Insulin Requirements According to Sex and Weight in a Population of 9036 Adult Persons With Type 1 Diabetes Using Closed-Loop Insulin Delivery.

BACKGROUND: The prediction of the individual insulin needs may facilitate the initiation of insulin therapy. Our aim was to explore the relationships between body weight, sex, and daily amounts of insulin delivered by a hybrid closed-loop system. METHODS: We performed a retrospective data collection of all consenting adult patients with type 1 diabetes who were equipped in Europe with the Diabeloop Generation 1 (DBLG1) hybrid closed-loop insulin delivery device between March 1, 2021 and February 28, 2023. RESULTS: A total of 9036 users (59% females, age 45.6 ± 14.3 years) were included, reaching a mean follow-up of 320 ± 143 days, an overall 2 887 188 days of data. We observed a mean insulin-weight ratio of 0.617 ± 0.207 U/kg (0.665 ± 0.217 for males and 0.584 ± 0.193 for females, P < .001). Exploratory analysis of a subset of 4066 patients reaching >70% Time in Range (70-180 mg/dL) showed a mean insulin-weight ratio of 0.55 ± 0.17 U/kg (P < .001) (0.59 ± 0.18 for the 1438 males and 0.53 ± 0.16 for the 2628 females). CONCLUSION: This large real-world analysis provides a quantitative estimation of the daily insulin requirements in adult patients with type 1 diabetes and shows significant differences between sex. These findings have relevant implications in the practical management of insulin therapy.

Oscillococcinum® for upper respiratory tract infections and exacerbations in COPD: an observational, prospective study (OXITUNIS).

BACKGROUND: Upper respiratory tract infections (URTIs) are a major cause of exacerbations in patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of Oscillococcinum® in the protection from URTIs in patients with COPD who had been vaccinated against influenza infection over the 2018-2019 winter season. METHODS: Patients (n=106; mean ± standard deviation age: 66.0 ± 10.3 years; 89.6% men) were randomized into two groups: group V received influenza vaccination only and group OV received influenza vaccination plus Oscillococcinum® (one oral dose per week from inclusion in the study until the end of follow-up, with a maximum of 6 months follow-up over the winter season). The primary endpoint was the incidence rate of URTIs (number of URTIs/1000 patient-treatment exposure days) during follow-up compared between the two groups. RESULTS: There was no significant difference in any of the demographic characteristics, baseline COPD, or clinical data between the two treatment groups (OV and V). The URTI incidence rate was significantly higher in group V than in group OV (2.9 versus 1.2 episodes/1000 treatment days, difference OV-V = -1.7; p=0.0312). There was a significant delay in occurrence of an URTI episode in the OV group versus the V group (mean ± standard error: 48.7 ± 3.0 versus 67.0 ± 2.8 days, respectively; p=0.0158). Limitations to this study include its small population size and the self-recording by patients of the number and duration of URTIs and exacerbations. CONCLUSION: Oscillococcinum may decrease the incidence rate and delay the appearance of URTIs in patients with COPD.

Daily volume of cases in emergency call centers: construction and validation of a predictive model.

BACKGROUND: Variations in the activity of emergency dispatch centers are an obstacle to the rationalization of resource allocation. Many explanatory factors are well known, available in advance and could predict the volume of emergency cases. Our objective was to develop and evaluate the performance of a predictive model of daily call center activity. METHODS: A retrospective survey was conducted on all cases from 2005 to 2011 in a large medical emergency call center (1,296,153 cases). A generalized additive model of daily cases was calibrated on data from 2005 to 2008 (1461 days, development sample) and applied to the prediction of days from 2009 to 2011 (1095 days, validation sample). Seventeen calendar and epidemiological variables and a periodic function for seasonality were included in the model. RESULTS: The average number of cases per day was 507 (95% confidence interval: 500 to 514) (range, 286 to 1251). Factors significantly associated with increased case volume were the annual increase, weekend days, public holidays, regional incidence of influenza in the previous week and regional incidence of gastroenteritis in the previous week. The adjusted R for the model was 0.89 in the calibration sample. The model predicted the actual number of cases within ± 100 for 90.5% of the days, with an average error of -13 cases (95% CI: -17 to 8). CONCLUSIONS: A large proportion of the variability of the medical emergency call center's case volume can be predicted using readily available covariates.

Evaluation of eight biomarkers to predict short-term mortality in patients with acute severe dyspnea.

BACKGROUND: Being able to better predict risk and optimal care for patients presenting with acute dyspnea is critical. Prognostic biomarkers are well known: amino-terminal pro-B-type Natriuretic Peptide, troponin, C-reactive protein, procalcitonin. Some were more recently developed: mid-regional pro-A-type natriuretic peptide (Mid Pro-ANP), mid-regional-pro-adrenomedullin (MR-proADM), pro-endothelin, copeptin. The aim of the paper was to evaluate prognostic value of clinical findings and 8 biomarkers in patients with severe acute dyspnea. METHODS: We designed a prospective cohort study targeting patients admitted in the Emergency Department and in Intensive Care Unit of a University Hospital. Inclusion criteria were acute dyspnea with SpO2 less than 92% and/or respiratory rate (RR) greater than or equal to 25 bpm. Clinical and biological data, including biomarker levels, were recorded. The contribution of the biomarkers in the prognosis was assessed using AUC-ROC curves and by multiple logistic regression. RESULTS: Three hundred and eighty four patients (median age 74 years, 28-day mortality 17%) were enrolled. All biomarkers were available for 317 patients. Main diagnoses were sepsis in 141 cases (36.7%), and acute heart failure in 84 (21.9%) cases. All biomarkers were correlated with prognosis. Pro-ADM (AUC-ROC=0.731; 95% CI: 0.658-0.804) showed the best accuracy. The parameters independently associated with prognosis led to a clinical/biological model with an AUC=0.809 and a good calibration (P (HLchi2)=0.9). Three biomarkers added prognostic information to the model: MR-proADM (P=0.005), copeptin (P=0.006) and troponin (P=0.05). CONCLUSIONS: Biomarkers can contribute to determine the day-28 outcome of patients with acute severe dyspnea.

Complications of intravascular catheters in ICU: definitions, incidence and severity. A randomized controlled trial comparing usual transparent dressings versus new-generation dressings (the ADVANCED study).

PURPOSE: To describe all post-insertion complications involving most used intravascular access, and to determine whether the use of a new-generation transparent dressing (3M™ IV Advanced) might reduce their number and impact on ICU patient outcomes. METHODS: Patients older than 18, with an expected length of stay ≥48 h and requiring at least one central venous catheter (CVC), arterial catheter (AC), haemodialysis catheter (HDC), pulmonary arterial catheters (PAC) or peripheral venous catheter (PVC) were randomized into two groups: a new-generation transparent dressing, or the hospital's classical transparent dressing, and were followed daily for any infectious and non-infectious complications. Complications were graduated for severity by an independent international multicentre multidisciplinary panel of practitioners using a Delphi process. RESULTS: We included 628 patients, 2214 catheters (873 PVCs, 630 CVCs, 512 ACs and 199 HDCs and PACs) and 4836 dressings. Overall incidence rate was of 60.9/1000 catheter-days. The most common complication was dysfunction (34.6/1000 catheter-days), mainly for PVCs (16/1000 catheter-days) and ACs (12.9/1000 catheter-days). Infectious complications incidence rate in CVCs and ACs was of 14.5/1000, mostly due to colonization (14.2/1000 catheter-days). Thrombosis incidence was of 3.8/1000 catheter-days with severe and very severe complications in 16 cases (1.8/1000 catheter-days) and one thrombosis-related death. 3M™ IV Advanced dressing did not decrease the rate of catheters with at least a minor complication [57.37/1000 vs. 57.52/1000 catheter-days, HR 1.03, CI (0.84-1.27), p = 0.81]. Incidence rates for each single complication remained equivalent: infectious [HR 0.93 (0.62-1.40), p = 0.72], deep thrombosis [HR 0.90 (0.39-2.06), p = 0.80], extravasation and phlebitis [HR 1.40 (0.69-2.82), p = 0.35], accidental removal [1.07 (0.56-2.04), p = 0.84] and dysfunction [HR 1.04 (0.80-1.35), p = 0.79]. CONCLUSION: The ADVANCED study showed the overall risk of complications to intravascular catheters in ICU patients being dysfunction, infection and thrombosis. The 3M™ IV Advanced dressing did not decrease complication rates as compared to standard dressings.

Ethanol lock and risk of hemodialysis catheter infection in critically ill patients. A randomized controlled trial.

RATIONALE: Ethanol rapidly eradicated experimental biofilm. Clinical studies of ethanol lock to prevent catheter-related infections (CRIs) suggest preventive efficacy. No such studies have been done in intensive care units (ICU). OBJECTIVES: To determine whether ethanol lock decreases the risk of major CRI in patients with short-term dialysis catheters (DCs). METHODS: A randomized, double-blind, placebo-controlled trial was performed in 16 ICUs in seven university hospitals and one general hospital in France between June 2009 and December 2011. Adults with insertion of a nontunneled, nonantimicrobial-impregnated double-lumen DC for an expected duration greater than 48 hours, to perform renal-replacement therapy or plasma exchange, were randomly allocated (1:1) to receive a 2-minute catheter lock with either 60% wt/wt ethanol solution (ethanol group) or 0.9% saline solution (control group) at the end of DC insertion and after each renal-replacement therapy or plasma exchange session. The main outcome was major CRI defined as either catheter-related clinical sepsis without bloodstream infection or catheter-related bloodstream infection during the ICU stay. MEASUREMENTS AND MAIN RESULTS: The intent-to-treat analysis included 1,460 patients (2,172 catheters, 12,944 catheter-days, and 8,442 study locks). Median DC duration was 4 days (interquartile range, 2-8) and was similar in both groups. Major CRI incidence did not differ between the ethanol and control groups (3.83 vs. 2.64 per 1,000 catheter-days, respectively; hazard ratio, 1.55; 95% confidence interval, 0.83-2.87; P = 0.17). No significant differences occurred for catheter colonization (P = 0.57) or catheter-related bloodstream infection (P = 0.99). CONCLUSIONS: A 2-minute ethanol lock does not decrease the frequency of infection of DCs in ICU patients. Clinical trial registered with www.clinicaltrials.gov (NCT 00875069).

The Iatroref study: medical errors are associated with symptoms of depression in ICU staff but not burnout or safety culture.

PURPOSE: Staff behaviours to optimise patient safety may be influenced by burnout, depression and strength of the safety culture. We evaluated whether burnout, symptoms of depression and safety culture affected the frequency of medical errors and adverse events (selected using Delphi techniques) in ICUs. METHODS: Prospective, observational, multicentre (31 ICUs) study from August 2009 to December 2011. RESULTS: Burnout, depression symptoms and safety culture were evaluated using the Maslach Burnout Inventory (MBI), CES-Depression scale and Safety Attitudes Questionnaire, respectively. Of 1,988 staff members, 1,534 (77.2 %) participated. Frequencies of medical errors and adverse events were 804.5/1,000 and 167.4/1,000 patient-days, respectively. Burnout prevalence was 3 or 40 % depending on the definition (severe emotional exhaustion, depersonalisation and low personal accomplishment; or MBI score greater than -9). Depression symptoms were identified in 62/330 (18.8 %) physicians and 188/1,204 (15.6 %) nurses/nursing assistants. Median safety culture score was 60.7/100 [56.8-64.7] in physicians and 57.5/100 [52.4-61.9] in nurses/nursing assistants. Depression symptoms were an independent risk factor for medical errors. Burnout was not associated with medical errors. The safety culture score had a limited influence on medical errors. Other independent risk factors for medical errors or adverse events were related to ICU organisation (40 % of ICU staff off work on the previous day), staff (specific safety training) and patients (workload). One-on-one training of junior physicians during duties and existence of a hospital risk-management unit were associated with lower risks. CONCLUSIONS: The frequency of selected medical errors in ICUs was high and was increased when staff members had symptoms of depression.

Evaluation of RECIST in chemotherapy-treated lung cancer: the Pharmacogenoscan Study.

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST) are widely used to assess the effect of chemotherapy in patients with cancer. We hypothesised that the change in unidimensional tumour size handled as a continuous variable was more reliable than RECIST in predicting overall survival (OS). METHODS: The prospective Pharmacogenoscan study enrolled consecutive patients with non-small-cell lung cancer (NSCLC) at any stage seen between 2005 and 2010 at six hospitals in France, given chemotherapy. After exclusion of patients without RECIST or continuous-scale tumour size data and of those with early death, 464 patients were left for the survival analyses. Cox models were built to assess relationships between RECIST 1.1 categories or change in continuous-scale tumour size and OS. The best model was defined as the model minimising the Akaike Information Criterion (AIC). RESULTS: OS was 14.2 months (IQR, 7.3-28.9 months). According to RECIST 1.1, 146 (31%) patients had a partial or complete response, 245 (53%) stable disease, and 73 (16%) disease progression. RECIST 1.1 predicted better OS than continuous-scale tumour in early (<6 months) predicted survival analyses (p = 0.03) but the accuracy of the two response evaluation methods was similar in late (≥6 months) predicted survival analyses (p = 0.15). CONCLUSION: In this large observational study, change in continuous-scale tumour size did not perform better than RECIST 1.1 in predicting survival of patients given chemotherapy to treat NSCLC. TRIAL REGISTRATION: NCT00222404.

Initiation of nutritional support is delayed in critically ill obese patients: a multicenter cohort study.

BACKGROUND: A high catabolic rate characterizes the acute phase of critical illness. Guidelines recommend an early nutritional support, regardless of the previous nutritional status. OBJECTIVE: We aimed to assess whether the nutritional status of patients, which was defined by the body mass index (BMI) at admission in an intensive care unit (ICU), affected the time of nutritional support initiation. DESIGN: We conducted a cohort study that reported a retrospective analysis of a multicenter ICU database (OUTCOMEREA) by using data prospectively entered from January 1997 to October 2012. Patients who needed orotracheal intubation within the first 72 h and >3 d were included. RESULTS: Data from 3257 ICU stays were analyzed. The delay before feeding was different according to BMI groups (P = 0.035). The delay was longer in obese patients [BMI (in kg/m²) ≥30; n = 663] than in other patients with either low weight (BMI <20; n = 501), normal weight (BMI ≥20 and <25; n = 1135), or overweight (BMI ≥25 and <30; n = 958). The association between nutritional status and a delay in nutrition initiation was independent of potential confounding factors such as age, sex, and diabetes or other chronic diseases. In comparison with normal weight, the adjusted RR (95% CI) associated with a delayed nutrition initiation was 0.92 (0.86, 0.98) for patients with low weight, 1.00 (0.94, 1.05) for overweight patients, and 1.06 (1.00, 1.12) for obese patients (P = 0.004). CONCLUSIONS: The initiation of nutritional support was delayed in obese ICU patients. Randomized controlled trials that address consequences of early compared with delayed beginnings of nutritional support in critically ill obese patients are needed.

ICU physician-based determinants of life-sustaining therapy during nights and weekends: French multicenter study from the Outcomerea Research Group.

OBJECTIVE: Patient- and organization-related factors are the most common influences affecting the ICU decision-making process. Few studies have investigated ICU physician-related factors and life-sustaining treatment use during nights and weekends, when staffing ratios are low. Here, we described patients admitted during nights/weekends and looked for physician-related determinants of life-sustaining treatment use in these patients after adjustment for patient- and center-related factors. DESIGN: Multicenter observational cohort study of admission procedures during nights/weekends shifts. SUBJECTS: ICU physicians working nights/weekends in 6 French ICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient characteristics and intensity of care were extracted from the prospective Outcomerea database. Physician characteristics were age, gender, religion and religiosity, ICU experience, specialty, being a permanent ICU staff member, degree in ethics, and degree in intensive care. We used hierarchical mixed models to adjust on center, physician random effects, and admission patient characteristics. Of 156 physicians contacted, 119 (77%) participated. Patients admitted during nights/weekends were younger and had fewer comorbidities and lower treatment intensity during the shift. ICU physicians who are younger than 35 years used more renal replacement therapy (odds ratio, 1.04; 95% CI, 1-1.07; p = 0.04), invasive mechanical ventilation (odds ratio, 1.09; 95% CI, 1.1-1.19; p = 0.04), and vasopressors (odds ratio, 1.16; 95% CI, 1.09-1.23; p < 0.0001). Internal or emergency medicine as the primary specialty was associated with invasive mechanical ventilation (odds ratio, 1.14; 95% CI, 1.04-1.24; p = 0.004) and vasopressor use (odds ratio, 1.09; 95% CI, 1.02-1.17; p = 0.01). Noninvasive ventilation was used less often by physicians with more than 10 years of night/weekend shifts and more often by those with religious beliefs (odds ratio, 1.05; 95% CI, 1.01-1.08; p = 0.008). CONCLUSIONS: Patients admitted during nights/weekends were younger and had fewer comorbidities. Age, specialty, ICU experience, and religious beliefs of the physicians were significantly associated life-sustaining treatments used.

Sepsis severe or septic shock: outcome according to immune status and immunodeficiency profile.

OBJECTIVES: This study evaluated the influence of the immune profile on the outcome at day 28 (D28) of patients admitted to the ICU for septic shock or severe sepsis. METHODS: We conducted an observational study using a prospective multicenter database and included all patients admitted to 11 ICUs for severe sepsis or septic shock from January 1997 to August 2011. Seven profiles of immunodeficiency were defined. The prognostic analysis used a competitive risk model (Fine and Gray), in which being alive at ICU or hospital discharge before D28 competed with death. RESULTS: Among the 1,981 included patients, 607 (31%) were immunocompromised (including nonneutropenic solid tumor [19.6%], nonneutropenic hematologic malignancies [26.3%], and all-cause neutropenia [28%]). Compared with immunocompetent patients, immunocompromised patients were younger, with less comorbidity, were more often admitted for medical reasons, and presented less often with septic shock. The D28 crude mortality was 31.3% in immunocompromised patients and 28.8% in immunocompetent patients (P = .26). However, after adjustment for other prognostic factors, immunodeficiency was an independent risk factor for death at D28 (subdistribution hazard ratio [sHR], 1.37; 95% CI, 1.12-1.67). The immunodeficiency profiles independently associated with death were AIDS (sHR = 1.9), non-neutropenic solid tumor (sHR = 1.8), nonneutropenic hematologic malignancies (sHR = 1.4), and all-cause neutropenia (sHR = 1.7). CONCLUSIONS: Immunodeficiency is common in patients with severe sepsis or septic shock. Despite a similar crude mortality, immunodeficiency was associated with an increased risk of short-term mortality after multivariate analysis. Neutropenia and specific, but not all, profiles of immunodeficiency were independently associated with an increased risk of death.

Long-term adherence with non-invasive ventilation improves prognosis in obese COPD patients.

BACKGROUND AND OBJECTIVE: Long-term non-invasive ventilation (NIV) has become a widespread modality of treatment in chronic obstructive pulmonary disease (COPD) patients with chronic respiratory failure. However, benefits in terms of patient-related outcomes are still under debate. Both NIV adherence and heterogeneous responses in different COPD phenotypes may contribute to the difficulty of demonstrating NIV benefits. Our aim was to assess the impact of NIV adherence on the rate of hospitalization for acute exacerbation and death. METHODS: This is a prospective multi-centre cohort study of COPD patients treated by long-term NIV. Comorbidities, anthropometrics, respiratory parameters were collected at inclusion in the study. Follow-up data included vital status, NIV adherence and hospitalizations. The influence of NIV adherence on prognosis was tested using an adjusted Cox model. Sensitivity analyses for obese and non-obese COPD subtypes were also conducted. RESULTS: Two hundred thirteen patients (48% obese) were included with 45.5% died during 47.7 [interquartile range = 27.8; 73] months' follow-up. Survival was better in obese COPD than non-obese COPD. The use of NIV > 9 h/day was associated with an increased risk of death or hospitalization for acute exacerbation [HR = 1.6; 95CI: 1.1-2.4]. In obese COPD, this risk described a U-shaped curve from >1 to >9 h/day NIV usage with an improvement in prognosis when NIV adherence was > 5 h/day [HR = 0.5; 95CI: 0.2-0.9]. CONCLUSIONS: Adherence to NIV was associated with better prognosis only in obese COPD. NIV use > 9 h/day predicted poor outcomes.

Aspergillus in the lower respiratory tract of immunocompetent critically ill patients.

OBJECTIVES: To shed light on the meaning of Aspergillus-positive lower-respiratory-tract samples in non immunocompromized critically ill patients. METHODS: Multicentre matched case-control (1:5) study. We used prospectively collected data to identify risk factors for Aspergillus-positive specimens, as well as outcomes in Aspergillus-positive patients. RESULTS: 66 cases (5 with definite invasive pulmonary aspergillosis (IPA), 18 with probable IPA, and 43 colonisations) were matched to 330 controls. In the multivariate conditional logistic model, independent risk factors for at least one Aspergillus-positive respiratory-tract specimen were worse SAPSII at admission [OR, 1.10; 95%CI, 1.00-1.21], ARDS [OR, 2.64; 95%CI, 1.29-5.40]; long-term steroid therapy [OR, 4.77; 95%CI, 1.49-15.23]; steroid therapy started in the ICU [OR, 11.03; 95%CI, 4.40-27.67]; and bacterial infection [OR, 2.73; 95%CI, 1.37-5.42]. The risk of death, compared to the controls, was not higher in the cases overall [HR, 0.66; 95%CI, 0.41-1.08; p = 0.1] or in the subgroups with definite IPA [HR, 1.60; 95%CI, 0.43-5.94; p = 0.48], probable IPA [HR, 0.84; 95%CI, 0.28-2.50; p = 0.76], or colonisation [HR, 0.58; 95%CI, 0.33-1.02; p = 0.06]. In cases who received antifungal therapy, mortality was not lower than in untreated cases [HR, 0.67; 95%CI, 0.36-1.24; p = 0.20]. CONCLUSIONS: In critically ill immunocompetent patients, risk factors for presence of Aspergillus in lower respiratory tract specimens are steroid therapy (either chronic or initiated in the ICU), ARDS, and high severity of the acute illness. Prospective studies are warranted to further examine these risk factors and to investigate immune functions as well as the impact of antifungal therapy on patient outcomes.

Noninvasive mechanical ventilation in acute respiratory failure: trends in use and outcomes.

PURPOSE: Noninvasive ventilation (NIV) had proven benefits in clinical trials that included selected patients admitted to highly skilled centers. Whether these benefits apply to every patient and in everyday practice deserves appraisal. The aim of the study was to assess the use and outcomes of NIV over the last 15 years. METHODS: Multicenter database study of critically ill patients who required ventilatory support for acute respiratory failure between 1997 and 2011. The impact of first-line NIV on 60-day mortality was evaluated using a marginal structural model. Follow-up was censored on day 60. RESULTS: Of 3,163 patients, 1,232 (39 %) received NIV. Over the study period, first-line NIV increased from 29 to 42 %, and NIV success rates increased from 69 to 84 %. NIV decreased 60-day mortality [adjusted hazard ratio (aHR), 0.75; 95 % confidence interval (95 % CI), 0.68-0.83; P < 0.0001]. This protective effect was observed in patients with acute-on-chronic respiratory failure (aHR, 0.71; 95 % CI, 0.57-0.90; P = 0.004), but not in patients with cardiogenic pulmonary edema (aHR, 0.85; 95 % CI, 0.70-1.03; P = 0.10) or in patients with hypoxemic ARF, either immunocompetent (aHR, 1.18; 95 % CI, 0.87-1.59; P = 0.30) or immunocompromised (aHR, 0.89; 95 % CI, 0.70-1.13; P = 0.35). NIV failure was an independent time-dependent risk factor for mortality (aHR, 4.2; 95 % CI, 2.8-6.2; P < 0.0001). CONCLUSIONS: The use of NIV increased steadily over the study period. First-line NIV was associated with better 60-day survival and fewer ICU-acquired infections compared to first-line intubation. Survival benefits from NIV occurred only in patients with acute-on-chronic respiratory failure and immunocompromised patients.

Immunohistochemistry evaluation of biomarker expression in non-small cell lung cancer (Pharmacogenoscan study).

OBJECTIVES: Platinum-based chemotherapy regimens are the standard treatment of non-small cell lung cancer (NSCLC). In this study, our objective was to identify tumor tissue protein biomarkers that might predict a benefit from these treatments. MATERIALS AND METHODS: The Pharmacogenoscan study prospectively included consecutive chemotherapy-naive NSCLC patients at any stage between 2005 and 2010 at six hospitals in the Rhône-Alpes-Auvergne region of France. Of the 537 patients in the full analysis set, 460 had a complete histological diagnosis. We used the tumor tissue samples for an immunohistochemical evaluation of eight biomarkers: ERCC1, BRCA1, p53, p27kip1, class III ß-tubulin (TUBB3), Bax, Fas, and FasL. We looked for associations between these biomarkers and the disease control rate (DCR) after 2/3 cycles of platinum-based chemotherapy, progression-free survival (PFS), and overall survival (OS). RESULTS: A tissue sample adequate for testing at least one biomarker was available for 289 patients. We found no significant association between biomarker expression levels and clinical or pathological variables; TUBB3 showed a trend toward higher expression in adenocarcinomas (P=0.005). For none of the biomarkers were significant associations found between expression level and DCR, PFS, or OS. TUBB3-negative and FasL-negative tumors showed associations of borderline significance with higher DCR. CONCLUSION: In a large cohort of patients with predominantly advanced or metastatic NSCLC, none of eight tested immunohistochemical biomarkers predicted the chemotherapy response or survival. Our data indicate limited usefulness of protein biomarkers in metastatic NSCLC and a need for further research based on molecular signatures of greater complexity.

Diagnosis and management of temperature abnormality in ICUs: a EUROBACT investigators' survey.

INTRODUCTION: Although fever and hypothermia are common abnormal physical signs observed in patients admitted to intensive care units (ICU), little data exist on their optimal management. The objective of this study was to describe contemporary practices and determinants of management of temperature abnormalities among patients admitted to ICUs. METHODS: Site leaders of the multi-national EUROBACT study were surveyed regarding diagnosis and management of temperature abnormalities among patients admitted to their ICUs. RESULTS: Of the 162 ICUs originally included in EUROBACT, responses were received from 139 (86%) centers in 23 countries in Europe (117), South America (8), Asia (5), North America (4), Australia (3) and Africa (2). A total of 117 (84%) respondents reported use of a specific temperature threshold in their ICU to define fever. A total of 14 different discrete levels were reported with a median of 38.2°C (inter-quartile range, IQR, 38.0°C to 38.5°C). The use of thermometers was protocolized in 91 (65%) ICUs and a wide range of methods were reportedly used, with axillary, tympanic and urinary bladder sites as the most common as primary modalities. Only 31 (22%) of respondents indicated that there was a formal written protocol for temperature control among febrile patients in their ICUs. In most or all cases practice was to control temperature, to use acetaminophen, and to perform a full septic workup in febrile patients and that this was usually directed by physician order. While reported practice was to treat nearly all patients with neurological impairment and most patients with acute coronary syndromes and infections, severe sepsis and septic shock, this was not the case for most patients with liver failure and fever. CONCLUSIONS: A wide range of definitions and management practices were reported regarding temperature abnormalities in the critically ill. Documenting temperature abnormality management practices, including variability in clinical care, is important to inform planning of future studies designed to optimize infection and temperature management strategies in the critically ill.

EMPIRICUS micafungin versus placebo during nosocomial sepsis in Candida multi-colonized ICU patients with multiple organ failures: study protocol for a randomized controlled trial.

BACKGROUND: The potential interest of antifungal treatment of non-immunocompromized patients with sepsis, extra-digestive Candida colonization and multiple organ failure is unknown. It represents three-quarters of antifungals prescribed in Intensive Care Units. It may allow early treatment of invasive fungal infection in the incubation phase but expose patients to unnecessary antifungal treatments with subsequent cost and fungal selection pressure. As early diagnostic tests for invasive candidiasis are still considered to be insufficient, the potential interest in this strategy needs to be demonstrated. METHODS: This prospective multicenter, double blind, randomized-controlled trial is conducted in 23 French Intensive Care Units. All adult patients, mechanically ventilated for more than four days with sepsis of unknown origin and with at least one extradigestive fungal colonization site and multiple organ failure are eligible for randomization. Patients with proven invasive candidiasis are not included. After a complete mycological screening, patients are allocated to receive micafungin 100 mg intravenously once a day or placebo for 14 days. We plan to enroll 260 patients. The main objective is to demonstrate that micafungin increases survival of patients without invasive candidiasis at day 28 as compared to placebo. Other outcomes include day 28 and 90 survival and organ failure evolution. Additionally, pharmacokinetics of micafungin in enrolled patients will be measured and evolution of fungal biomarkers and susceptibility profiles of infecting fungi will also be followed. DISCUSSION: This study will help to provide guidelines for treating non-immunocompromized patients with fungal colonization multiple organ failure and sepsis of unknown origin. TRIAL REGISTRATION: Clinicaltrials.gov number NCT01773876.

Pseudomonas aeruginosa ventilator-associated pneumonia. predictive factors of treatment failure.

RATIONALE: The predictive factors of treatment failure for ventilator-associated pneumonia (VAP) caused by Pseudomonas aeruginosa (PA) remain uncertain. OBJECTIVES: To describe PA-VAP recurrence prognosis and to identify associated risk factors in a large cohort of intensive care unit patients with PA-VAP. METHODS: From the multicenter OUTCOMEREA database (1997-2011), PA-VAP onset and recurrence were recorded. All suspected cases of VAP were confirmed by a positive quantitative culture of a respiratory sample. Multidrug-resistant PA strains were defined by the resistance to two antibiotics among piperacillin, ceftazidime, imipenem, colistine, and fluoroquinolones (FQ). An extensively resistant PA was defined by resistance to piperacillin, ceftazidime, imipenem, and FQ. A treatment failure was defined as a PA-VAP recurrence or by the death occurrence. MEASUREMENTS AND MAIN RESULTS: A total of 314 patients presented 393 PA-VAP. Failure occurred for 112 of them, including 79 recurrences. Susceptible, multidrug resistant, and extensively resistant PA represented 53.7%, 32%, and 14.3% of the samples, respectively. Factors associated with treatment failure were age (P = 0.02); presence of at least one chronic illness (P = 0.02); limitation of life support (P = 0.0004); a high Sepsis-Related Organ Failure Assessment score (P < 0.0001); PA bacteremia (P = 0.003); and previous use of FQ before the first PA-VAP (P = 0.0007). The failure risk was not influenced by the strain resistance profile or by the biantibiotic treatment, but decreased in case of VAP treatment that includes FQ (subdistribution hazard ratio, 0.5 [0.3-0.7]; P = 0.0006). However, the strain resistance profile slowed down the intensive care unit discharge hazard (subdistribution hazard ratio, 0.6 [0.4-1.0]; P = 0.048). CONCLUSIONS: Neither resistance profile nor biantibiotic therapy decreased the risk of PA-VAP treatment failure. However, the profile of PA resistance prolonged the length of stay. Better evaluation of the potential benefit of an initial treatment containing FQ requires further randomized trials.

Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers.

Activation of normally silent tissue-specific genes and the resulting cell "identity crisis" are the unexplored consequences of malignant epigenetic reprogramming. We designed a strategy for investigating this reprogramming, which consisted of identifying a large number of tissue-restricted genes that are epigenetically silenced in normal somatic cells and then detecting their expression in cancer. This approach led to the demonstration that large-scale "off-context" gene activations systematically occur in a variety of cancer types. In our series of 293 lung tumors, we identified an ectopic gene expression signature associated with a subset of highly aggressive tumors, which predicted poor prognosis independently of the TNM (tumor size, node positivity, and metastasis) stage or histological subtype. The ability to isolate these tumors allowed us to reveal their common molecular features characterized by the acquisition of embryonic stem cell/germ cell gene expression profiles and the down-regulation of immune response genes. The methodical recognition of ectopic gene activations in cancer cells could serve as a basis for gene signature-guided tumor stratification, as well as for the discovery of oncogenic mechanisms, and expand the understanding of the biology of very aggressive tumors.

Reporting and handling missing values in clinical studies in intensive care units.

INTRODUCTION: Missing values occur in nearly all clinical studies, despite the best efforts of the investigators, and cause frequently unrecognised biases. Our aims were (1) to assess the reporting and handling of missing values in the critical care literature; (2) to describe the impact of various techniques for handling missing values on the study results; (3) to provide guidance on the management of clinical study analysis in case of missing data. METHODS: We reviewed 44 published manuscripts in three critical care research journals. We used the Conflicus study database to illustrate how to handle missing values. RESULTS: Among 44 published manuscripts, 16 (36.4 %) provided no information on whether missing data occurred, 6 (13.6 %) declared having no missing data, 20 (45.5 %) reported that missing values occurred but did not handle them and only 2 (4.5 %) used sophisticated missing data handling methods. In our example using the Conflicus study database, we evaluated correlations linking job strain intensity to the type and proportion of missing values. Overall, 8 % of data were missing; however, using only complete cases would have resulted in discarding 24 % of the questionnaires. A greater number and a higher percentage of missing values for a particular variable were significantly associated with a lower job strain score (indicating greater stress). Among respondents who fully completed the job strain questionnaire, the comparison of those whose questionnaires did and did not have missing values showed significant differences in terms of age, number of children and country of birth. We provided an algorithm to manage clinical studies analysis in case of missing data. CONCLUSION: Missing data are common and generate interpretation biases. They should be reported routinely and taken into account when modelling data from clinical studies.