EEG features), seizures, and rhythmic or periodic patterns. BEHAVIORAL STATE Standardized descriptions of the behavioral state and sleep–wake cycling are particularly useful in considering whether a neonatal record is normal or abnormal. Features of a full-term neonatal EEG and polysomnographic recording emerge over time in the premature infant. A behavioral state is said to be present when features of that state are present for 1 minute or longer (Table 2).TABLE 2: Behavioral StateAwake Term A healthy term neonate is awake when the eyes are open, and the EEG background has continuous, low to medium voltage [25–50 µV peak-to-peak (pp)] mixed frequency activity with a predominance of theta and delta and overriding beta activity (Fig. 1) (all voltages included in this article refer to pp values). This is traditionally or EEG background term infants have and there are spontaneous of the and 1: of EEG background A healthy preterm infant is awake when the eyes are This clinical to weeks of when polysomnographic respiratory or and the of and are also with of the awake EEG are continuous at weeks of The awake background is continuous weeks and continuous weeks and in the neonate is as and has distinctive EEG and polysomnographic features. The healthy term neonate in has the eyes of rapid and with and The EEG background from that of normal the normal in healthy preterm This EEG is of high voltage µV activity that are low voltage interburst µV (Clancy and 2011). The duration of the low voltage interburst is on being in the PMA infants. The of EEG activity have expected and such as delta activity and patterns that are before weeks of and of continuous EEG activity first in state and with rapid at weeks of PMA et al., and in to be or and to weeks of there are with features of rapid and continuous has continuous EEG 2: the between and EEG of and In the are very low There are no from activity or and the respiratory is In this of there is an of high and low voltages but no that are There are no from activity or and the respiratory is This record from a term infant with an encephalopathy with normal features present during such as the in extremely and of abnormal In the healthy term is absence of rapid and for activity or The EEG background evolves from the less in the preterm It the in which voltage µV of delta activity and to with voltage µV et al., interburst of mixed theta and delta These interburst of in the of with low to medium mixed frequency with age and is weeks and it is in the continuous background of µV delta and theta to first within this continuous weeks of In the very preterm of the EEG background is in behavioral and are from greater of is the of first emerging approximately weeks of to is only in The of time with a with increasing PMA that a term infant has of in et al., 37 to 40 as In between of and there are in which features for a specific behavioral state are These clinical and EEG features of the and behavioral not the polysomnographic and EEG background criteria for a specific as For example, in the from to an infant but an EEG that is between and This of the two is and the criteria for can be of as a period of as of the EEG in which the eyes are but in which clinical and EEG features not to or are as These the features for to a is a of of the is in very preterm infants in there is not a between the EEG background and polysomnographic a of time is in healthy term infants. A high of time that is would be abnormal at cycling is the of behavioral is distinctive and to recognize in term compared with preterm It is also to in recordings than et al., In the term a and has a duration of to hours et al., An 40 to and in a The awake term infant first an This is about term may in the first of and be continuous Term neonates approximately to of the in to in and to in The of time in state also age et al., 1988; et al., The first evidence of cycling can be at weeks of to weeks of to is in to in and in 35 weeks of infants to of the time in in and to in The duration of a and is to for neonates weeks of PMA and to to 35 weeks of state changes. In a infant with of normal background features, it may be or to identify specific However, infants can have state changes, as cycling between EEG patterns as the of background or with at 1 minute in each EEG BACKGROUND The of normal neonatal EEG background with In the following the features of both normal and abnormal EEG will be (Table EEG EEG activity is continuous when there is activity with of voltage µV The of the normal EEG background from the in behavioral in extremely premature infants to continuous EEG in in infants. EEG activity is as voltage of activity voltage The of are termed interburst intervals The in of the are a function of age, being in very preterm infants and during at We the as a period in which activity is to µV pp for 2 or The has historically various for EEG patterns on the of The are from these et al., et al., (Table The background can be there is activity within the in a single or a single in and There is a in normal with increasing PMA et al., et al., 1999). as is a normal EEG in preterm infants The activity within the includes graphoelements such as rhythmic delta activity and named patterns that are It is present in from to 40 weeks of It first in and weeks of only in and is in infants of PMA or older et al., as a of from to It is only in In the from to the of the voltages the of have been of to µV delta activity with voltage theta activity of to these voltage In contrast to the voltages are µV pp et al., the of this is first at to weeks of which weeks and is no longer weeks of In infants have a of of encephalopathy as the two of background are and low voltage for PMA (Clancy et al., 2011). We the term to with that normal patterns and graphoelements that are or voltage for as the in (Clancy and 2011). This is an that can be and future standardized to correlate with of EEG in the This of EEG and low voltage as voltages µV pp However, the definition for with activity during the up to µV pp or less than 2 with activity up to µV pp or in voltage in In the EEG should be with no spontaneous changes of and no EEG of of of the infant. The of high µV or low µV voltage activity in the should be The of the of the EEG activity is and but is of specific graphoelements such as delta delta or This is a from has no normal features within the have normal patterns within the is an variability or and duration should be characterization should include a of the of the of a and and of In the are of but in within the In the normal neonatal and the of named graphoelements should be between of the two The and should be or less of each This for to considering the record The of than a difference in voltages between of the two or a of background features, the and the of specific graphoelements between the two is abnormal. for up to of neonatal EEG background are not and may be is as the of of activity that between in the of the recording. For example, a single within would be the of the and within of each The the of that are within the of the The of is not a function of to weeks of EEG activity is (Clancy et al., et al., and weeks of EEG activity may only be approximately approximately to 37 weeks of activity term when the EEG is of is expected and normal between and 37 weeks of weeks of the EEG should not of This is as a of EEG for PMA that than between the of activity in each during the of the recording. studies have the normal for voltage (or in premature infants. there will be no to normal voltage criteria for in this The focus of this will be the of normal voltage for the term infant (Fig. 1). as with the older child or adult, voltage should be interpreted with many as or and can result in low voltage EEG activity or voltage voltage are to A healthy term infant should have EEG activity µV pp in behavioral This is as a continuous EEG background normal activity and graphoelements with voltages at µV but The clinical significance of low voltage is not voltage There are various in the of an abnormal background of a low voltage or voltage et al., et al., et al., We a definition of low voltage activity without normal background features. The voltage is µV The background can be with voltage µV activity for In the record is with no and with no EEG changes from This neurologic with or of the cortical of EEG This terminology is used to describe the absence of cerebral activity µV pp when at a of 2 and The term has the terms and recordings, are the guidelines the technical for an EEG to for Clinical Neurophysiology These are from the technical for neonatal EEG recordings. the EEG is not to these the term should not be there is no cerebral but the recording not to the the report should that the recording may be with but should that cannot be without the technical is a when with clinical is used to determine cerebral and and et al., are to guidelines regarding the of brain for as spontaneous EEG to such as that during sleep–wake It is first present weeks when the EEG changes with should be weeks of PMA and to weeks of The EEG can of changes in or It is to note that from can result in of EEG which should not be for should be recorded as or For example, variability would be present in a recording, which behavioral such as and The last for example, in a recording that only an awake of EEG is when there is a cerebral EEG to these EEG also of changes in or The clinical and behavioral of can include and respiratory changes. It is to note that or behavioral may from or activity that may changes of the EEG first at to weeks of but it not been with each and should be recorded as or of should be noted. The in which the term very premature infants with such as EEG background features to at the same as PMA There a between PMA and as the of EEG This in between the PMA and is termed as an EEG that would be normal for an infant at 2 weeks than the The EEG is abnormal and is with an risk of abnormal neurologic et al., and BACKGROUND In neonatal graphoelements are and named EEG background patterns that first and during particular epochs of neonatal are of specific are a of the of the normal EEG background and are of specific is included we have the (Table This occurs between and weeks of PMA and of high voltage to µV delta activity with a It may be but is (Clancy et al., and and have been many or of These are between and weeks of PMA and of a of to of to µV pp with activity or et al., 1999). is between and weeks of are in up to weeks and that are in and and are in between and 37 weeks of PMA (Clancy et al., et al., are in up to 40 weeks of This occurs between and weeks of It of to µV pp theta frequency activity for over the It is and between and weeks of PMA (Clancy et al., et al., et al., similar activity can be at the and this is a normal It first at weeks and 44 weeks of It of to µV pp delta which may in or for a few over the (Clancy et al., et al., 1999). It is and This is to and the two are over the (Fig. between and 44 weeks of PMA and of to µV pp with a initial and a (Clancy and et al., et al., 1999). are and are present in and in the from to (Clancy et al., et al., the between and are present and in both A is in the in the periodic are in the These and in the same The first are with to the EEG which is the cerebral there are also EEG patterns that may the background (Table EEG Many healthy neonates have abnormal or that There regarding the that separate from are or and A has an initial and that is A has an initial and that is to be from the background as separate and not background are to are It is that the neonatal of time the of the and many EEG features will than the recording at the adult or of of the of number of or minute at a such as the or should be in the continuous of the neonatal or In the of the particularly during the EEG have activity within the rather than EEG separate from the can at may as or in or to are in the of healthy and term infants (Fig. are the of a normal EEG background for in in the and are in the and are between of the are but a few may in or et al., These as or (Fig. in the of an abnormal EEG background for may also in the or may be in or rather than being or may also be in such as the or may be compared with for neonates at 1 or older that than hour for preterm and hour for term infants are abnormal et al., and and et al., et al., et al., EEG are than to in or these first in the of preterm infants in the and it that many at the with to the (Clancy and It is that and are with et al., In the term in the can such a or However, these are to can be in term infants. that up to hour for preterm and hour for term neonates may be normal and et al., This EEG of rhythmic patterns of activity that many with seizures but are very with a duration of et al., et al., These have been in the as and rhythmic that the significance of these is the term rhythmic will be used are in the of an abnormal EEG background are in in a normal this significance is not However, studies in that clinical changes can with 2 in duration et al., a similar and neurologic for infants with as with seizures et al., 2011). is to understand the and significance of in the neonate. seizures are traditionally as clinical or only A clinical only seizure of a sudden of abnormal clinical changes that not correlate with a EEG These clinical changes may include sudden or or or An seizure features clinical seizure with an EEG seizure and An EEG only seizure refers to the of a EEG seizure that not specific visible clinical For the of this the term refers to seizures, with or without clinical of seizure (Table and seizure is a abnormal EEG a and with a 2 µV pp voltage and duration of at A seizure is an abnormal and should not be with background changes, such as with or from is as an in or In rhythmic but with would be and not activity than but without would be periodic or rhythmic activity but not a seizure (Fig. 2 µV pp the of the beginning and end of each the voltages as the seizure evolves and can be up to µV pp or seizures in older and there is no frequency in the definition of be as separate seizures, or must separate two seizure (Clancy and et al., of a seizure can be In the older child and adult, the American Clinical Neurophysiology Society standardized research terminology the and frequency during a seizure (Hirsch et al., 2005). This is of significance in the neonate. can be in terms of the focus of and the number of terminology to describe seizure includes the of seizures of extensive This with and can have and a seizure with activity in two but which and of each seizure from to of the seizure within a single or When a seizure is to a it can be as or or it can be as and When seizures from a single general can be as seizures from at with at in each It is not for such as a to seizures, such as may has been in various (Clancy and et al., Murray et al., et al., et al., 2011). We seizure for clinical of the following the number of seizures hour or of the record with the duration of the seizures the duration of an of or The of seizure that be used for research includes the of seizures in each of hour et al., In this the neonatal be of and (or and each single is only The seizure can be calculated for each of the of which provides a of seizure is to determine the of these The definition of status in and is a single seizure than or a of seizures at between which brain function has not been These criteria are to to the status and the high of of neonatal status have been et al., In consensus with the we a status as present when the duration of seizures of an In or of hour of recording seizures, status exists for that In a population of neonates with recorded seizures, the of recording time in which seizures are from to It is that definition of status is a and that there are no that specifically the of over as especially or research of status be based on the regarding of neonatal In two studies in the EEG seizure 1 with of seizures (Clancy and and In these and the of seizure duration to and the seizure 2 to (Clancy and et al., and In future it will be useful to of seizure and duration of status as to rhythmic patterns not the in or of These are of in the older population in intensive care are and clinical significance is rhythmic and periodic patterns in preterm and term neonates but are not and It is whether research terminology that has been in is to the neonate (Hirsch et al., 2005). We the patterns from the adult which have been in neonatal (Table and of are in the adult terminology as a in which have a and there is a between and the at are as with no than the no than or or of number of In are as than and at the at is as a from to the in the of (Fig. are not in neonates but can with such as or et al., et al., and delta activity is in the adult terminology as the of a with and duration but without an between as the duration of the of the rhythmic must from the duration of the for the of this EEG may not be abnormal in neonates and is with normal neonatal rhythmic delta activity and The periodic or rhythmic must be present for at for or for 2 can be in terms of the focus of and can be or includes and In there is of The term can be to the activity has a may also be or information may include a of the For can or not is as an in that is at greater than that in on an or recording. is as an in that is at greater than that in on an or recording. is as an in that is at greater than in on an or recording. For or can the or or specific is not and whether the activity is or activity is but the or or can be over both patterns can be terms to the American Clinical Neurophysiology Society Standardized Critical Care EEG The not to neonates this a neonatal that from the adult terminology are the is not continuous, the duration of is are and the adult terminology also recording the continuous duration. hour to 1 to to from for of In periodic duration in the preterm infant less than 1 minute and than 1 minute in term infants and of preterm and term infants duration we duration to be with terminology used in the intensive care for adult we recognize that very few neonatal EEG patterns will the or In neonatal recordings, should be in the and should be for the with the only for a only to periodic and the of not rhythmic delta is as or only to periodic and the of but not to rhythmic delta should be for a for both the with and the include the have a duration measured at the EEG have a duration of to theta and delta have a to of the at but are in duration to as a have a or This document is a collaborative to the neonatal EEG terminology. We this multicenter collaboration to determine the significance of continuous EEG in critically ill may on this to establish the of the terms and definitions, both in the research and clinical This terminology will be and based on the feedback and future research.

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