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Background: Non-invasive ventilation has never been compared with high-flow oxygen to determine whether it reduces the risk of severe hypoxaemia during intubation. We aimed to determine if preoxygenation with non-invasive ventilation was more efficient than high-flow oxygen in reducing the risk of severe hypoxaemia during intubation., Methods: The FLORALI-2 multicentre, open-label trial was done in 28 intensive care units in France. Adult patients undergoing tracheal intubation for acute hypoxaemic respiratory failure (a partial pressure of arterial oxygen [PaO 2 ] to fraction of inspired oxygen [FiO 2 ] ratio of ≤300 mm Hg) were randomly assigned (1:1; block size, four participants) to non-invasive ventilation or high-flow oxygen during preoxygenation, with stratification by PaO 2 /FiO 2 ratio (≤200 mm Hg vs >200 mm Hg). Key exclusion criteria were intubation for cardiac arrest, altered consciousness (defined as a Glasgow coma score of less than eight points), other contraindications to non-invasive ventilation (recent laryngeal, oesophageal, or gastric surgery, and substantial facial fractures), pulse oximetry not available, pregnant or breastfeeding women, and refusal to participate. The primary outcome was the occurrence of severe hypoxaemia (pulse oximetry <80%) during the procedure, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02668458., Findings: Between April 15, 2016, and Jan 8, 2017, 2079 patients were intubated in the 28 participating units, and 322 were enrolled. We excluded five patients with no recorded data, two who withdrew consent or were under legal protection, one who was not intubated, and one who had a cardiac arrest. Of the 313 patients included in the intention-to-treat analysis, 142 were assigned to non-invasive ventilation and 171 to high-flow oxygen therapy. Severe hypoxaemia occurred in 33 (23%) of 142 patients after preoxygenation with non-invasive ventilation and 47 (27%) of 171 with high-flow oxygen (absolute difference -4·2%, 95% CI -13·7 to 5·5; p=0·39). In the 242 patients with moderate-to-severe hypoxaemia (PaO 2 /FiO 2 ≤200 mm Hg), severe hypoxaemia occurred less frequently after preoxygenation with non-invasive ventilation than with high-flow oxygen (28 [24%] of 117 patients vs 44 [35%] of 125; adjusted odds ratio 0·56, 0·32 to 0·99, p=0·0459). Serious adverse events did not differ between treatment groups, with the most common immediate complications being systolic arterial hypotension (70 [49%] patients in the non-invasive ventilation group vs 86 [50%] patients in the high-flow oxygen group) and chest infiltrate on x-ray (28 [20%] vs 33 [19%]), and the most common late complications being death at day 28 (53 [37%] vs 58 [34%]) and ventilator-associated pneumonia during ICU stay (31 [22%] vs 35 [20%])., Interpretation: In patients with acute hypoxaemic respiratory failure, preoxygenation with non-invasive ventilation or high-flow oxygen therapy did not change the risk of severe hypoxaemia. Future research should explore the effect of preoxygenation method in patients with moderate-to-severe hypoxaemia at baseline., Funding: French Ministry of Health., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Left ventricular ejection fraction lacks accuracy in predicting sudden cardiac death, resulting in unnecessary implantation of cardioverter defibrillators for the primary prevention of sudden cardiac death. Baroreflex sensitivity could help to stratify patients at risk of ventricular arrhythmia., Aim: To assess the association between cardiac baroreflex sensitivity and ventricular arrhythmias in patients implanted with an implantable cardioverter defibrillator for the primary prevention of sudden cardiac death after myocardial infarction., Methods: This case-control single-centre study took place between 2015 and 2016. Cases (n=10) had experienced ventricular arrhythmias treated by the implantable cardioverter defibrillator in the previous 3 years; controls (n=22) had no arrhythmia during the same period. Baroreflex sensitivity was assessed using the temporal sequence method (mean slope) and cross-spectral analysis (low-frequency gain and high-frequency gain)., Results: The mean age was 65 years; 94% of the patients were men. 24-hour Holter electrocardiogram autonomous nervous system variables, left ventricular ejection fraction and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) concentration did not differ between cases and controls. The mean slope was lower in cases than in controls (8 vs. 15ms/mmHg [P=0.009] in the supine position; 7 vs. 12ms/mmHg [P=0.038] in the standing position). The mean slope in the supine position was still significantly different between groups after adjustment for age, left ventricular ejection fraction and NT-proBNP (P=0.03). By comparison, low-frequency gain and high-frequency gain did not differ between groups in either the supine or the standing position., Conclusion: Patients with ventricular arrhythmias had a lower mean slope compared with those who were free of arrhythmia. A prospective study is needed to confirm this association., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Parkinson disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of the dopaminergic neurons in the substantia nigra, presumably due to increased apoptosis. In previous studies, we showed altered expression of proteins involved in mammalian target of rapamycin (mTOR) antiapoptotic and double-stranded RNA-dependent protein kinase (PKR) apoptotic pathways of translational control in experimental cellular and animal models of PD., Results: In this work, our results showed clear modifications in the expression of kinases involved in mTOR and PKR apoptosis pathways, in lymphocytes of PD patients treated or not with anti-PD treatment (levodopa), which confirmed the role played by apoptosis in the pathogenesis of this disease and the positive effect of treatment with medication on this parameter. Others proteins involved in apo-ptosis were also evaluated in lymphocytes of patients as the expression of the peripheral benzodiazepine receptor and caspase-3., Conclusion: Translational control is altered in PD and hence its evaluation in peripheral blood mononuclear cells may serve as an early marker of apoptosis and indicate the efficacy of the dopaminergic treatment., (© 2020 S. Karger AG, Basel.)

Aims/hypothesis: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the gold standard prognostic biomarker for diagnosis and occurrence of heart failure. Here, we compared its prognostic value for the occurrence of congestive heart failure with that of plasma mid-region pro-adrenomedullin (MR-proADM), a surrogate for adrenomedullin, a vasoactive peptide with vasodilator and natriuretic properties, in people with type 2 diabetes., Methods: Plasma MR-proADM concentration was measured in baseline samples of a hospital-based cohort of consecutively recruited participants with type 2 diabetes. Our primary endpoint was heart failure requiring hospitalisation., Results: We included 1438 participants (age 65 ± 11 years; 604 women and 834 men). Hospitalisation for heart failure occurred during follow-up (median 64 months) in 206 participants; the incidence rate of heart failure was 2.5 (95% CI 2.2, 2.9) per 100 person-years. Plasma concentrations of MR-proADM and NT-proBNP were significantly associated with heart failure in a Cox multivariable analysis model when adjusted for age, diabetes duration, history of coronary heart disease, proteinuria and baseline eGFR ( adj HR [95%CI] 1.83 [1.51, 2.21] and 2.20 [1.86, 2.61], respectively, per 1 SD log 10 increment, both p < 0.001). MR-proADM contributed significant supplementary information to the prognosis of heart failure when we considered the clinical risk factors (integrated discrimination improvement [IDI, mean ± SEM] 0.021 ± 0.007, p = 0.001) (Table 3). Inclusion of NT-proBNP in the multivariable model including MR-proADM contributed significant complementary information on prediction of heart failure (IDI [mean ± SEM] 0.028 ± 0.008, p < 0.001). By contrast, MR-proADM did not contribute supplementary information on prediction of heart failure in a model including NT-proBNP (IDI [mean ± SEM] 0.003 ± 0.003, p = 0.27), with similar results for heart failure with reduced ejection fraction and preserved ejection fraction., Conclusions/interpretation: MR-proADM is a prognostic biomarker for heart failure in people with type 2 diabetes but gives no significant complementary information on prediction of heart failure compared with NT-proBNP.

Objective: Inflammation and oxidative stress play an important role in the pathogenesis of lower-extremity artery disease (LEAD). We assessed the prognostic values of inflammatory and redox status biomarkers on the risk of LEAD in individuals with type 2 diabetes., Research Design and Methods: Plasma concentrations of tumor necrosis factor-α receptor 1 (TNFR1), angiopoietin-like 2, ischemia-modified albumin (IMA), fluorescent advanced glycation end products, protein carbonyls, and total reductive capacity of plasma were measured at baseline in the SURDIAGENE (Survie, Diabete de type 2 et Genetique) cohort. Major LEAD was defined as the occurrence during follow-up of peripheral revascularization or lower-limb amputation., Results: Among 1,412 participants at baseline (men 58.2%, mean [SD] age 64.7 [10.6] years), 112 (7.9%) developed major LEAD during 5.6 years of follow-up. High plasma concentrations of TNFR1 (hazard ratio [95% CI] for second vs. first tertile 1.12 [0.62-2.03; P = 0.71] and third vs. first tertile 2.16 [1.19-3.92; P = 0.01]) and of IMA (2.42 [1.38-4.23; P = 0.002] and 2.04 [1.17-3.57; P = 0.01], respectively) were independently associated with an increased risk of major LEAD. Plasma concentrations of TNFR1 but not IMA yielded incremental information, over traditional risk factors, for the risk of major LEAD as follows: C-statistic change (0.036 [95% CI 0.013-0.059]; P = 0.002), integrated discrimination improvement (0.012 [0.005-0.022]; P < 0.001), continuous net reclassification improvement (NRI) (0.583 [0.294-0.847]; P < 0.001), and categorical NRI (0.171 [0.027-0.317]; P = 0.02)., Conclusions: Independent associations exist between high plasma TNFR1 or IMA concentrations and increased 5.6-year risk of major LEAD in people with type 2 diabetes. TNFR1 allows incremental prognostic information, suggesting its use as a biomarker for LEAD., (© 2018 by the American Diabetes Association.)

Introduction: Recent practice guidelines suggest applying non-invasive ventilation (NIV) to prevent postextubation respiratory failure in patients at high risk of extubation failure in intensive care unit (ICU). However, such prophylactic NIV has been only a conditional recommendation given the low certainty of evidence. Likewise, high-flow nasal cannula (HFNC) oxygen therapy has been shown to reduce reintubation rates as compared with standard oxygen and to be as efficient as NIV in patients at high risk. Whereas HFNC may be considered as an optimal therapy during the postextubation period, HFNC associated with NIV could be an additional means of preventing postextubation respiratory failure. We are hypothesising that treatment associating NIV with HFNC between NIV sessions may be more effective than HFNC alone and may reduce the reintubation rate in patients at high risk., Methods and Analysis: This study is an investigator-initiated, multicentre randomised controlled trial comparing HFNC alone or with NIV sessions during the postextubation period in patients at high risk of extubation failure in the ICU. Six hundred patients will be randomised with a 1:1 ratio in two groups according to the strategy of oxygenation after extubation. The primary outcome is the reintubation rate within the 7 days following planned extubation. Secondary outcomes include the number of patients who meet the criteria for moderate/severe respiratory failure, ICU length of stay and mortality up to day 90., Ethics and Dissemination: The study has been approved by the ethics committee and patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals., Trial Registration Number: NCT03121482., Competing Interests: Competing interests: AWT and J-DR report travel expenses coverage to attend scientific meetings by Fisher & Paykel. AD and SE received research grants from Fisher & Paykel. J-PF reports consulting fees from Fisher & Paykel., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cardiovascular disease and kidney damage are tightly associated in people with type 2 diabetes. Experimental evidence supports a causal role for vasopressin (or antidiuretic hormone) in the development of diabetic kidney disease (DKD). Plasma copeptin, the COOH-terminal portion of pre-provasopressin and a surrogate marker of vasopressin, was shown to be positively associated with the development and progression of DKD. Here we assessed the association of plasma copeptin with the risk of cardiovascular events during follow-up in two prospective cohorts of type 2 diabetic patients, and we examined if this association could be mediated by deleterious effects of vasopressin on the kidney., Methods: We studied 3098 and 1407 type 2 diabetic patients from the French cohorts DIABHYCAR and SURDIAGENE, respectively. We considered the incidence during follow-up (median: 5 years) of a combined end point composed of myocardial infarction, coronary revascularization, hospitalization for congestive heart failure, or cardiovascular death. Copeptin concentration was measured in baseline plasma samples by an immunoluminometric assay., Results: The cumulative incidence of cardiovascular events during follow-up by sex-specific tertiles of baseline plasma copeptin was 15.6% (T1), 18.7% (T2) and 21.7% (T3) in DIABHYCAR (p = 0.002), and 27.7% (T1), 34.1% (T2) and 47.6% (T3) in SURDIAGENE (p < 0.0001). Cox proportional hazards survival regression analyses confirmed the association of copeptin with cardiovascular events in both cohorts: hazard ratio with 95% confidence interval for T3 vs. T1 was 1.29 (1.04-1.59), p = 0.02 (DIABHYCAR), and 1.58 (1.23-2.04), p = 0.0004 (SURDIAGENE), adjusted for sex, age, BMI, duration of diabetes, systolic blood pressure, arterial hypertension, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, estimated glomerular filtration rate (eGFR), urinary albumin concentration (UAC), active tobacco smoking, and previous history of myocardial infarction at baseline. No interaction was observed between plasma copeptin and eGFR (p = 0.40) or UAC (p = 0.61) categories on the risk of cardiovascular events in analyses of pooled cohorts., Conclusions: Plasma copeptin was positively associated with major cardiovascular events in people with type 2 diabetes. This association cannot be solely accounted for by the association of copeptin with kidney-related traits.

Stress might impair clinical performance in real life and in simulation-based education (SBE). Subjective or objective measures can be used to assess stress during SBE. This monocentric study aimed to evaluate the effects of simulation of life-threatening events on measurements of various stress parameters (psychological, biological, and electrophysiological parameters) in multidisciplinary teams (MDTs) during SBE. The effect of gender and status of participants on stress response was also investigated. Twelve emergency MDTs of 4 individuals were recruited for an immersive simulation session. Stress was assessed by: (1) self-reported stress; (2) Holter analysis, including heart rate and heart rate variability in the temporal and spectral domain (autonomic nervous system); (3) salivary cortisol (hypothalamic pituitary adrenal axis). Forty-eight participants (54.2% men, <7years of experience) were included. Measures were performed at baseline (T0), after simulation (T1), after debriefing (T2), and 30min after debriefing (T3). There was an increase in stress level at T1 (p<0.001) and a decrease at T2 (p<0.001). However, the variations of stress parameters induced by simulation (T0-T1 difference and T1-T2 difference) estimated by the three approaches were not correlated, while, as expected, Holter parameters were well-correlated to each other. Immersive SBE produced a change of stress level in all MDT members with no evidence for status effect but with gender difference. None developed a PTSD. These results support the hypothesis of a complementarity of the stress paths (collective reaction with increased stress level during simulation and a decrease during debriefing) but with relative independence of these paths (lack of correlation to each other). This study also suggests that because of the lack of correlation, stress response should be assessed by a combination of psychological, biological and electrophysiological parameters., (Copyright © 2017 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Patients with type 2 diabetes (T2D) face a high amputation rate. We investigated the relationship between the level of amputation and the presence of micro or macro-vascular disease and related circulating biomarkers, Tumor Necrosis Factor Receptor 1 (TNFR1) and Angiopoietin like-2 protein (ANGPTL2)., Methods: We have analyzed data from 1468 T2D participants in a single center prospective cohort (the SURDIAGENE cohort). Our outcome was the occurrence of lower limb amputation categorized in minor (below-ankle) or major (above ankle) amputation. Microvascular disease was defined as a history of albuminuria [microalbuminuria: uACR (urinary albumine-to-creatinine ratio) 30-299 mg/g or macroalbuminuria: uACR ≥ 300 mg/g] and/or severe diabetic retinopathy or macular edema. Macrovascular disease at baseline was divided into peripheral arterial disease (PAD): peripheral artery revascularization and/or major amputation and in non-peripheral macrovascular disease: coronary artery revascularization, myocardial infarction, carotid artery revascularization, stroke. We used a proportional hazard model considering survival without minor or major amputation., Results: During a median follow-up period of 7 (0.5) years, 79 patients (5.5%) underwent amputation including 29 minor and 50 major amputations. History of PAD (HR 4.37 95% CI [2.11-9.07]; p < 0.001), severe diabetic retinopathy (2.69 [1.31-5.57]; p = 0.0073), male gender (10.12 [2.41-42.56]; p = 0.0016) and serum ANGPTL2 concentrations (1.25 [1.08-1.45]; p = 0.0025) were associated with minor amputation outcome. History of PAD (6.91 [3.75-12.72]; p < 0.0001), systolic blood pressure (1.02 [1.00-1.03]; p = 0.004), male gender (3.81 [1.67-8.71]; p = 0.002), and serum TNFR1 concentrations (HR 13.68 [5.57-33.59]; p < 0.0001) were associated with major amputation outcome. Urinary albumin excretion was not significantly associated with the risk of minor and major amputation., Conclusions: This study suggests that the risk factors associated with the minor vs. major amputation including biomarkers such as TNFR1 should be considered differently in patients with T2D.

Objectives: The primary objective was to determine whether technical and nontechnical performances were in some way correlated during immersive simulation. Performance was measured among French Emergency Medical Service workers at an individual and a team level. Secondary objectives were to assess stress response through collection of physiologic markers (salivary cortisol, heart rate, the proportion derived by dividing the number of interval differences of successive normal-to-normal intervals > 50 ms by the total number of normal-to-normal intervals [pNN50], low- and high-frequency ratio) and affective data (self-reported stress, confidence, and dissatisfaction), and to correlate them to performance scores., Design: Prospective observational study performed as part of a larger randomized controlled trial., Setting: Medical simulation laboratory., Subjects: Forty-eight participants distributed among 12 Emergency Medical System teams., Interventions: Individual and team performance measures and individual stress response were assessed during a high-fidelity simulation. Technical performance was assessed by the intraosseous access performance scale and the Team Average Performance Assessment Scale; nontechnical performance by the Behavioral Assessment Tool for leaders, and the Clinical Teamwork Scale. Stress markers (salivary cortisol, heart rate, pNN50, low- and high-frequency ratio) were measured both before (T1) and after the session (T2). Participants self-reported stress before and during the simulation, self-confidence, and perception of dissatisfaction with team performance, rated on a scale from 0 to 10., Measurements and Main Results: Scores (out of 100 total points, mean ± SD) were intraosseous equals to 65.6 ± 14.4, Team Average Performance Assessment Scale equals to 44.6 ± 18.1, Behavioral Assessment Tool equals to 49.5 ± 22.0, Clinical Teamwork Scale equals to 50.3 ± 18.5. There was a strong correlation between Behavioral Assessment Tool and Clinical Teamwork Scale (Rho = 0.97; p = 0.001), and Behavioral Assessment Tool and Team Average Performance Assessment Scale (Rho = 0.73; p = 0.02). From T1 to T2, all stress markers (salivary cortisol, heart rate, pNN50, and low- and high-frequency ratio) displayed an increase in stress level (p < 0.001 for all). Self-confidence was positively correlated with performance (Clinical Teamwork Scale: Rho = 0.47; p = 0.001, Team Average Performance Assessment Scale: Rho = 0.46; p = 0.001). Dissatisfaction was negatively correlated with performance (Rho = -0.49; p = 0.0008 with Behavioral Assessment Tool, Rho = -0.47; p = 0.001 with Clinical Teamwork Scale, Rho = -0.51; p = 0.0004 with Team Average Performance Assessment Scale). No correlation between stress response and performance was found., Conclusions: There was a positive correlation between leader (Behavioral Assessment Tool) and team (Clinical Teamwork Scale and Team Average Performance Assessment Scale) performances. These performance scores were positively correlated with self-confidence and negatively correlated with dissatisfaction.

Aim: To investigate whether plasma concentrations of proprotein-convertase-subtilisin/kexin type 9 (PCSK9) were associated with cardiovascular (CV) events in two cohorts of patients with type 2 diabetes mellitus., Methods: We considered patients from the DIABHYCAR (n = 3137) and the SURDIAGENE (n = 1468) studies. Baseline plasma PCSK9 concentration was measured using an immunofluorescence assay. In post hoc, but preplanned, analyses we assessed the relationship between PCSK9 and the following endpoints: (1) a combined endpoint of major CV events: CV death, non-fatal myocardial infarction (MI), stroke and heart failure-related hospital admission; (2) a composite of all CV events: MI, stroke, heart failure-related hospital admission, coronary/peripheral angioplasty or bypass, CV death; (3) MI; (4) stroke/transient ischaemic attack (TIA); and (5) CV death., Results: In the DIABHYCAR study, plasma PCSK9 tertiles were associated with the incidence of MI, all CV events and stroke/TIA (P for trend <.05). In adjusted Cox analysis, plasma PCSK9 was associated, independently of classic risk factors, with the incidence of major CV events (hazard ratio [HR] for 1-unit increase of log[PCSK9] 1.28 [95% confidence interval {CI} 1.06-1.55]), the incidence of MI (HR 1.66 [95% CI 1.05-2.63]), and the incidence of all CV events (HR 1.22 [95% CI 1.04-1.44]), but not with CV death. Plasma PCSK9 was not associated with the incidence of CV disease in the participants of the SURDIAGENE study with high CV risk treated with statins and insulin., Conclusions: We found that PCSK9 was inconsistently associated with CV events in populations with type 2 diabetes. The association may depend on the level of CV risk and the background treatment., (© 2017 John Wiley & Sons Ltd.)

Background: Despite pathophysiological relevance and promising experimental data, the usefulness of biomarkers of oxidative stress for cardiac risk prediction is unclear. The aim of our study was to investigate the prognostic value of 6 biomarkers exploring different pathways of oxidative stress for predicting adverse cardiovascular outcomes in patients with type 2 diabetes mellitus beyond established risk factors., Methods and Results: The SURDIAGENE (Survie, Diabete de type 2 et Genetique) prospective cohort study consecutively recruited 1468 patients with type 2 diabetes mellitus. Assays were performed at baseline, and incident cases of major adverse cardiovascular events (MACE)-first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke-were recorded during a median of 64 months. Advanced oxidation protein products, oxidative hemolysis inhibition assay, ischemia-modified albumin, and total reductive capacity of plasma were not associated with the risk of MACE in univariate analyses. Fluorescent advanced glycation end products and carbonyls were associated with MACE (hazard ratio=1.38 per SD, 95% confidence interval 1.24-1.54, P <0.001 and hazard ratio=1.15 per SD, 95% confidence interval 1.04-1.27, P =0.006, respectively) in univariate analysis, but when added to a multivariate predictive model including traditional risk factors for MACE, these markers did not significantly improve c-statistics or integrated discrimination index of the model., Conclusions: These plasma concentrations of 6 markers, which cover a broad spectrum of oxidative processes, were not significantly associated with MACE occurrence and were not able to improve MACE risk discrimination and classification beyond classical risk factors in type 2 diabetes mellitus patients., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Objectives: In patients with acute hypoxemic respiratory failure, noninvasive ventilation and high-flow nasal cannula oxygen are alternative strategies to conventional oxygen therapy. Endotracheal intubation is frequently needed in these patients with a risk of delay, and early predictors of failure may help clinicians to decide early. We aimed to identify factors associated with intubation in patients with acute hypoxemic respiratory failure treated with different noninvasive oxygenation techniques., Design: Post hoc analysis of a randomized clinical trial., Setting: Twenty-three ICUs., Patients: Patients with a respiratory rate greater than 25 breaths/min and a PaO2/FIO2 ratio less than or equal to 300 mm Hg., Intervention: Patients were treated with standard oxygen, high-flow nasal cannula oxygen, or noninvasive ventilation., Measurement and Main Results: Respiratory variables one hour after treatment initiation. Under standard oxygen, patients with a respiratory rate greater than or equal to 30 breaths/min were more likely to need intubation (odds ratio, 2.76; 95% CI, 1.13-6.75; p = 0.03). One hour after high-flow nasal cannula oxygen initiation, increased heart rate was the only factor associated with intubation. One hour after noninvasive ventilation initiation, a PaO2/FIO2 ratio less than or equal to 200 mm Hg and a tidal volume greater than 9 mL/kg of predicted body weight were independent predictors of intubation (adjusted odds ratio, 4.26; 95% CI, 1.62-11.16; p = 0.003 and adjusted odds ratio, 3.14; 95% CI, 1.22-8.06; p = 0.02, respectively). A tidal volume above 9 mL/kg during noninvasive ventilation remained independently associated with 90-day mortality., Conclusions: In patients with acute hypoxemic respiratory failure breathing spontaneously, the respiratory rate was a predictor of intubation under standard oxygen, but not under high-flow nasal cannula oxygen or noninvasive ventilation. A PaO2/FIO2 below 200 mm Hg and a high tidal volume greater than 9 mL/kg were the two strong predictors of intubation under noninvasive ventilation.

Peripheral inflammatory processes are involved in Alzheimer's disease (AD). We aimed to determine whether plasma inflammatory mediator levels at diagnosis are associated with cognitive decline through a 2-year follow-up in AD patients. Patients (n = 109, mean age 79.44 (6.82) years) were included at diagnosis with MMSE scores between 16 and 25, with C-reactive protein <10 mg/L, and without any acute or chronic inflammation status. Plasma IL-1β, IL-6, TNF-α, and CCL5 were measured using Luminex X-MAP technology at baseline, and after one year and two years of follow-up. The mean values of IL-1β, IL-6, TNF-α, and CCL5 at diagnosis were 0.3, 1.94, 6.57, and 69,615.81 pg/mL, respectively. Mean cognitive decline in MMSE was 3.35 points. No correlation between plasmatic value of IL-1β, IL-6, TNF-α, or CCL5 at diagnosis and cognitive decline during the two years of follow-up was found. Cognitive decline in AD does not appear to be predictable by the tested inflammatory mediators.

Introduction: Endotracheal intubation in intensive care unit (ICU) is a procedure at high risk of life-threatening complications. Among them, severe oxygen desaturation, usually defined as a drop of pulse oxymetry (SpO 2 ) below 80%, is the most common. Preoxygenation enables delaying oxygen desaturation occurring during apnea induced by anaesthetic drugs. Data suggest that non-invasive ventilation (NIV) or high-flow nasal cannula (HFNC) oxygen therapy could further increase PaO 2 before intubation procedure and prevent oxygen desaturation episodes as compared with standard oxygen. However, no recommendation favours one technique rather than the other, since they have never been compared. Hence, whether a strategy of preoxygenation with NIV or HFNC is more effective than the other in patients with acute hypoxaemic respiratory failure remains to be established., Methods and Analysis: The FLORALI-2 study is a multicentre randomised controlled trial comparing a preoxygenation strategy with either NIV or HFNC in patients with acute hypoxaemic respiratory failure needing intubation in ICU. The 320 patients will be randomised with a ratio 1:1 in two groups according to the strategy of preoxygenation. The primary outcome is the occurrence of an episode of severe oxygen desaturation defined by a drop of SpO 2 below 80% during the intubation procedure. Secondary outcomes include feasibility of the two strategies, immediate and late complications related to intubation., Ethics and Dissemination: The study has been approved by the central ethics committee (Ethics Committee Ouest-III, Poitiers, France) and patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals., Trial Registration Number: NCT02668458; Pre-results., Competing Interests: Competing interests: J-PF reports consulting fees from Fisher and Paykel. J-DR reports travel expenses coverage to attend scientific meetings by Fisher & Paykel., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent., (© 2017 Wiley Periodicals, Inc.)

Background: Allergic bronchopulmonary aspergillosis (ABPA) affects 3-13% of patients with asthma. Its natural history includes possibly life-threatening exacerbations and evolution towards fixed obstructive ventilatory disorders or even irreversible lung fibrosis lesions. ABPA prognosis is directly associated with exacerbation control and the main objective of the treatment is to decrease their frequency and duration. Recommendations regarding dosage and duration of treatment are not very precise. The currently used combination of itraconazole and corticosteroid therapy has many limitations. The interests of a therapeutic strategy using nebulized liposomal amphotericin B (LAmB) are to heighten antifungal lung tissue concentration, to circumvent drug interactions and decrease the potential toxicity of systemic antifungal treatments. Finally, this association leads to improved eradication of Aspergillus, thereby limiting the risk of side effects and the emergence of treatment-resistant Aspergillus strains., Methods: This is a phase II, multicentre, randomized, single blind, controlled therapeutic study, with the objective of comparing the potential benefit on exacerbation control of a maintenance therapy by LAmB nebulization. The main objective of the study is to compare the incidence of severe clinical exacerbations in ABPA treatment, between a maintenance treatment strategy with nebulized LAmB and a conventional strategy without antifungal maintenance therapy., Expected Results: The results will guide practitioners in the management of ABPA treatments and help to define the place of aerosols of LAmB on "evidence base medicine" criteria., (Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Greater renal function decline (RFD) in type 2 diabetes (T2DM) has been suggested in men compared with women, and imbalances in estrogen/androgen levels have been associated with cardiovascular disease mortality in elderly men, but it remains unclear whether sex hormone disequilibrium is related to diabetic nephropathy (DN) in men with T2DM., Objective: This study examined the relationship between sex steroid concentrations and renal outcomes in male T2DM patients., Population and Methods: Total testosterone (T), total estradiol (E2), sex hormone-binding globulin (SHBG), and total and calculated free (cf) E2/T ratios were compared in 735 male T2DM patients with (n=513) and without (n=222) DN, using a cross-sectional approach. Also, in a pilot complementary prospective nested case-control cohort, total E2/total T and cfE2/cfT were evaluated according to a hard renal outcome (HRO): end-stage renal disease/doubling of baseline serum creatinine (36 HRO cases, 72 HRO controls) and rate of eGFR decline (68 rapid vs 68 slow RFD)., Result: With the cross-sectional approach, E2 and cfE2 were higher in DN cases vs DN controls (95.5 vs 86.8pmol/L [P=0.0246] and 2.59 vs 2.36pmol/L [P=0.005], respectively). The difference in E2 persisted on multivariate analysis. In the prospective approach, E2 and T concentrations, and total E2/total T and cfE2/cfT2 ratios did not differ in HRO cases vs controls or in patients with rapid vs slow RFD., Conclusion: Although positively related to DN in the cross-sectional analysis, progression of renal disease in male patients with T2DM was not related to either sex hormone levels or aromatase index as reflected by E2/T ratio., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Objective: Selenium deficiency adversely affects the clinical outcome of measles in the tropics. In developed countries, serum selenium level has never been investigated during acute measles. The aim of this study was to determine serum selenium concentrations in French patients with acute measles and to seek correlations with clinical and virological findings., Patients and Methods: We studied serum selenium concentrations in 94 French patients with acute measles and in 99 healthy controls matched for age and sex., Results: The mean of selenium concentration was significantly lower in the patients than in the controls (46.4±14.1μg/L versus 86.5±13.9μg/L, P<0.0001). In the patients, selenium concentrations were not associated with age, sex, vaccination status, clinical signs or specific antibody responses. Selenium levels did not differ significantly between patients with uncomplicated measles (45.8±14.2μg/L) and patients with complications (52.7±13.2μg/L) (P=0.15)., Conclusion: Acute measles is associated with significant reduction of selenium level that did not seem to negatively affect the course of the disease suggesting compensating mechanisms in patients from developed countries against the disease., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Objective: We explored the prognostic value of three circulating candidate biomarkers-midregional-proadrenomedullin (MR-proADM), soluble tumor necrosis factor receptor 1 (sTNFR1), and N-terminal prohormone brain natriuretic peptide (NT-proBNP)-for change in renal function in patients with type 2 diabetes., Research Design and Methods: Outcomes were defined as renal function loss (RFL), ≥40% decline of estimated glomerular filtration rate (eGFR) from baseline, and rapid renal function decline (RRFD), absolute annual eGFR slope <-5 mL/min/year. We used a proportional hazard model for RFL and a logistic model for RRFD. Adjustments were performed for established risk factors (age, sex, diabetes duration, HbA 1c , blood pressure, baseline eGFR, and urinary albumin-to-creatinine ratio [uACR]). C-statistics were used to assess the incremental predictive value of the biomarkers to these risk factors., Results: Among 1,135 participants (mean eGFR 76 mL/min, median uACR 2.6 mg/mmol, and median GFR slope -1.6 mL/min/year), RFL occurred in 397, RRFD developed in 233, and 292 died during follow-up. Each biomarker predicted RFL and RRFD. When combined, MR-proADM, sTNFR1, and NT-proBNP predicted RFL independently from the established risk factors (adjusted hazard ratio 1.59 [95% CI 1.34-1.89], P < 0.0001; 1.33 [1.14-1.55], P = 0.0003; and 1.22 [1.07-1.40], P = 0.004, respectively) and RRFD (adjusted odds ratio 1.56 [95% CI 1.7-2.09], P = 0.003; 1.72 [1.33-2.22], P < 0.0001; and 1.28 [1.03-1.59], P = 0.02, respectively). The combination of the three biomarkers yielded the highest discrimination (difference in C-statistic = 0.054, P < 0.0001; 0.067, P < 0.0001 for RFL; and 0.027, P < 0.0001 for RRFD)., Conclusions: In addition to established risk factors, MR-proADM, sTNFR1, and NT-proBNP improve risk prediction of loss of renal function in patients with type 2 diabetes., (© 2017 by the American Diabetes Association.)

Background Paraganglioma is a rare neuroendocrine tumour arising anywhere along the paravertebral sympathetic and parasympathetic chains. In the neck, paraganglioma may affect the carotid body (carotid body tumour). Case report We describe a 43-year-old woman who presented with a reversible vasoconstriction syndrome associated with a posterior reversible encephalopathy syndrome following a surgery for a left carotid paraganglioma (with a past medical history of surgery for a right carotid paraganglioma a few months before). Conclusion A consequence of a baroreflex modification is discussed in order to explain the rare occurrence of such symptoms.

Objective: Sodium intake is associated with cardiovascular outcomes. However, no study has specifically reported an association between cardiovascular mortality and urinary sodium concentration (U Na ). We examined the association of U Na with mortality in a cohort of type 2 diabetes (T2D) patients., Methods: Patients were followed for all-cause death and cardiovascular death. Baseline U Na was measured from second morning spot urinary sample. We used Cox proportional hazard models to identify independent predictors of mortality. Improvement in prediction of mortality by the addition of U Na to a model including known risk factors was assessed by the relative integrated discrimination improvement (rIDI) index., Results: Participants ( n = 1,439) were followed for a median of 5.7 years, during which 254 cardiovascular deaths and 429 all-cause deaths were recorded. U Na independently predicted all-cause and cardiovascular mortality. An increase of one standard deviation of U Na was associated with a decrease of 21% of all-cause mortality and 22% of cardiovascular mortality. U Na improved all-cause and cardiovascular mortality prediction beyond identified risk factors (rIDI = 2.8%, P = 0.04 and rIDI = 4.6%, P = 0.02, resp.)., Conclusions: In T2D, U Na was an independent predictor of mortality (low concentration is associated with increased risk) and improved modestly its prediction in addition to traditional risk factors., Competing Interests: No competing interests were known or perceived.

Aims/hypothesis: A high serum angiopoietin-like 2 (ANGPTL2) concentration is an independent risk factor for developing diabetes and is associated with insulin resistance and atherosclerosis. In this work, we have examined the impact of serum ANGPTL2 on improving cardiovascular (CV) risk stratification in patients with type 2 diabetes., Methods: A prospective, monocentric cohort of consecutive type 2 diabetes patients (the SURDIAGENE cohort; total of 1353 type 2 diabetes patients; 58% men, mean ± SD age 64 ± 11 years) was followed for a median of 6.0 years for death as primary endpoint and major adverse CV events (MACE; i.e. CV death, myocardial infarction or stroke) as a secondary endpoint. Patients with end-stage renal disease, defined as a requirement for dialysis or a history of kidney transplantation, were excluded. Patients were grouped into quartiles according to ANGPTL2 concentrations at inclusion: <11.2 (Q1), 11.2-14.7 (Q2), 14.8-19.5 (Q3) or >19.5 (Q4) ng/ml., Results: During follow up, 367 patients (representing 4.5% of the total person-years) died and 290 patients (representing 3.7% of the total person-years) presented with MACE. Both the survival and MACE-free survival rates were significantly different between ANGPTL2 quartiles (logrank 82.12, p < 0.0001 for death; and logrank 65.14, p < 0.0001 for MACE). Patients with ANGPTL2 concentrations higher than 19.5 ng/ml (Q4) had a significantly higher risk of death and MACE than those with ANGPTL2 levels of 19.5 ng/ml or less (Q1-3) (HR for death 2.44 [95% CI 1.98, 3.00], p < 0.0001; HR for MACE 2.43 [95% CI 1.92, 3.06], p < 0.0001) after adjustment for sex, age and established CV risk factors. Using ANGPTL2 concentrations, prediction of the risk of mortality, as assessed by integrated discrimination improvement (IDI), was significantly improved (IDI 0.006 ± 0.002, p = 0.0002)., Conclusions/interpretation: In patients with type 2 diabetes, serum ANGPTL2 concentrations were independently associated with death and MACE. Therefore, ANGPTL2 is a promising candidate biomarker for improving risk stratification in type 2 diabetes patients, and may prove to be a valuable therapeutic target.

Background: The use of non-invasive ventilation is controversial in immunocompromised patients with acute respiratory failure, whereas the use of high-flow nasal cannula oxygen therapy is growing as an alternative to standard oxygen. We aimed to compare outcomes of immunocompromised patients with acute respiratory failure treated with standard oxygen with those treated with high-flow nasal cannula oxygen alone or high-flow nasal cannula oxygen associated with non-invasive ventilation., Methods: We did a post-hoc subgroup analysis in a subset of immunocompromised patients with non-hypercapnic acute respiratory failure from a multicentre, randomised, controlled trial. In the trial, patients from 23 intensive care units in France and Belgium were randomly assigned (1:1:1) to receive either standard oxygen, high-flow nasal cannula alone, or non-invasive ventilation interspaced with high-flow nasal cannula between non-invasive ventilation sessions (non-invasive ventilation group). Patients with profound neutropenia, acute-on-chronic respiratory failure, cardiogenic pulmonary oedema, shock, or altered consciousness were excluded. The primary outcome was the proportion of patients who required endotracheal intubation within 28 days after randomisation., Findings: Of the 82 immunocompromised patients, 30 were treated with standard oxygen, 26 with high-flow nasal cannula alone, and 26 with non-invasive ventilation plus interspaced high-flow nasal cannula. 8 (31%) of 26 patients treated with high-flow nasal cannula alone, 13 (43%) of 30 patients treated with standard oxygen, and 17 (65%) of 26 patients treated with non-invasive ventilation required intubation at 28 days (p=0·04). Odds ratios (ORs) for intubation were higher in patients treated with non-invasive ventilation than in those treated with high-flow nasal cannula: OR 4·25 (95% CI 1·33-13·56). ORs were not significantly different between patients treated with high-flow nasal cannula alone and standard oxygen: OR 1·72 (0·57-5·18). After multivariable logistic regression, the two factors independently associated with endotracheal intubation and mortality were age and use of non-invasive ventilation as first-line therapy., Interpretation: Non-invasive ventilation might be associated with an increased risk of intubation and mortality and should be used cautiously in immunocompromised patients with acute hypoxaemic respiratory failure., Funding: French Ministry of Health, the French societies of intensive care (Société de Réanimation de Langue Française, SRLF) and pneumology (Société de Pneumologie de Langue Française, SPLF), La Mutuelle de Poitiers, AADAIRC (Association pour l'Assistance à Domicile Aux Insuffisants Respiratoires Chroniques), and Fisher&Paykel Healthcare., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To evaluate whether early administration of high-dose methylprednisolone limits the fall of platelets in preeclampsia., Methods: A randomized trial of 180 mg methylprednisolone or placebo administered in divided doses over 36 hours was conducted in women admitted for preeclampsia and platelet counts below 150×10/L in four French academic centers. Patients were not included when platelet counts were below 50×10/L or when immediate delivery was required. The primary study outcome was the proportion of patients with platelet counts above 100×10/L 36 hours after the first dose of study medication. The total sample size needed to detect a 23% difference in the rate of this outcome between groups with a one-tailed α of 0.05 and 90% power was 94 patients., Results: Thirty-six patients were randomly assigned to receive methylprednisolone and 34 placebo between October 2007 and May 2011. Platelet counts above 100×10/L at 36 hours after the first dose of study medication were recorded in 30 (83%) in the active group and 29 (85%) in the placebo group (relative risk 0.98, 95% confidence interval 0.80-1.20; P=.82). The only adverse potentially study-related event was hyperglycemia in one woman allocated to methylprednisolone., Conclusion: In women with preeclampsia and platelet counts under 150×10/L, methylprednisolone was not effective in maintaining platelet counts above 100×10/L., Clinical Trial Registration: EU Clinical Trials Register, http://clinicaltrialsregister.eu, EudraCT 2006-004881-15-FR.

Objective: The pattern of renal function decline prior to cardiovascular (CV) events in type 2 diabetes is not well known. Our aim was to describe the association between renal function trajectories and the occurrence of a CV event., Research Design and Methods: We considered patients with type 2 diabetes from the SURDIAGENE (Survie, Diabete de type 2 et Genetique) study (discovery cohort) and the DIABHYCAR (Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril) study (replication cohort). Global patterns of estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) and serum creatinine (SCr) prior to a major CV event (MACE) or last update were determined using a linear mixed-effects model and annual individual slopes computed by simple linear regression., Results: In the 1,040 participants of the discovery cohort, establishment of global patterns including 22,227 SCr over 6.3 years of follow-up showed an annual eGFR decline and an annual SCr increase that were significantly greater in patients with MACE compared with patients without (-3.0 and -1.7 mL/min/1.73 m(2)/year and +10.7 and +4.0 μmol/L/year, respectively; P < 0.0001 for both). Median annual individual slopes were also significantly steeper in patients with MACE, and adjusted risk of MACE was 4.11 times higher (3.09-5.45) in patients with rapid decline in eGFR (change less than -5 mL/min/1.73 m(2)/year). Consideration of renal function trajectories provided significant additive information helping to explain the occurrence of MACE for both SCr and eGFR (PIDI < 0.0001 and P = 0.0005, respectively). These results were confirmed in the replication cohort., Conclusions: Renal function decline was associated with a higher risk of MACE. The pattern of renal function decline, beyond baseline kidney function, is an independent factor of CV risk., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: Human error and system failures continue to play a substantial role in adverse outcomes in healthcare. Simulation improves management of patients in critical condition, especially if it is undertaken by a multidisciplinary team. It covers technical skills (technical and therapeutic procedures) and non-technical skills, known as Crisis Resource Management. The relationship between stress and performance is theoretically described by the Yerkes-Dodson law as an inverted U-shaped curve. Performance is very low for a low level of stress and increases with an increased level of stress, up to a point, after which performance decreases and becomes severely impaired. The objectives of this randomized trial are to study the effect of stress on performance and the effect of repeated simulation sessions on performance and stress., Methods: This study is a single-center, investigator-initiated randomized controlled trial including 48 participants distributed in 12 multidisciplinary teams. Each team is made up of 4 persons: an emergency physician, a resident, a nurse, and an ambulance driver who usually constitute a French Emergency Medical Service team. Six multidisciplinary teams are planning to undergo 9 simulation sessions over 1 year (experimental group), and 6 multidisciplinary teams are planning to undergo 3 simulation sessions over 1 year (control group). Evidence of the existence of stress will be assessed according to 3 criteria: biological, electrophysiological, and psychological stress. The impact of stress on overall team performance, technical procedure and teamwork will be evaluated. Participant self-assessment of the perceived impact of simulations on clinical practice will be collected. Detection of post-traumatic stress disorder will be performed by self-assessment questionnaire on the 7(th) day and after 1 month., Discussion: We will concomitantly evaluate technical and non-technical performance, and the impact of stress on both. This is the first randomized trial studying repetition of simulation sessions and its impact on both clinical performance and stress, which is explored by objective and subjective assessments. We expect that stress decreases team performance and that repeated simulation will increase it. We expect no variation of stress parameters regardless of the level of performance., Trial Registration: ClinicalTrials.gov registration number NCT02424890.

Inadequate blood pressure (BP) control may be linked with poor adherence to guidelines by the treating physician. This study aimed at assessing the rates of controlled hypertension as per the 2009 Reappraisal of the 2007 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines in 2185 hypertensive adults across five countries (Algeria, Pakistan, Ukraine, Egypt and Venezuela). The rates of controlled hypertension according to physician perception, type of therapy and risk factors were evaluated. Overall, 40% of patients had controlled hypertension according to the guidelines. A marked divergence in the rates of controlled hypertension as assessed by physicians and guidelines was observed (72% vs 40%). The presence of high/very high risks was linked to poor BP control. High salt intake [29%; odds ratio (OR) 9.94, 95% confidence interval (CI) 6.72;14.69], treatment non-adherence (27%; OR 7.32, 95% CI 4.82;11.13), lack of understanding of the treatment's importance (25%; OR 4.95, 95% CI 3.16;7.75), comorbidity (13%) and depression (9%; OR 10.50, 95% CI 5.37;20.54) were major reasons for not achieving hypertension control. Addition of another drug was the most frequent medication change prescribed. Poor rates of BP control warrant repeated promotion of guidelines while identifying potential contributing factors and implementing strategies that re-establish BP control.

Background: The potential influence of bed availability on triage to intensive care unit (ICU) admission is among the factors that may influence the ideal ratio of ICU beds to population: thus, high bed availability (HBA) may result in the admission of patients too well or too sick to benefit, whereas bed scarcity may result in refusal of patients likely to benefit from ICU admission., Methods: Characteristics and outcomes of patient admitted in four ICUs with usual HBA, defined by admission refusal rate less than 11 % because of bed unavailability, were compared to patients admitted in six ICUs with usual low bed availability (LBA), i.e., an admission refusal rate higher than 10 % during a 90-day period., Results: Over the 90 days, the mean number of days with no bed available was 30 ± 16 in HBA units versus 48 ± 21 in LBA units (p < 0.01). The proportion of admitted patients was significantly higher in the HBA (80.1 %; n = 659/823) than in the LBA units [61.6 %: n = 480/779; (p < 0.0001)]. The proportion of patients deemed too sick to benefit from admission was higher in LBA (9.0 %; n = 70) than in the HBA (6.3 %; n = 52) units (p < 0.05). The HBA group had a significantly greater proportion of patients younger than 40 years of age (22.5 %; n = 148 versus 14 %; n = 67 in LBA group; p < 0.001) and higher proportions of patients with either high or low simplified acute physiologic score II values., Conclusions: Bed availability affected triage decisions. Units with HBA trend to admit patients too sick or too well to benefit.

Objective: Subjects with diabetes are prone to the development of cardiovascular and noncardiovascular complications. In separate studies, acute kidney injury (AKI), albuminuria, and low estimated glomerular filtration rate (eGFR) were shown to predict adverse outcomes, but, when considered together, their respective prognostic value is unknown., Research Design and Methods: Patients with type 2 diabetes consecutively recruited in the SURDIAGENE cohort were prospectively followed up for major diabetes-related events, as adjudicated by an independent committee: death (with cause), major cardiovascular events (myocardial infarction, stroke, congestive heart failure, amputation, and arterial revascularization), and renal failure (i.e., sustained doubling of serum creatinine level or end-stage renal disease)., Results: Intrahospital AKI occurred in 411 of 1,371 patients during the median follow-up period of 69 months. In multivariate analyses, AKI was significantly associated with cardiovascular and noncardiovascular death, including cancer-related death. In multivariate analyses, AKI was a powerful predictor of major adverse cardiovascular events, heart failure requiring hospitalization, myocardial infarction, stroke, lower-limb amputation or revascularization, and carotid artery revascularization. AKI, eGFR, and albuminuria, even when simultaneously considered in multivariate models, predicted all-cause and cardiovascular deaths. All three renal biomarkers were also prognostic of most adverse outcomes and of the risk of renal failure., Conclusions: AKI, low eGFR, and elevated albuminuria, separately or together, are compelling biomarkers of major adverse outcomes and death in diabetes., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: Besides the neurofibrillary tangles and amyloid plaques, an inflammatory process is involved at central and peripheral levels in Alzheimer's disease (AD). We aimed to determine whether peripheral inflammatory parameter levels, in plasma and in peripheral blood mononuclear cells (PBMCs), could be correlated with the cognitive status at the time of AD diagnosis., Methods: Patients were included at diagnosis with MMSE score between 16 and 25 and were naive of symptomatic treatment for AD. C-reactive protein >10 mg/L and any acute or chronic inflammation were considered as exclusion criteria. Cognitive assessment also included the ADAScog scale. Plasma interleukins (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and the chemokine ligand 5 (CCL5) were measured using Luminex(®) X-MAP(®) technology. A subgroup of patients also underwent measures of these parameters in extracellular and intracellular compartments of PBMCs (ancillary study)., Results: One hundred and nine patients were included; mean age 79.4 ± 6.8 years with 37 patients in the ancillary study. The mean values of IL-1β, TNF-α, IL-6 and CCL5 values were 1.49, 7.18, 3.09 and 69,615.81 pg/mL, respectively. No correlation between plasma cytokines or chemokine levels and cognitive scores was found. In PBMCs, the levels of cytokines were detectable but did not either show any correlation with cognitive scores., Conclusion: Our data indicate that at diagnosis, peripheral levels of cytokines and CCL5 display low values without any correlation with the cognitive status. Further results of our study will show if these circulating markers are related to the progression of AD.

Recent findings indicate that microglia in Alzheimer's disease (AD) is senescent whereas peripheral blood mononuclear cells (PBMCs) could infiltrate the brain to phagocyte amyloid deposits. However, the molecular mechanisms involved in the amyloid peptide clearance remain unknown. Autophagy is a physiological degradation of proteins and organelles and can be controlled by pro-inflammatory cytokines. The purpose of this study was to evaluate the impact of inflammation on autophagy in PBMCs from AD patients at baseline, 12 and 24 months of follow-up. Furthermore, PBMCs from healthy patients were also included and treated with 20 μM amyloid peptide 1-42 to mimic AD environment. For each patient, PBMCs were stimulated with the mitogenic factor, phytohaemagglutin (PHA), and treated with either 1 μM C16 as an anti-inflammatory drug or its vehicle. Autophagic markers (Beclin-1, p62/sequestosome 1 and microtubule-associated protein-light chain 3: LC3) were quantified by western blot and cytokines (Interleukin (IL)-1β, Tumor necrosis Factor (TNF)-α and IL-6) by Luminex X-MAP® technology. Beclin-1 and TNF-α levels were inversely correlated in AD PBMCs at 12 months post-inclusion. In addition, Beclin-1 and p62 increased in the low inflammatory environment induced by C16. Only LC3-I levels were inversely correlated with cognitive decline at baseline. For the first time, this study describes longitudinal changes in autophagic markers in PBMCs of AD patients under an inflammatory environment. Inflammation would induce autophagy in the PBMCs of AD patients while an anti-inflammatory environment could inhibit their autophagic response. However, this positive response could be altered in a highly aggressive environment.

Background: We previously reported that the low-frequency, loss-of-function variant p.R270H in FFAR4 encoding the lipid sensor GPR120 was associated with obesity. Gpr120-deficient mice develop obesity and both impaired fasting glucose and glucose intolerance under a high-fat diet. We aimed to assess the contribution of p.R270H to type 2 diabetes (T2D) risk and the variation of glucose-related traits., Methods: We genotyped p.R270H in 8996 non-diabetic individuals (among whom 4523 had an oral glucose tolerance test (OGTT)) and in a T2D case-control study including 4725 cases and 4339 controls. The regression models were adjusted for age, sex and body mass index (BMI)., Results: We found a significant association between p.R270H and increased fasting glucose levels (β=0.092±0.05 mmol/L; p=4.13×10(-4)). Furthermore, p.R270H nominally contributed to decreased homeostasis model of pancreatic β-cell function (HOMA-B; β=-0.090±0.06; p=6.01×10(-3)). Despite a high statistical power, we did not find any significant association between p.R270H and T2D risk or the variation of fasting insulin levels, the homeostasis model of insulin resistance or OGTT-derived indices., Conclusions: These results suggest that the low-frequency p.R270H variant which inhibits GPR120 activity might influence fasting glucose levels in a normal physiological range. This study does not exclude that other coding mutations in FFAR4 with stronger functional effect than p.R270H may be associated with T2D., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Production of adrenomedullin (ADM), a vasodilator peptide, increases in response to ischemia and hypoxia in the vascular wall and the kidney. This may be an adaptive response providing protection against organ damage. We investigated the hypothesis that ADM has a nephroprotective effect in two prospective cohorts of patients with type 2 diabetes recruited in France. The highest tertile of plasma MR-proADM (a surrogate for ADM) concentration at baseline was associated with the risk of renal outcomes (doubling of plasma creatinine concentration and/or progression to end-stage renal disease) during follow-up in both cohorts. Four SNPs in the ADM gene region were associated with plasma MR-proADM concentration at baseline and with eGFR during follow-up in both cohorts. The alleles associated with lower eGFR were also associated with lower plasma MR-proADM level. In conclusion, plasma MR-proADM concentration was associated with renal outcome in patients with type 2 diabetes. Our data suggest that the ADM gene modulates the genetic susceptibility to nephropathy progression. Results are consistent with the hypothesis of a reactive rise of ADM in diabetic nephropathy, blunted in risk alleles carriers, and with a nephroprotective effect of ADM. A possible therapeutic effect of ADM receptor agonists in diabetic renal disease would be worth investigating., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Diabetic macular edema (DME) is the main cause of visual loss associated with diabetes but any association between DME and cardiovascular events is unclear.This study aims to describe the possible association between DME and cardiovascular events in a multicenter cross-sectional study of patients with type 2 diabetes.Two thousand eight hundred seven patients with type 2 diabetes were recruited from diabetes and nephrology clinical institutional centers participating in the DIAB 2 NEPHROGENE study focusing on diabetic complications. DME (presence/absence) and diabetic retinopathy (DR) classification were based on ophthalmological report and/or on 30° color retinal photographs. DR was defined as absent, nonproliferative (background, moderate, or severe) or proliferative. Cardiovascular events were stroke, myocardial infarction, and lower limb amputation.Details regarding associations between DME and cardiovascular events were evaluated.The study included 2807 patients with type 2 diabetes, of whom 355 (12.6%) had DME. DME was significantly and independently associated with patient age, known duration of diabetes, HbA1c, systolic blood pressure, and DR stage. Only the prior history of lower limb amputation was strongly associated with DME in univariate and multivariate analyses, whereas no association was found with regard to myocardial infarction or stroke. Moreover, both major (n = 32) and minor lower limb (n = 96) amputations were similarly associated with DME, with respective odds ratio of 3.7 (95% confidence interval [CI], 1.77-7.74; P = 0.0012) and of 4.29 (95% CI, 2.79-6.61; P < 0.001).DME is strongly and independently associated with lower limb amputation in type 2 diabetic patients.

Background: Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated. Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia., Methods: We performed a multicenter, open-label trial in which we randomly assigned patients without hypercapnia who had acute hypoxemic respiratory failure and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 mm Hg or less to high-flow oxygen therapy, standard oxygen therapy delivered through a face mask, or noninvasive positive-pressure ventilation. The primary outcome was the proportion of patients intubated at day 28; secondary outcomes included all-cause mortality in the intensive care unit and at 90 days and the number of ventilator-free days at day 28., Results: A total of 310 patients were included in the analyses. The intubation rate (primary outcome) was 38% (40 of 106 patients) in the high-flow-oxygen group, 47% (44 of 94) in the standard group, and 50% (55 of 110) in the noninvasive-ventilation group (P=0.18 for all comparisons). The number of ventilator-free days at day 28 was significantly higher in the high-flow-oxygen group (24±8 days, vs. 22±10 in the standard-oxygen group and 19±12 in the noninvasive-ventilation group; P=0.02 for all comparisons). The hazard ratio for death at 90 days was 2.01 (95% confidence interval [CI], 1.01 to 3.99) with standard oxygen versus high-flow oxygen (P=0.046) and 2.50 (95% CI, 1.31 to 4.78) with noninvasive ventilation versus high-flow oxygen (P=0.006)., Conclusions: In patients with nonhypercapnic acute hypoxemic respiratory failure, treatment with high-flow oxygen, standard oxygen, or noninvasive ventilation did not result in significantly different intubation rates. There was a significant difference in favor of high-flow oxygen in 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique Interrégional 2010 of the French Ministry of Health; FLORALI ClinicalTrials.gov number, NCT01320384.).

Background: Lumbar spinal stenosis is a major public health issue. Interspinous devices implanted using minimally invasive techniques may constitute an alternative to the reference standard of bony decompression with or without intervertebral fusion. However, their indications remain unclear, due to a paucity of clinical and biomechanical data. Our objective was to evaluate the effects of four interspinous process devices implanted at L4-L5 on the intervertebral foramen surface areas at the treated and adjacent levels, in flexion and in extension., Materials and Method: Six fresh frozen human cadaver lumbar spines (L2-sacrum) were tested on a dedicated spinal loading frame, in flexion and extension, from 0 to 10 N·m, after preparation and marking of the L3-L4, L4-L5, and L5-S1 foramina. Stereoscopic 3D images were acquired at baseline then after implantation at L4-L5 of each of the four devices (Inspace(®), Synthes; X-Stop(®), Medtronic; Wallis(®), Zimmer; and Diam(®), Medtronic). The surface areas of the three foramina of interest were computed., Results: All four devices significantly opened the L4-L5 foramen in extension. The effects in flexion separated the devices into two categories. With the two devices characterized by fixation in the spinous processes (Wallis(®) and Diam(®)), the L4-L5 foramen opened only in extension; whereas with the other two devices (X-Stop(®) and Inspace(®)), the L4-L5 foramen opened not only in extension, but also in flexion and in the neutral position. None of the devices implanted at L4-L5 modified the size of the L3-L4 foramen. X-Stop(®) and Diam(®) closed the L5-S1 foramen in extension, whereas the other two devices had no effect at this level., Conclusion: Our results demonstrate that interspinous process devices modify the surface area of the interspinous foramina in vitro. Clinical studies are needed to clarify patient selection criteria for interspinous process device implantation., Level of Evidence: Level IV. Investigating an orthopaedic device., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: The aim of this study was to evaluate the clinical efficacy of humidified oxygen via high-flow nasal cannula (HFNC) alternating with noninvasive ventilation (NIV) in acute hypoxemic respiratory failure (AHRF)., Methods: We performed a prospective observational study in a 12-bed ICU of a university hospital. All subjects with a PaO2 /FIO2 of ≤300 mm Hg with standard mask oxygen and a breathing frequency of > 30 breaths/min or signs of respiratory distress were included and treated with HFNC first and then NIV. Ventilatory parameters, blood gases, and tolerance were recorded during 2 consecutive sessions of NIV and HFNC. Outcome was assessed after continuation of this noninvasive strategy., Results: Twenty-eight subjects with AHRF were studied, including 23 (82%) with ARDS. Compared with standard oxygen therapy, PaO2 significantly increased from 83 (68-97) mm Hg to 108 (83-140) mm Hg using HFNC and to 125 (97-200) mm Hg using NIV (P<.01), whereas breathing frequency significantly decreased. HFNC was significantly better tolerated than NIV, with a lower score on the visual analog scale. The non-intubated subjects received HFNC for 75 (27-127) h and NIV for 23 (8-31) h. Intubation was required in 10 of 28 subjects (36%), including 8 of 23 subjects with ARDS (35%). After HFNC initiation, a breathing frequency of ≥30 breaths/min was an early factor associated with intubation., Conclusions: HFNC was better tolerated than NIV and allowed for significant improvement in oxygenation and tachypnea compared with standard oxygen therapy in subjects with AHRF, a large majority of whom had ARDS. Thus, HFNC may be used between NIV sessions to avoid marked impairment of oxygenation., (Copyright © 2015 by Daedalus Enterprises.)

Background: Left ventricular hypertrophy (LVH) and kidney damage (abnormal urinary albumin-to-creatinine ratio [uACR] or estimated glomerular filtration rate [eGFR]) are predictive of major cardiovascular events (MACE) in patients with type 2 diabetes (T2D) but are rarely used in cardiovascular score calculators. Our study aimed to assess their respective prognostic values for MACE and the additive information they provide to score calculators., Methods: A total of 1298 T2D (43% women) aged 65 (SD 11) years were followed up for a median of 65 months, with MACE as a primary composite end point: cardiovascular death, nonfatal myocardial infarction, or stroke. Electrocardiogram (ECG)-derived LVH was defined using Sokolow, Gubner, and Cornell product indexes; uACR was considered as abnormal if >2.5 mg/mmol in men or >3.5 mg/mmol in women and eGFR if <60 mL/min per 1.73 m(2)., Results: Urinary albumin-to-creatinine ratio was higher in subjects with electrocardiographic LVH (ECG-LVH) than in subjects without (median [interquartile range] 7.61 [43.48] and 2.56 [10.53], respectively; P < .0001). After adjustment for age, history of myocardial infarction, and peripheral artery disease, ECG-LVH and kidney damage were strong predictors for MACE (adjusted hazard ratio [1.64; 95% CI 1.23-2.20], [1.90; 95% CI 1.43-2.53], and [1.85; 95% CI 1.42-2.41] for ECG-LVH, uACR, and eGFR, respectively). Net reclassification improvement was higher with the model including both ECG-LVH and uACR than models with ECG-LVH alone (P < .0001) or uACR alone (P < .0001). In addition, using cardiovascular risk calculators (Framingham score and others), we observed an additional prognostic value of ECG-LVH for each one of them., Conclusions: Electrocardiographic LVH is complementary to kidney damage for MACE prediction in T2D., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Measuring foraminal stenosis is generally determined by an area calculation. It is difficult to know exactly where it is most appropriate to measure. No precise data are available on a method for calculating the foraminal volume using a CT. To develop a new method for measuring lumbar foraminal volume, we analyzed repeatability and reliability for measuring methods for foraminal volume using CT., Methods: The measurements were performed using a CT scan from ten healthy patients, with a mean age of 26.3 years. L3-L4, L4-L5 and L5-S1 foramen were studied, to obtain 60 foraminal measurements. Inter- and intra-observer reproducibility was calculated. Each series was analyzed using the VitreaCore® reconstruction software for volume calculation., Results: Average volume measurements of 60 foramina and 20 L4-L5 foramina were, respectively, 1.17 and 1.25 mm(3) for observer 1 and 1.21 and 1.29 for observer 2. The intra-observer correlation coefficients for observer 1 when measuring all foramina and L4-L5 foramina were 0.98 and 0.99, respectively. For observer 2, coefficients were 0.90 and 0.92, respectively. The inter-observer correlation coefficients for observer 1 when measuring all foramina and L4-L5 foramina were 0.78 and 0.83, respectively. For observer 2, coefficients were 0.77 and 0.8, respectively. The average differences in intra- and inter-observer measurements regardless of the evaluator group were less than 0.2 mm(3)., Conclusions: This is the first study measuring lumbar foraminal volume using CT. The excellent reproducibility of this simple measure can supplement a range of foramen measurement tools.

Aims: Several reports have suggested a relationship between male sex and albuminuria in Type 2 diabetes, but impact on renal function decline has not been established. Our aim was to describe the influence of sex on renal function decline in Type 2 diabetes., Methods: SURDIAGENE, an inception cohort, consisted in 1470 people with Type 2 diabetes. Patients without renal replacement therapy and with ≥ 3 serum creatinine determinations during follow-up prior to end-stage renal disease were included in the study. Estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Primary outcome was steep estimated glomerular filtration rate (eGFR) decline, defined as a yearly slope value lower than -3.5 ml min(-1) 1.73 m(-2). Secondary outcomes were estimated glomerular filtration rate trajectories according to sex and occurrence of end-stage renal disease., Results: A total of 22 914 serum creatinine determinations were considered in 1146 participants (60% men), aged 65 ± 11 years, with a median follow-up duration of 5.7 years (range 0.1-10.2). Median yearly estimated glomerular filtration rate slope was -1.31 ml min(-1) 1.73 m(-2) in women and -1.77 ml min(-1) 1.73 m(-2) in men (P < 0.001). Men were more likely than women to develop end-stage renal disease (22 men vs. 7 women; P(log-rank) = 0.03). Male sex was an independent risk factor of steep estimated glomerular filtration rate decline [adjusted odds ratio = 1.33 (1.02-1.76), P = 0.04] after adjustment for age, time from diagnosis of Type 2 diabetes, glycated haemoglobin, systolic blood pressure and urinary albumin:creatinine ratio. A multivariable linear mixed-effects model showed a significant difference of estimated glomerular filtration rate trajectories between men and women (P < 0.001)., Conclusion: Male sex is an important independent factor associated with renal function decline in Type 2 diabetes., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

Introduction: Circulatory failure during brain death organ donor resuscitation is a problem that compromises recovery of organs. Combined administration of steroid, thyroxine and vasopressin has been proposed to optimize the management of brain deceased donors before recovery of organs. However the single administration of hydrocortisone has not been rigorously evaluated in any trial., Methods: In this prospective multicenter cluster study, 259 subjects were included. Administration of low-dose steroids composed the steroid group (n = 102)., Results: Although there were more patients in the steroid group who received norepinephrine before brain death (80% vs. 66%: P = 0.03), mean dose of vasopressor administered after brain death was significantly lower than in the control group (1.18 ± 0.92 mg/H vs. 1.49 ± 1.29 mg/H: P = 0.03), duration of vasopressor support use was shorter (874 min vs. 1160 min: P < 0.0001) and norepinephrine weaning before aortic clamping was more frequent (33.8% vs. 9.5%: P < 0.0001). Using a survival approach, probability of norepinephrine weaning was significantly different between the two groups (P < 0.0001) with a probability of weaning 4.67 times higher in the steroid group than in the control group (95% CI: 2.30 - 9.49)., Conclusions: Despite no observed benefits of the steroid administration on primary function recovery of transplanted grafts, administration of glucocorticoids should be a part of the resuscitation management of deceased donors with hemodynamic instability.