Search

OBJECTIVES The antiarrhythmic effects of dexmedetomidine (DEX) have been suggested, but there are controversial reports on the effectiveness of intraoperative use of DEX to reduce the incidence of postoperative tachyarrhythmia (POT). METHODS From a local European Congenital Heart Surgery Association database, we included patients operated for congenital heart diseases under cardiopulmonary bypass within a 5-year period (2017–2021), during which intraoperative use of high dose of DEX (1–1.4 µg/kg/h) was implemented. A doubly robust matching estimation of the causal effect of DEX on the incidence of POT was conducted. We combined a multimodal estimation model in patients not exposed to DEX (disease risk score) as well as a regression analysis in a matched cohort for patients exposured to DEX. RESULTS From a cohort of 593 surgeries (514 patients) occurring during the study period, doubly matched analysis consisted of the analysis of 426 surgeries conducted under DEX or not (213 per group). The probability of developing POT in patients exposed to DEX was 6.6% (95% confidence interval 0.032–0.099) vs 14.5% (95% confidence interval 0.098–0.193) in the group of patients not exposed to DEX. The doubly robust matched estimation method showed a mean reduction of 8.8% (95% confidence interval −0.137 to −0.023) of POT when DEX is used for intraoperative anaesthesia. CONCLUSIONS The use of high doses of DEX during anaesthesia for congenital heart surgery in neonates and infants is associated with a moderate but significant reduction of POT.

Purpose Early prognostication of neurologic outcome in neonates and children supported with extra-corporeal membrane oxygenation (ECMO) is challenging. Amplitude-integrated EEG (aEEG) offers the advantages of continuous monitoring and 24-hours availability at the bedside for intensive care unit providers. The objective of this study was to describe the early electrophysiological background patterns of neonates and children undergoing ECMO and their association with neurologic outcomes. Methods This was a retrospective review of neonates and children undergoing ECMO and monitored with aEEG. Amplitude-integrated EEG was summarized as an aEEG background score determined within the first 24 hours of ECMO and divided in 3-hour periods. Screening for electrical seizures was performed throughout the full ECMO duration. Neurologic outcome was defined by the Pediatric Cerebral Performance Category score at hospital discharge. Results Seventy-three patients (median age 79 days [8-660], median weight 4.78 kg [3.24-10.02]) were included in the analysis. Thirty-two patients had a favorable neurologic outcome and 41 had an unfavorable neurologic outcome group at hospital discharge. A 24-hour aEEG background score >17 was associated with an unfavorable outcome with a sensitivity of 44%, a specificity of 97%, a positive predictive value of 95%, and a negative predictive value of 57%. In multivariate analysis, 24-hour aEEG background score was associated with unfavorable outcome (hazard ratio, 6.1; p = 0.001; 95% confidence interval, 2.31-16.24). The presence of seizures was not associated with neurologic outcome at hospital discharge. Conclusions Continuous aEEG provides accurate neurologic prognostication in neonates and children supported with ECMO. Early aEEG monitoring may help intensive care unit providers to guide clinical care and family counseling.

The impact of cervical cannulation on neurologic outcome has not been yet studied among children receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) in the context of severe sepsis or septic shock. A retrospective cohort study was performed using the extracorporeal life support organization (ELSO) registry. A total of 559 children weighing less than 20 kg with a primary or secondary diagnosis of severe sepsis, septic shock or toxic shock syndrome were included between January 1, 2010, and December 31, 2019. Cervical cannulation was performed in 485 children (87%) and central cannulation in 74 children (13%). The prevalence of acute neurologic event (ANE) was 32%, including clinical and/or electroencephalographic seizures, cerebral infarction, cerebral hemorrhage, and/or brain death. In multivariable analysis, we did not find an association between cervical cannulation and greater/lesser odds of ANE during ECMO (adjusted odds ratio [aOR] = 1.39, 95% confidence interval [CI] 0.72-2.65; P = 0.326). Only pre-ECMO acidosis was independently associated with the development of ANE (pH < 6.99; aOR = 2.71, 95% CI 1.34-5.49; P = 0.006; pH 6.99 to

OBJECTIVES Diaphragmatic paralysis following congenital cardiac surgery is associated with significant morbidity and mortality. Spontaneous recovery of diaphragmatic function has been described, contrasting with centres providing early diaphragmatic plication. We aimed to describe the outcomes of a conservative approach, as well as to identify factors associated with a failure of the strategy. METHODS This is a retrospective study of patients admitted after cardiac surgery and suffering unilateral diaphragmatic paralysis within 2 French Paediatric Cardiac Surgery Centers. The conservative approach, defined by the prolonged use of ventilation until successful weaning from respiratory support, was the primary strategy adopted in both centres. In case of unsuccessful evolution, a diaphragmatic plication was scheduled. Total ventilation time included invasive and non-invasive ventilation. Diaphragm asymmetry was defined by the number of posterior rib segments counted between the 2 hemi-diaphragms on the chest X-ray after cardiac surgery. RESULTS Fifty-one neonates and infants were included in the analysis. Patients’ median age was 12.0 days at cardiac surgery (5.0–82.0), and median weight was 3.5 kg (2.8–4.9). The conservative approach was successful for 32/51 patients (63%), whereas 19/51 patients (37%) needed diaphragm plication. There was no difference in patients’ characteristics between groups. Respiratory support prolonged for 21 days or more and diaphragm asymmetry more than 2 rib segments were independently associated with the failure of the conservative strategy [odds ratio (OR) 6.9 (1.29–37.3); P = 0.024 and OR 6.0 (1.4–24.7); P = 0.013, respectively]. CONCLUSIONS The conservative approach was successful for 63% of the patients. We identified risk factors associated with the strategy’s failure.

Tumors with microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). To date however, tools for predicting efficacy of these new therapies are lacking. Here we combined high-throughput DNA and RNA sequencing of tumors from 117 patients with MSI mCRC treated with anti-PD-1 +/- anti-CTLA-4 and enrolled into two cohorts, i.e., the NIPICOL clinical trial (NCT03350126) and the ImmunoMSI prospective cohort that were used as discovery and validation cohorts in this ancillary study, respectively. All analyses based on previously suggested DNA/RNA biomarkers of resistance failed to identify robust predictors of treatment response in patients, e.g., the level of MSI, mutational burden, the presence of specific somatic DNA variants as assessed by exome-sequencing and the activity of canonical signaling pathways or the presence of specific cellular contingents within the tumor bulk as estimated by RNA-sequencing. By contrast, resistance to ICI was found to depend both on a small subset of somatic DNA variants located in microsatellite-containing genes with very diverse biological functions and the expression of a stromal-oriented RNA component. Testing of these predictors in 5 large additional independent retrospective and prospective cohorts (IDEA and MOSAIC clinical trials) regrouping 446 patients with nonmetastatic or metastatic MSI CRC untreated with ICI allowed us to validate the specificity of the predictive nature of these indicators regarding ICI-treated MSI mCRC patients. The use of these DNA/RNA predictors will help to refine the ICI-based precision therapy of patients with metastatic MSI mCRC.

Cerebral autoregulation (CA) impairment may pose a risk factor for neurological complications among children supported by extracorporeal membrane oxygenation (ECMO). Our first objective was to investigate the feasibility of CA continuous monitoring during ECMO treatment and to describe its evolution over time. The second objective was to analyze the association between CA impairment and neurological outcome. Observational prospective study. Twenty-nine children treated with veno-arterial or veno-venous ECMO in the PICU of Nantes University Hospital, France, and the PICU of the IRCCS Giannina Gaslini Institute in Genoa, Italy. A correlation coefficient between the variations of regional cerebral oxygen saturation and the variations of mean arterial blood pressure (MAP) was calculated as an index of CA (cerebral oxygenation reactivity index, COx). A COx > 0.3 was considered as indicative of autoregulation impairment. COx—MAP plots were investigated allowing determining optimal MAP (MAPopt) and limits of autoregulation: lower (LLA) and upper (ULA). Neurological outcome was assessed by the onset of an acute neurological event (ANE) after ECMO start. We included 29 children (median age 84 days, weight 4.8 kg). MAPopt, LLA, and ULA were detected in 90.8% (84.3–93.3) of monitoring time. Mean COx was significantly higher during day 1 of ECMO compared to day 2 [0.1 (0.02–0.15) vs. 0.01 (− 0.05 to 0.1), p = 0.002]. Twelve children experienced ANE (34.5%). The mean COx and the percentage of time spent with a COx > 0.3 were significantly higher among ANE+ compared to ANE− patients [0.09 (0.01–0.23) vs. 0.04 (− 0.02 to 0.06), p = 0.04 and 33.3% (24.8–62.1) vs. 20.8% (17.3–23.7) p = 0.001]. ANE+ patients spent significantly more time with MAP below LLA [17.2% (6.5–32.9) vs. 5.6% (3.6–9.9), p = 0.02] and above ULA [13% (5.3–38.4) vs. 4.2% (2.7–7.4), p = 0.004], respectively. CA assessment is feasible in pediatric ECMO. The first 24 h following ECMO represents the most critical period regarding CA. Impaired autoregulation is significantly more severe among patients who experience ANE.

Children supported by extracorporeal membrane oxygenation present a high risk of neurological complications. Although carotid cannulation is known to be associated with neurologic injury, conflicting data exist with regard to the predominance of right- or left-sided lesions. We describe here two infants requiring veno-arterial extracorporeal membrane oxygenation for septic shock who encountered right watershed infarction ipsilateral to carotid artery cannulation. Hemodynamic failure seems to be the most probable underlying mechanism. The asymmetry of transcranial Doppler metrics in one case and the low right regional cerebral oxygen saturation value observed soon after right cannulation in both cases suggest an insufficient cerebral collateral flow compensation. The risk of ipsilateral watershed injury should be considered before cervical cannulation, notably in the context of sepsis and an evaluation of the cerebral collateral blood flow before and just after cannulation may be interesting in order to identify infants with higher risk of ipsilateral ischemic lesions.

OBJECTIVES To assess the ability of amplitude-integrated electroencephalography monitoring within 24 hours of the return of spontaneous circulation to prognosticate neurologic outcomes in children following cardiac arrest DESIGN:: Retrospective review of prospectively recorded data. An amplitude-integrated electroencephalography background score was calculated according to background activity during the first 24 hours after return of spontaneous circulation, a higher score correlating with more impaired background activity. The primary endpoint was the neurologic outcome as defined by the Pediatric Cerebral Performance Category at PICU discharge (Pediatric Cerebral Performance Category 1-3: a good neurologic outcome; Pediatric Cerebral Performance Category 4-6: a poor neurologic outcome). SETTING A referral PICU. PATIENTS Thirty children with a median age of 10 months (2-38 mo) and a male/female sex ratio of 1.3 were included. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Eighteen patients were assigned to the favorable outcome group and 12 to the unfavorable outcome group. The median time between return of spontaneous circulation and amplitude-integrated electroencephalography initiation was 4 hours (3-9 hr). The amplitude-integrated electroencephalography score within 24 hours after return of spontaneous circulation was significantly higher in the children with poor outcomes compared with those with good outcomes (12 ± 4 vs 25 ± 8; p < 0.001). Background activity during amplitude-integrated electroencephalography monitoring was able to predict poor neurologic outcomes at PICU discharge, with an area under the receiver operating characteristic curve of 0.91 (95% CI, 0.81-1.00). CONCLUSIONS Early amplitude-integrated electroencephalography monitoring may help predict poor neurologic outcomes in children within 24 hours following cardiac arrest.

Heat shock proteins (HSPs) play oncogenic roles in human tumours. We reported a somatic inactivating mutation of HSP110 (HSP110DE9) in mismatch repair-deficient (dMMR) cancers displaying microsatellite instability (MSI) but did not assess its impact. We evaluated the impact of the Hsp110DE9 mutation on tumour development and the chemotherapy response in a dMMR knock-in mouse model (Hsp110DE9

OBJECTIVES To describe the frequency and outcomes on the use of extracorporeal membrane oxygenation (ECMO) among critically ill neonates and children within a structured pediatric critical care network in the West of France. To assess the optimality of decision-making process for patients primarily admitted in non-ECMO centers. DESIGN Observational prospective population-based study from January 2015 to December 2019. PATIENTS Neonates over 34 weeks of gestational age, weighing more than 2,000 g and children under 15 years and 3 months old admitted in one of the 10 units belonging to a Regional Pediatric Critical Care Network. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Eight-thousand one hundred eighty-nine children and 3,947 newborns were admitted within one of the 10 units of the network over the study period. Sixty-five children (8.1% [95% CI, 6.2-10‰]) and 35 newborns (9.4% [95% CI, 6.4-12%]) required ECMO support. Of these patients, 31 were first admitted to a non-ECMO center, where 20 were cannulated in situ (outside the regional ECMO center) and 11 after transfer to the ECMO regional center. Cardiogenic shock, highest serum lactate level, and cardiac arrest prior to first phone call with the regional ECMO center were associated with higher rate of in situ cannulation. During the study period, most of the patients were cannulated for underlying cardiac issue (42/100), postoperative cardiac surgery instability (38/100), and pediatric (10/100) and neonatal (10/100) respiratory distress syndrome. Patients primarily admitted in non-ECMO centers or not had similar 28-day post-ICU survival rates compared with those admitted in the referral ECMO center (58% vs 51%; p = 0.332). Pre-ECMO cardiac arrest, ECMO, and lower pH at ECMO onset were associated with lower 28-day post-ICU survival. CONCLUSIONS Our local results suggest that a structured referral network for neonatal and pediatric ECMO in the region of Western France facilitated escalation of care with noninferior (or similar) early mortality outcome. Our data support establishing referral networks in other equivalent regions.

Background & Aims Next-generation sequencing (NGS) was recently approved by the United States Food and Drug Administration to detect microsatellite instability (MSI) arising from defective mismatch repair (dMMR) in patients with metastatic colorectal cancer (mCRC) before treatment with immune checkpoint inhibitors (ICI). In this study, we aimed to evaluate and improve the performance of NGS to identify MSI in CRC, especially dMMR mCRC treated with ICI. Methods CRC samples used in this post hoc study were reassessed centrally for MSI and dMMR status using the reference methods of pentaplex polymerase chain reaction and immunohistochemistry. Whole-exome sequencing (WES) was used to evaluate MSISensor, the Food and Drug Administration-approved and NGS-based method for assessment of MSI. This was performed in (1) a prospective, multicenter cohort of 102 patients with mCRC (C1; 25 dMMR/MSI, 24 treated with ICI) from clinical trials NCT02840604 and NCT033501260, (2) an independent retrospective, multicenter cohort of 113 patients (C2; 25 mCRC, 88 non-mCRC, all dMMR/MSI untreated with ICI), and (3) a publicly available series of 118 patients with CRC from The Cancer Genome Atlas (C3; 51 dMMR/MSI). A new NGS-based algorithm, namely MSICare, was developed. Its performance for assessment of MSI was compared with MSISensor in C1, C2, and C3 at the exome level or after downsampling sequencing data to the MSK-IMPACT gene panel. MSICare was validated in an additional retrospective, multicenter cohort (C4) of 152 patients with new CRC (137 dMMR/MSI) enriched in tumors deficient in MSH6 (n = 35) and PMS2 (n = 9) after targeted sequencing of samples with an optimized set of microsatellite markers (MSIDIAG). Results At the exome level, MSISensor was highly specific but failed to diagnose MSI in 16% of MSI/dMMR mCRC from C1 (4 of 25; sensitivity, 84%; 95% confidence interval [CI], 63.9%–95.5%), 32% of mCRC (8 of 25; sensitivity, 68%; 95% CI, 46.5%–85.1%), and 9.1% of non-mCRC from C2 (8 of 88; sensitivity, 90.9%; 95% CI, 82.9%–96%), and 9.8% of CRC from C3 (5 of 51; sensitivity, 90.2%; 95% CI, 78.6%–96.7%). Misdiagnosis included 4 mCRCs treated with ICI, of which 3 showed an overall response rate without progression at this date. At the exome level, reevaluation of the MSI genomic signal using MSICare detected 100% of cases with true MSI status among C1 and C2. Further validation of MSICare was obtained in CRC tumors from C3, with 96.1% concordance for MSI status. Whereas misdiagnosis with MSISensor even increased when analyzing downsampled WES data from C1 and C2 with microsatellite markers restricted to the MSK-IMPACT gene panel (sensitivity, 72.5%; 95% CI, 64.2%–79.7%), particularly in the MSH6-deficient setting, MSICare sensitivity and specificity remained optimal (100%). Similar results were obtained with MSICare after targeted NGS of tumors from C4 with the optimized microsatellite panel MSIDIAG (sensitivity, 99.3%; 95% CI, 96%–100%; specificity, 100%). Conclusions In contrast to MSISensor, the new MSICare test we propose performs at least as efficiently as the reference method, MSI polymerase chain reaction, to detect MSI in CRC regardless of the defective MMR protein under both WES and targeted NGS conditions. We suggest MSICare may rapidly become a reference method for NGS-based testing of MSI in CRC, especially in mCRC, where accurate MSI status is required before the prescription of ICI.

Assessment of the quality of initial care is necessary to target priority actions that can reduce the still high morbidity and mortality due to community-onset severe bacterial infections (COSBIs) among children.To study the prevalence, characteristics, and determinants of suboptimal care in the initial management of COSBIs.This prospective, population-based, cohort study and confidential enquiry was conducted between August 2009 and January 2014 in western France, a region accounting for 15% of the French pediatric population (1 968 474 children aged 1 month to 16 years) and including 6 pediatric intensive care units (PICUs) and 35 emergency departments. Participants included all children aged 1 month to 16 years who died before PICU admission or were admitted to a PICU with a COSBI (ie, bacterial sepsis, including meningitis, purpura fulminans, and pulmonary, osteoarticular, intra-abdominal, cardiac, and soft-tissue severe infections). Data were analyzed from March to June 2020.Suboptimal care determined according to evaluation of 8 types of care: (1) the delay in seeking care by family, (2) the physician's evaluation of severity, (3) the patient's referral at the first consultation with signs of severity, (4) the timing and (5) dosage of antibiotic treatment, (6) the timing and (7) volume of fluid bolus administration, and (8) the clinical reassessment after fluid bolus.Two experts assessed the quality of care before death or PICU admission as optimal, possibly suboptimal, or certainly suboptimal. The consequences and determinants of certainly suboptimal care were identified with multinomial logistic regression and generalized linear mixed models.Of the 259 children included (median [IQR] age, 24 [6-66] months; 143 boys [55.2%]), 27 (10.4%) died, and 25 (9.6%) had severe sequelae at PICU discharge. The quality of care was certainly suboptimal in 89 cases (34.4%). Suboptimal care was more frequent in children with sequelae (adjusted odds ratio [aOR], 5.61; 95% CI, 1.19-26.36) and less frequent in children who died (aOR, 0.16; 95% CI, 0.04-0.65) vs those surviving without sequelae. Factors independently associated with suboptimal care were age younger than 5 years (aOR, 3.15; 95% CI, 1.25-7.90), diagnosis of sepsis with no source (aOR, 5.77; 95% CI, 1.64-20.30) or meningitis (aOR, 3.39; 95% CI, 1.15-9.96) vs other severe infections, and care by a primary care physician (aOR, 3.22; 95% CI, 1.17-8.88) vs a pediatric hospital service.This study found that suboptimal care is frequent in the initial management of COSBI and is associated with severe sequelae. The paradoxical association with reduced risk of death may be explained by an insufficient adjustment on bacterial or host intrinsic factors. Management could be optimized by improving the quality of primary care, especially for young children.

Cerebral autoregulation (CA) impairment is associated with neurological complications among children supported by extracorporeal membrane oxygenation (ECMO). Severe variations of arterial CO2 (PaCO2) and O2 (PaO2) tension after ECMO onset are common and associate with mortality and poor neurological outcome. The impact of gas exchange on CA among critically ill patients is poorly studied. Retrospective analysis of data collected prospectively from 30 children treated with veno-arterial or veno-venous ECMO in the PICU of Nantes University Hospital, France. A correlation coefficient between the variations of regional cerebral oxygen saturation (rSO2) and the variations of mean arterial blood pressure (MAP) was calculated as an index of CA (cerebral oxygenation reactivity index, COx). Cox–MAP plots were investigated allowing determining lower limit of autoregulation (LLA) and upper limit of autoregulation (ULA) limits of autoregulation. Age-based normal blood pressure was used to adjust the MAP, LLA, and ULA data from each patient and then reported as percentage (nMAP, nLLA, and nULA, respectively). RSO2, COx, nMAP, nLLA, and nULA values were averaged over one hour before each arterial blood gas (ABG) sample during ECMO run. Thirty children (median age 4.8 months [Interquartile range (IQR) 0.7–39.1], median weight 5 kg [IQR 4–15]) experiencing 31 ECMO runs were included in the study. Three hundred and ninety ABGs were analyzed. The highest values of COx were observed on day 1 (D1) of ECMO. The relationship between COx and PaCO2 was nonlinear, but COx values tended to be lower in case of hypercapnia compared to normocapnia. During the whole ECMO run, a weak but significant correlation between PaCO2 and nULA was observed (R = 0.432, p = 0.02). On D1 of ECMO, this correlation was stronger (R = 0.85, p = 0.03) and a positive correlation between nLLA and PaCO2 was also found (R = 0.726, p

Background To assess the feasibility and early outcome of continuous cerebral and myocardial selective perfusion (CCMSP) during aortic arch surgery in neonates. Methods We performed a single-center retrospective study between 2008 and 2019 on neonates who underwent aortic arch surgery with or without associated heart lesion repair. CCMSP with moderate hypothermia levels (28°C) was achieved using selective brachiocephalic artery and ascending aorta cannulation. Target rates of cerebral and myocardial perfusion were 25 to 35 mL/kg/min and 150 ml/m2/min. Cardiopulmonary bypass (CPB) variables and clinical outcomes were analyzed. Results Overall, 69 neonates underwent either isolated aortic arch repair (n = 31) or aortic arch repair with ventricular septal defect (VSD) closure (n = 38). Age and weight medians were 8 [6 to 15] days and 3.4 [2.9-3.5] kg, respectively. Mean CPB and aortic clamping times were 134 ± 47 and 26 ± 5 minutes for isolated aortic arch repair, and 159 ± 47 and 75 ± 30 minutes for aortoplasty accompanied by VSD closure. Mean CCMSP time was 52 ± 21 minutes with cerebral rate of 32.6 ± 10 mL·kg-1 ·min-1 . Overall in hospital survival was 98.5% (68/69). Major complications were: postoperative cardiac failure requiring mechanical support followed by stroke (n = 1; 1.44%) and transient renal failure requiring dialysis (n = 2; 2.89%). Neither myocardial nor digestive complication occurred. Conclusion CCMSP is a safe and reproducible strategy for cerebral, myocardial and visceral protection in neonatal aortic arch repair, with or without VSD closure, resulting in low complication and mortality.

Cerebral autoregulation (CA) impairment may pose a risk factor for neurological complications among children supported by extracorporeal membrane oxygenation (ECMO). Our first objective was to investigate the feasibility of CA continuous monitoring during ECMO treatment and to describe its evolution over time. The second objective was to analyze the association between CA impairment and neurological outcome.Observational prospective study.Twenty-nine children treated with veno-arterial or veno-venous ECMO in the PICU of Nantes University Hospital, France, and the PICU of the IRCCS Giannina Gaslini Institute in Genoa, Italy.A correlation coefficient between the variations of regional cerebral oxygen saturation and the variations of mean arterial blood pressure (MAP) was calculated as an index of CA (cerebral oxygenation reactivity index, COx). A COx 0.3 was considered as indicative of autoregulation impairment. COx-MAP plots were investigated allowing determining optimal MAP (MAPopt) and limits of autoregulation: lower (LLA) and upper (ULA). Neurological outcome was assessed by the onset of an acute neurological event (ANE) after ECMO start.We included 29 children (median age 84 days, weight 4.8 kg). MAPopt, LLA, and ULA were detected in 90.8% (84.3-93.3) of monitoring time. Mean COx was significantly higher during day 1 of ECMO compared to day 2 [0.1 (0.02-0.15) vs. 0.01 (- 0.05 to 0.1), p = 0.002]. Twelve children experienced ANE (34.5%). The mean COx and the percentage of time spent with a COx 0.3 were significantly higher among ANE+ compared to ANE- patients [0.09 (0.01-0.23) vs. 0.04 (- 0.02 to 0.06), p = 0.04 and 33.3% (24.8-62.1) vs. 20.8% (17.3-23.7) p = 0.001]. ANE+ patients spent significantly more time with MAP below LLA [17.2% (6.5-32.9) vs. 5.6% (3.6-9.9), p = 0.02] and above ULA [13% (5.3-38.4) vs. 4.2% (2.7-7.4), p = 0.004], respectively.CA assessment is feasible in pediatric ECMO. The first 24 h following ECMO represents the most critical period regarding CA. Impaired autoregulation is significantly more severe among patients who experience ANE.

Objectives To describe the epidemiology of community-onset severe bacterial infections in children and its recent evolution. Design Prospective, observational, population-based study from 2009 to 2014. Setting An administrative area accounting for 13% of the French pediatric population. Patients All children 1 month to 16 years old who died before admission or were admitted to a PICU for a community-onset severe bacterial infection. Interventions None. Measurements and main results The incidence and mortality rate of community-onset severe bacterial infections were compared with data from a reference population-based study conducted between 2000 and 2006, that is, before national recommendations for antimeningococcal C and antipneumococcal generalized vaccinations. Among the 261 children included (median age 25 mo), 28 (10.7%) died. The main diagnoses were meningitis (n = 85; 32%) and purpura fulminans (n = 59; 22%). The most common isolated bacteria were Neisseria meningitidis (n = 75; 29%), including 47 (63%) cases of serogroup B and 15 (20%) serogroup C, Streptococcus pneumoniae (n = 49, 19%), and Staphylococcus aureus (n = 15; 6%). The incidence of community-onset severe bacterial infections was three per 100,000 person-years (95% CI, 2.6-3.3) and had decreased by 53% from the reference period. Mortality rate was 0.3 per 100,000 person-years (95% CI, 0.2-0.4) and had decreased by 73% from the reference period. The incidence of community-onset severe bacterial infections caused by N. meningitidis and S. pneumoniae was 0.8 and 0.5 per 100,000 person-years and had decreased by 70% and 67% from the reference period. The incidence of community-onset severe bacterial infections-related to Staphylococcus aureus was 0.16 per 100,000 person-years and had increased by 220% from the reference period. Conclusions The incidence and mortality rate of community-onset severe bacterial infections, except for S. aureus infection, have decreased in France. N. meningitidis and S. pneumoniae continue to account for many infections, which indicates the need for better vaccination coverage and spectrum.

Purposes Amplitude-integrated EEG (aEEG) has been widely developed in neonatal intensive care unit, but few studies focused on pediatric intensive care unit. Furthermore, reliability of aEEG under real-life conditions is unknown. Methods Participants were nurses from a 12-bed pediatric intensive care unit in a referral university hospital in France. Amplitude EEG was implemented after standardized training, including e-learning course, individual feedback and bedside teaching concerning monitoring installation, background classification patterns recognition, artefact analysis, and seizure detection. The primary judgment criterion was the agreement (Cohen Kappa) between nurses and aEEG experts for the detection of abnormal aEEG traces (moderately or severely altered background pattern according to Hellstrom-Westas classification and/or seizure activity). Results During the study period, 196 consecutives traces from 79 patients were analyzed by 51 nurses. According to expert's classification, 53% of traces were abnormal, including 17.5% of severely abnormal traces (severely altered traces and/or seizure activity) and 14% exhibiting seizure activity. Moderate agreement between experts and nurses was found for detection of any abnormal trace (k = 0.53; 95% confidence interval [CI]: 0.39-0.67). Substantial agreement was found for severely altered traces (k = 0.71; 95% CI: 0.57-0.85). Finally, fair agreement was found for seizure detection (irrespective of background classification, k = 0.40; 95% CI: 0.25-0.54). Conclusions These results suggest that aEEG monitoring may be implemented in routine nursing care in pediatric intensive care unit. Further training courses are needed to enhance nurses' skill in detecting seizures activity at the bedside.

Background In a context of suboptimal vaccination coverage and increasing vaccine hesitancy, we aimed to study morbidity and mortality in children related to missing or incomplete meningococcal C and pneumococcal conjugate vaccines. Methods We conducted a prospective, observational, population-based study from 2009 to 2014 in a French administrative area that included all children from age 1 month to 16 years who died before admission or were admitted to an intensive care unit for a community-onset bacterial infection. Vaccine-preventable infection was defined as an infection with an identified serotype included in the national vaccine schedule at the time of infection and occurring in a non- or incompletely vaccinated child. Death and severe sequelae were studied at hospital discharge. Frequencies of vaccine-preventable morbidity and mortality caused by meningococcus and pneumococcus were calculated. Results Among the 124 children with serotyped meningococcal (n = 75) or pneumococcal (n = 49) severe infections included (median age 26 months), 20 (16%) died and 12 (10%) had severe sequelae. Vaccine-preventable infections accounted for 18/124 infections (15%, 95% CI 9, 22), 5/20 deaths (25%, 95% CI 9, 49), and 3/12 severe sequelae cases (25%, 95% CI 0, 54). The vaccine schedule for meningococcal C and pneumococcal conjugate vaccinations was incomplete for 71/116 (61%) children targeted by at least one of these two vaccination programs. Conclusions Mortality and morbidity rates related to vaccine-preventable meningococcal or pneumococcal infection could be reduced by one quarter with better implementation of immunisation programs. Such information could help enhance the perception of vaccine benefits and fight vaccine hesitancy.

Pancreatic ductal adenocarcinoma (PDAC) is still the poorest prognostic tumor of the digestive system. We investigated the antitumoral role of orexin-A and almorexant in PDAC. We analyzed the orexin receptor type 1 (OX1R) expression by immunohistochemistry in human normal pancreas, PDAC and its precursor dysplastic intraepithelial lesions. We used PDAC-derived cell lines and fresh tissue slices to study the apoptotic role of hypocretin-1/orexin-A and almorexant in vitro and ex vivo. We analyzed in vivo the hypocretin-1/orexin-A and almorexant effect on tumor growth in mice xenografted with PDAC cell lines expressing, or not, OX1R. Ninety-six percent of PDAC expressed OX1R, while adjacent normal exocrine pancreas did not. OX1R was expressed in pre-cancerous lesions. In vitro, under hypocretin-1/orexin-A and almorexant, the OX1R-positive AsPC-1 cells underwent apoptosis, abolished by the tyrosine phosphatase SHP2 inhibitor, NSC-87877, whereas the OX1R-negative HPAF-II cell line did not. These effects were mediated by phosphorylation of OX1R and recruitment of SHP2. Ex vivo, caspase-3 positive tumor cells were significantly higher in fresh tumour slices treated 48h with hypocretin-1/orexin-A, as compared to control, whereas cellular proliferation, assessed by Ki-67 index, was not modified. In vivo, when AsPC-1 cells or patient-derived cells were xenografted in nude mice, hypocretin-1/orexin-A or almorexant, administrated both starting the day of cell line inoculation or after tumoral development, strongly slowed tumor growth. Hypocretin-1/orexin-A and almorexant induce, through OX1R, the inhibition of PDAC cellular growth by apoptosis. Hypocretins/orexins and almorexant might be powerful candidates for the treatment of PDAC.

Monocytic human leukocyte antigen DR (mHLA-DR) expression levels have been reported to be a marker of immunosuppression and a predictor of sepsis and mortality. There are, however, scant data regarding mHLA-DR monitoring in young infants after cardiopulmonary bypass. Our objectives were to investigate the kinetics of mHLA-DR expression and to determine whether mHLA-DR levels are associated with healthcare-associated infection (HAI) after cardiopulmonary bypass in young infants.mHLA-DR levels were analyzed by flow cytometry using a standardized method in 49 infants (3 months old) with congenital heart disease before and after cardiopulmonary bypass. Results are expressed as the number of anti-HLA-DR antibodies per cell (AB/c).Postoperative mHLA-DR expression was reduced in all infants. Eleven patients (22%) developed HAI, and 4 patients (8%) died during the 30-day follow-up. mHLA-DR expression was significantly lower on postoperative day 4 in the HAI group compared with those who without HAI (3768 AB/c [range, 1938-6144] vs 13,230 AB/c [range, 6152-19,130], P = .014). Although mHLA-DR expression was associated with postoperative severity, mHLA-DR ≤4500 AB/c in the first 72 hours among patients with higher postoperative severity (extracorporeal membrane oxygenation and/or corticoids and/or delayed closure of sternum) was associated with occurrence of HAI in the univariate analysis (odds ratio, 6.3; 95% confidence interval, 1.0-38.7; P = .037).Cardiopulmonary bypass induces a profound decrease in mHLA-DR expression in young infants. Among patients with higher postoperative severity, low level of mHLA-DR in the early postoperative period is associated with the development of HAI.

This conceptual paper briefly summarizes some of the important developments in the research on teaching conceptions and outline some key questions for moving forward with improving teaching and learning in higher education. It argues that the confusion and controversies found in social science research may be resolved using an integral approach and uses principles outlined in Ken Wilber’s integral methodological pluralism (IMP) to attempt a multi-perspectival framework for research into teaching conceptions. IMP offers a (broadly) scientific framework that goes beyond the unprincipled eclecticism that plagues many other integrative and multi-methodological approaches. Although not representing a fully comprehensive view of integral methodological pluralism, three major research perspectives are looked at to determine how they can give rise to complementary aspects of teaching beliefs and actions. More analytically, in this case study we see the world as having four ontologically differentiated dimensions, demarked conceptually by quadrants which distinguish the internal-external aspects of reality on one side, and its individual-collective aspects on the other. Thus, there are subjective/intentional (1st person), objective/behavioral (3rd person), intersubjective/cultural (2nd person) and inter-objective/social (3rd person “plural”) aspects of reality. The study applied a variety of perspectives to an inquiry into teaching conceptions. From a 3rd person perspective, an objective measure of teaching conceptions and teaching practices could arise from administering a recognized teaching conceptions survey and observing lessons. Follow-up interviews could take a 1st person perspective to unearth the meanings individual instructors associated with their observed lesson, the survey, and their experience in the institution as a whole. A 2nd person, participatory perspective could engage participants in a project to effect positive change in their context. Subsequently, observing whether changes occurred by reusing initial 3rd person objective measures may reveal changes and inspire further research. For a more integral approach, investigation into the lower-right quadrant (objectively knowable systems) could provide additional context. This could mainly be done through documentary analysis of rules, policies, procedures and examination of other artifacts (e.g. educational technologies) relevant to teaching conceptions and practices within the case of interest. The observation policy co-developed in the participatory action research phase of this case study could contribute to such data. The research approach presented in this paper has implications for researchers from a wide variety of fields interested in interdisciplinary and integrative methodologies.

e15537 Background: Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic TRK ( NTRK) fusion-driven cancers, regardless of tumor histotype or cell of origin. NTRK gene fusions are observed in less than 1% of colorectal cancers (CRCs). CRCs harboring wild-type BRAF and KRAS and MisMatch Repair deficiency (dMMR)/MicroSatellite Instability (MSI) due to MLH1 hypermethylation have been associated with NTRK fusions in small cohorts of non-metastatic tumors. We aimed at evaluating the incidence of NTRK fusions among dMMR/MSI metastatic CRCs (mCRC) for which there is a need for innovative therapies, as well as the associated clinical characteristics of these patients (pts) carrying NTRK fusion-positive tumors. Methods: Tumor samples of dMMR/MSI mCRC pts, paired primary and metastasis or primary alone, were obtained from a French multicenter retrospective cohort and from a single-center cohort of patients treated by immune checkpoint inhibitors (ICI) (Saint-Antoine Hospital, Paris). Clinico-pathological data including KRAS and BRAFV600E status, MMR proteins and MLH1 methylation status were available for all pts. All samples were screened for TRK expression by immunohistochemistry (IHC) using a pan-TRK antibody (clone EPR17341, Abcam; positivity: 1% of labeled tumor cells)) and for NTRK1 and NTRK3 gene rearrangements, by fluorescent in situ hybridation (FISH). A threshold of 15% nuclei positive for a break apart signal was considered positive for gene rearrangement. Results: A total of 158 pts with dMMR/MSI mCRCs (paired samples: n=39; primary only: n=119) were screened. Tumor samples of 10 patients (6.3%) harbored NTRK fusion genes by FISH ( NTRK1=8; NTRK3=2). Only four of these 10 patients had TRK immunoreactivity. One patient showed a discordance between metastasis harboring NTRK1 fusion (+) and primary tumor being negative. Eight tumors were sporadic with MLH1 hypermethylation. The remaining 2 cases were related to a MMR gene germline mutation (Lynch syndrome) with concurrent loss of MSH2 and MSH6 expression and isolated loss of MSH6 respectively. One Lynch-related tumor was KRAS mutated, one sporadic MLH1-negative tumor was BRAF V600E mutated. Four patients out of 91 treated by ICI had tumors with NTRK fusions. Three have shown radiological response according to iRECIST criteria (two complete responses, one partial response with 25 to 54 months of follow up) and one had primary resistance to ICI. Conclusions: Frequency of NTRK1/3 fusions is 6.3% in our dMMR/MSI mCRCs population. These fusions are not restricted to sporadic cases. The diagnostic accuracy of pan-TRK IHC is low. Optimal testing algorithms for theragnostics remain to be defined in this setting.

Summary Background Paediatric acute respiratory distress syndrome (PARDS) is associated with high mortality in children, but until recently no paediatric-specific diagnostic criteria existed. The Pediatric Acute Lung Injury Consensus Conference (PALICC) definition was developed to overcome limitations of the Berlin definition, which was designed and validated for adults. We aimed to determine the incidence and outcomes of children who meet the PALICC definition of PARDS. Methods In this international, prospective, cross-sectional, observational study, 145 paediatric intensive care units (PICUs) from 27 countries were recruited, and over a continuous 5 day period across 10 weeks all patients were screened for enrolment. Patients were included if they had a new diagnosis of PARDS that met PALICC criteria during the study week. Exclusion criteria included meeting PARDS criteria more than 24 h before screening, cyanotic heart disease, active perinatal lung disease, and preparation or recovery from a cardiac intervention. Data were collected on the PICU characteristics, patient demographics, and elements of PARDS (ie, PARDS risk factors, hypoxaemia severity metrics, type of ventilation), comorbidities, chest imaging, arterial blood gas measurements, and pulse oximetry. The primary outcome was PICU mortality. Secondary outcomes included 90 day mortality, duration of invasive mechanical and non-invasive ventilation, and cause of death. Findings Between May 9, 2016, and June 16, 2017, during the 10 study weeks, 23 280 patients were admitted to participating PICUs, of whom 744 (3·2%) were identified as having PARDS. 95% (708 of 744) of patients had complete data for analysis, with 17% (121 of 708; 95% CI 14–20) mortality, whereas only 32% (230 of 708) of patients met Berlin criteria with 27% (61 of 230) mortality. Based on hypoxaemia severity at PARDS diagnosis, mortality was similar among those who were non-invasively ventilated and with mild or moderate PARDS (10–15%), but higher for those with severe PARDS (33% [54 of 165; 95% CI 26–41]). 50% (80 of 160) of non-invasively ventilated patients with PARDS were subsequently intubated, with 25% (20 of 80; 95% CI 16–36) mortality. By use of PALICC PARDS definition, severity of PARDS at 6 h after initial diagnosis (area under the curve [AUC] 0·69, 95% CI 0·62–0·76) discriminates PICU mortality better than severity at PARDS diagnosis (AUC 0·64, 0·58–0·71), and outperforms Berlin severity groups at 6 h (0·64, 0·58–0·70; p=0·01). Interpretation The PALICC definition identified more children as having PARDS than the Berlin definition, and PALICC PARDS severity groupings improved the stratification of mortality risk, particularly when applied 6 h after PARDS diagnosis. The PALICC PARDS framework should be considered for use in future epidemiological and therapeutic research among children with PARDS. Funding University of Southern California Clinical Translational Science Institute, Sainte Justine Children's Hospital, University of Montreal, Canada, Reseau en Sante Respiratoire du Fonds de Recherche Quebec-Sante, and Children's Hospital Los Angeles, Department of Anesthesiology and Critical Care Medicine.

International audience; Monocyte HLA-DR expression has been reported as a marker of immunosuppression and a predictor of sepsis development. However, to date, there is no report on monocyte HLA-DR monitoring exclusively in neonates (

BACKGROUND: Recent findings suggest that using alveolar PCO2 (PACO2) estimated by volumetric capnography in the Bohr equation instead of PaCO2 (Enghoff modification) could be appropriate for the calculation of physiological dead space to tidal volume ratio (VD/VT Bohr and VD/VT Enghoff, respectively). We aimed to describe the relationship between these 2 measurements in mechanically ventilated children and their significance in cases of ARDS. METHODS: From June 2013 to December 2013, mechanically ventilated children with various respiratory conditions were included in this study. Demographic data, medical history, and ventilatory parameters were recorded. Volumetric capnography indices (NM3 monitor) were obtained over a period of 5 min preceding a blood sample. Bohr9s and Enghoff9s dead space, S2 and S3 slopes, and the S2/S3 ratio were calculated breath-by-breath using dedicated software (FlowTool). This study was approved by Ste-Justine research ethics review board. RESULTS: Thirty-four subjects were analyzed. Mean VD/VT Bohr was 0.39 ± 0.12, and VD/VT Enghoff was 0.47 ± 0.13 (P = .02). The difference between VD/VT Bohr and VD/VT Enghoff was correlated with PaO2/FIO2 and with S2/S3. In subjects without lung disease (PaO2/FIO2 ≥ 300), mean VD/VT Bohr was 0.36 ± 0.11, and VD/VT Enghoff was 0.39 ± 0.11 (P = .056). Two children with status asthmaticus had a major difference between VD/VT Bohr and VD/VT Enghoff in the absence of a low PaO2/FIO2. CONCLUSIONS: This study suggests that VD/VT Bohr and VD/VT Enghoff are not different when there is no hypoxemia (PaO2/FIO2 > 300) except in the case of status asthmaticus. In subjects with a low PaO2/FIO2, the method to measure VD/VT must be reported, and results cannot be easily compared if the measurement methods are not the same.

International audience; Objectives: To evaluate the impact of a nurse-driven sedation protocol on the length of mechanical ventilation, total daily doses of sedatives, and complications of sedation. Design: A single-center prospective before and after study was conducted from October 2010 to December 2013. Setting: Twelve-bed surgical and medical PICU of the university-affiliated hospital in Nantes, France. Patients: A total of 235 patients, between 28 days and 18 years old, requiring mechanical ventilation for at least 24 hours were included in the study; data from 194 patients were analyzed. Interventions: During the first study phase, no protocol was used. During the second phase, patients were sedated according to a nurse-driven protocol. Measurements and Main Results: In the whole population, the length of mechanical ventilation did not differ between protocol and control groups (protocol, 4 [3-8] vs control, 5 [3-7.5]; p = 0.44). Analyzing age subgroups, the length of mechanical ventilation was significantly shorter in the protocol group than in the control group in children older than 12 months (4 [3-8] vs 5 [2.75-11.25] d; p = 0.04). Daily dose of midazolam decreased during the protocol phase compared with the control phase (1 [0.56-1.8] and 1.2 [0.85-2.4] mg/kg/d, respectively; p = 0.02). No differences were shown regarding other daily dose of drugs. In the control group, 68% of children had more than 20% of COMFORT-behavior scale assessment under the target (oversedation) versus 59% in the protocol group (p = 0.139).

Objectives The aim of our pilot study was to develop a model to better predict Paco2 in mechanically ventilated children using noninvasive parameters including volumetric capnography. Design Prospective clinical pilot study. Setting Level III PICU. Patients Sixty-five mechanically ventilated children. Interventions None. Materials and methods We conducted a prospective clinical pilot study that included all children admitted to the PICU ( 3 kg; mechanically ventilated, > 6 hr; with an arterial line). A predictive model for PaCO2 was developed using linear multivariable regression. Among the data collected in PICU patients, candidate predictors of PaCO2 were defined by a panel of experts and included end-tidal partial pressure of carbon dioxide, ventilation parameters, and data resulting from the analysis of volumetric capnogram recorded 5 minutes before an arterial blood gas. Children with tidal volume less than 30 mL were excluded because of technical limits. Results A total of 65 children (43 boys, 65%) (65 [21-150] mo old) were analyzed. By linear multivariable regression, the best model included the mean airway pressure, end-tidal partial pressure of carbon dioxide, FIO2, and the capnographic index with an R equal to 0.90, p value less than 0.001. After correction, 95% (n = 62) of children had an estimated PaCO2 at ± 5 mm Hg. Conclusion Our model developed provides an accurate estimation of the PaCO2 using end-tidal CO2 and noninvasive variables. Studies are needed to validate the equation in PICUs.

Studies suggest that metformin, widely used for treating Type 2 diabetes, possesses innate antineoplastic properties. For metabolic syndrome patients with hepatocellular carcinoma (HCC), metformin may provide antitumoral effects. We evaluated the impact of metformin on tumour growth and visceral fat composition using relevant preclinical models of metabolic syndrome. Studies were performed in three hepatoma cell lines, in HepG2 xenograft mice fed with standard chow (SC) diet, 60% high-fat diet (HFD) or 30% fructose diet (FR), and an ex vivo model of human cultured HCC slices. Visceral fatty acid composition was analysed by magnetic resonance imaging (MRI). Metformin had a dose-dependent inhibitory effect on cell proliferation and apoptosis in vitro through the deregulation of mTOR/AMPK, AKT and extracellular signal regulated kinase (ERK) signalling pathways. Tumour engraftment rates were higher in HFD mice than SC mice (hepatic: 79% compared with 25%, P=0.02) and FR mice (subcutaneous: 86% compared with 50%, P=0.04). Subcutaneous tumour volume was increased in HFD mice (+64% compared with FR and SC, P=0.03). Metformin significantly decreased subcutaneous tumour growth via cell-cycle block and mammalian target of rapamycin (mTOR) pathway inhibition, and also induced hypoxia and decreased angiogenesis. In ex vivo tumour slices, metformin treatment led to increased necrosis, decreased cyclin D1 and increased carbonic anhydrase-9 (CA-9). Metformin caused qualitative changes in visceral fat composition of HFD mice, with decreased proportions of polyunsaturated fatty acids (14.6% ± 2.3% compared with 17.9% ± 3.0%, P=0.04). The potent antitumoral effects of metformin in multiple preclinical models implicating several molecular mechanisms provide a strong rationale for clinical trials including combination studies in HCC patients.

In a previous behavioral study, it was shown that early blind individuals were superior to sighted ones in discriminating two-dimensional (2D) tactile angle stimuli. The present study was designed to assess the neural substrate associated with a haptic 2D angle discrimination task in both sighted and blind individuals. Subjects performed tactile angle size discriminations in order to investigate whether the pattern of crossmodal occipital recruitment was lateralized as a function of the stimulated hand. Task-elicited activations were also compared across different difficulty levels to ascertain the potential modulatory role of task difficulty on crossmodal processing within occipital areas. We show that blind subjects had more widespread activation within the right lateral and superior occipital gyri when performing the haptic discrimination task. In contrast, the sighted activated the left cuneus and lingual gyrus more so than the blind when performing the task. Furthermore, activity within visual areas was shown to be predictive of tactile discrimination thresholds in the blind, but not in the sighted. Activity within parietal and occipital areas was modulated by task difficulty, where the easier angle comparison elicited more focal occipital activity along with bilateral posterior parietal activity, whereas the more difficult comparison produced more widespread occipital activity combined with reduced parietal activation. Finally, we show that crossmodal reorganization within the occipital cortex of blind individuals was primarily right lateralized, regardless of the stimulated hand, supporting previous evidence for a right-sided hemispheric specialization of the occipital cortex of blind individuals for the processing of tactile and haptic inputs.

International audience

Introduction L’implementation des vaccins pneumococcique conjugue et meningococcique a transforme l’epidemiologie des infections bacteriennes severes (IBS) communautaires de l’enfant dans les pays avec une economie avancee. Dans un contexte national de forte hesitation vaccinale et de faibles taux de couverture vaccinale, notre objectif etait d’etudier pour la premiere fois en population l’evolution de cette epidemiologie en France. Materiels et methodes Une etude prospective en population a inclus tous les enfants âges de 1 mois a 16 ans admis en reanimation pediatrique ou decedes avant l’admission dans un contexte d’IBS communautaire entre 2009 et 2014 sur un territoire representant 13 % de la population pediatrique francaise. Les bacteries isolees ont ensuite ete comparees, pour le sous-groupe des enfants âges de 3 mois a 16 ans, a celles d’une etude en population menee entre 2000 et 2006, c’est-a-dire avant les recommandations pour la vaccination antipneumococcique generalisee et la vaccination anti-meningococcique C, dans 2 departements de cette region. Resultats Chez les 262 enfants inclus (âge median 25 mois), les diagnostics principaux etaient : meningite (n = 85, 32 %), purpura fulminans (n = 59, 22 %), choc sans origine identifiee (n = 44, 17 %) et pneumopathie hypoxemiante avec ou sans epanchement (n = 41, 16 %). Les bacteries les plus frequemment isolees etaient le meningocoque (n = 75, 29 %), dont 63 % du serogroupe B (n = 47/75) et 20 % du serogroupe C (n = 15/75), le pneumocoque (n = 49, 19 %) dont 31 % (n = 15/49) avec un serotype vaccinal (inclus dans le PCV-13), 31 % (n = 15/49) avec un serotype non vaccinal et 38 % (n = 19/49) avec un serotype non connu, et S. aureus (n = 15, 6 %). En comparaison a la periode de reference pour le sous-groupe des enfants âges de 3 mois a 16 ans, la proportion d’infections a meningocoque est passee de 47 % (n = 54/114) a 31 % (n = 28/89) (p = 0,02), celle a pneumocoque de 27 % (n = 31/114) a 21 % (n = 19/89) (p = 0,3) et celle a S. aureus de 1 % (n = 1/114) a 9 % (n = 8/89) (p = 0,01). Conclusion L’epidemiologie des IBS communautaires de l’enfant a evolue beaucoup plus lentement en France que dans les pays avec une economie avancee qui ont obtenu des couvertures vaccinales satisfaisantes, avec une proportion d’infections a prevention vaccinale qui reste importante.

Myocyte death could play a role in heart failure (HF) irrespective of the presence of coronary artery disease. The study aimed to assess this hypothesis by use of the cardiac troponin I (cTnI) assay.Seventy-one patients with nonischemic HF, New York Heart Association (NYHA) class II-IV, with a normal coronary angiogram and after exclusion of myocardiopathies were evaluated in the study. The control group included 9 healthy subjects and 15 patients hospitalized for severe noncardiac dyspnea. Cardiac TnI concentrations were determined at admission with a research reagent (cTnIus) characterized by a detection limit of 0.026 ng/mL and a high analytic sensitivity of 0.002 ng/mL. cTnIus levels were more than 0.026 ng/mL in 19 HF patients, ranging between 0.027 and 0.463 ng/mL, whereas no cTnIus level was detectable in the control group. With use of a reference assay, only 2 HF patients had abnormal cTnI values. Severe HF was observed in 17 of these 19 patients, assessed by NYHA class IV or by the presence of pulmonary edema. Patients with an increased cTnIus level had a more restrictive mitral Doppler pattern (P.001) and a more distinctive left ventricular (LV) concentric remodeling (P.0001), whereas LV ejection fraction was similar in both HF groups. The increased cTnIus level was also associated with a LV wall strain biologic marker (ie, an increased brain natriuretic peptide plasma level) (P.001).cTnI assay is a promising biochemical method for detecting cardiac myolysis in HF, independent of the presence of coronary artery disease. This subtle myolysis could be in part related to the severely increased LV wall strain.

Supportive care as a bridge to transplant or recovery remains challenging in children suffering from acute liver failure (ALF). We report our experience in children using the Molecular Absorbent Recirculating System (MARS(®)).Retrospective data from children receiving therapy using MARS(®) from October 2009 to October 2012 were included in this single-center retrospective study. Patient characteristics, clinical presentation and complications of ALF, clinical and biological data before and after each MARS(®) session, technical modalities and adverse events were recorded.A total of six children underwent 17 MARS(®) sessions during the study period. Two adolescents were treated with the adult filter MARSFLUX(®) and four infants were treated with the MiniMARS(®) filter. The mean PEdiatric Logistic Dysfunction (PELOD) score at admission was 19 (range 11-33). All patients were mechanically ventilated, and four had acute kidney injury. The neurological course improved in one case, judged as stable in two cases and worsened in one case; data were unavailable in two cases. Mean serum ammonia levels decreased significantly following treatment with MARS(®) from an initial 89 ± 29 to 58 ± 35 mcmol/L (p = 0.02). No other significant biological improvement was observed. Hemodynamic status improved/remained unchanged in the adolescent group, but in the infants four of the seven sessions were poorly tolerated and two sessions were aborted. Three patients died, two were successfully transplanted and one recovered without transplantation.In our experience, treatment with MARS(®) is associated with encouraging results in adolescents, but it needs modification for very sick infants to improve tolerance.

Purpose: Activating KRAS mutations are frequent (>90%) in pancreatic ductal adenocarcinoma (PDAC) and drive downstream deregulation of both MAPK and PI3K-mTOR pathways. MEK inhibitors (MEKi) are under clinical evaluation in PDAC, in combination with other agents including PI3K-mTOR inhibitors. While RAS and BRAF mutations, EMT, PI3K-mTOR activation, and pERK inhibition have been suggested as predictive markers for MEKi efficacy, they are not validated in PDAC. We aimed to explore the cellular and molecular effects of MEKi GSK1120212 (GSK212) alone or in combination with PI3K-mTOR inhibitors, in PDAC cell lines and on an innovative ex vivo system. Methods: GSK212 is an allosteric non-ATP competitive MEKi, everolimus (Ev) a mTORC1 inhibitor, and BKM120 a pan-class PI3K inhibitor. Effects on proliferation were evaluated by MTT assay. Combinations were analyzed by the Chou-Talalay method. Protein expression was assessed by Western blot. Ex vivo drug assays were performed at different drug concentrations on cultures of fresh tumor tissue slices prepared from patient surgical specimens. Apoptosis and proliferation were assessed by cleaved caspase 3 (Cas-3) and MIB-1 (Ki67) immunostainings, respectively; MEKi sensitivity was defined as cleaved Cas-3 expression in 30% or more of cancer cells. Correlations between protein expressions were explored using linear regression and Pearson’s R2 calculation. Samples will be classified into PDAC subtypes according to Collisson’s, Moffit’s and Bailey’s transcriptomic signatures using non-negative matrix factorization and correlation methods. Results: MIAPaCa-2 and PANC-1 are two mesenchymal KRAS mutated/BRAF wild-type PDAC cell lines with very different response to GSK212, MIAPaCa-2 being sensitive (72h-IC50=0.009µM) and PANC-1 resistant (72h-IC50=33µM). MIAPaCa-2 was more sensitive than PANC-1 to Ev (IC50=23.3µM vs 47.0µM) and BKM120 (IC50=4.19µM vs 31.6µM). Combination of GSK212 and Ev or BKM120 for 72h resulted in synergistic effects (CI0.50 discriminated between sensitive and resistant tumors. There was no correlation with RAS/RAF mutation status. Predictive value of transcriptomic signatures for MEKi response will be presented. Conclusion: Response to combined MEK/mTOR pathway inhibition was not correlated with known biomarkers of response to MEKi. Besides the therapeutic potential of MEK/mTOR pathway inhibition in PDAC, this work provides the first evidence of feasibility of pharmacodynamic biomarker monitoring on fresh PDAC tissue slices. Citation Format: Cindy Neuzillet, Annemilaï Tijeras-Raballand, Anguraj Sadanandam, Pierre Bourgoin, Philippe Bourget, Pawan Poudel, Maria Serova, Armand De Gramont, Philippe Ruszniewski, Valérie Paradis, Eric Raymond, Jérôme Cros, Pascal Hammel.{Authors}. Effects of MEK inhibition alone or in combination with PI3K-mTOR pathway inhibitors in pancreatic ductal adenocarcinoma in vitro and on an innovative ex vivo fresh tumor tissue culture model. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B57.

As synthesised ZIF-8 nanoparticles (size ∼ 60 nm and specific surface area ∼ 1300-1600 m2 g-1) were directly incorporated into a model polymer matrix (Matrimid® 5218) by solution mixing. This produces flexible transparent membranes with excellent dispersion of nanoparticles (up to loadings of 30 wt%) with good adhesion within the polymer matrix, as confirmed by scanning electron microscopy, dynamic mechanical thermal analysis and gas sorption studies. Pure gas (H2, CO2, O2, N2 and CH4) permeation tests showed enhanced permeability of the mixed matrix membrane with negligible losses in selectivity. Positron annihilation lifetime spectroscopy (PALS) indicated that an increase in the free volume of the polymer with ZIF-8 loading together with the free diffusion of gas through the cages of ZIF-8 contributed to an increase in gas permeability of the composite membrane. The gas transport properties of the composite membranes were well predicted by a Maxwell model whilst the processing strategy reported can be extended to fabricate other polymer nanocomposite membranes intended for a wide range of emerging energy applications. This journal is © The Royal Society of Chemistry 2012.