Multi-view confocal microscopy enables multiple organ and whole organism live-imaging.

Understanding how development is coordinated in multiple tissues and gives rise to fully functional organs or whole organisms necessitates microscopy tools. Over the last decade numerous advances have been made in live-imaging, enabling high resolution imaging of whole organisms at cellular resolution. Yet, these advances mainly rely on mounting the specimen in agarose or aqueous solutions, precluding imaging of organisms whose oxygen uptake depends on ventilation. Here, we implemented a multi-view multi-scale microscopy strategy based on confocal spinning disk microscopy, called Multi-View confocal microScopy (MuViScopy). MuViScopy enables live-imaging of multiple organs with cellular resolution using sample rotation and confocal imaging without the need of sample embedding. We illustrate the capacity of MuViScopy by live-imaging Drosophila melanogaster pupal development throughout metamorphosis, highlighting how internal organs are formed and multiple organ development is coordinated. We foresee that MuViScopy will open the path to better understand developmental processes at the whole organism scale in living systems that require gas exchange by ventilation.

Burden of Candida-related vascular graft infection: a nested-case control study.

PURPOSE: We aimed to assess risk factors of candida-related Vascular Graft Infections (VGIs). METHODS: We did a case-control study (1:4) matched by age and year of infection, nested in a cohort of patient with a history of VGIs. Cases were defined by a positive culture for Candida spp. in biological samples and controls were defined by a positive culture for bacterial strains only in biological samples. Risk factors for Candida-related VGIs were investigated using multivariate logistic regression. Mortality were compared using survival analysis. RESULTS: 16 Candida-related VGIs were matched to 64 bacterial-related VGIs. The two groups were comparable regarding medical history and clinical presentation. Candida-related VGIs were associated with bacterial strains in 88% (14/16). Gas/fluid-containing collection on abdominal CT scan and the presence of an aortic endoprosthesis were risk factors for Candida spp.-related VGIs [RRa 10.43 [1.81-60.21] p = 0.009 RRa and 6.46 [1.17-35.73] p = 0.03, respectively]. Candida-related VGIs were associated with a higher mortality when compared to bacterial-related VGIs (p = 0.002). CONCLUSIONS: Candida-related VGIs are severe. Early markers of Candida spp. infection are needed to improve their outcome. The suspicion of aortic endoprosthesis infection may necessitate probabilistic treatment with antifungal agents.

Real-Time Tracking of Parental Histones Reveals Their Contribution to Chromatin Integrity Following DNA Damage.

Chromatin integrity is critical for cell function and identity but is challenged by DNA damage. To understand how chromatin architecture and the information that it conveys are preserved or altered following genotoxic stress, we established a system for real-time tracking of parental histones, which characterize the pre-damage chromatin state. Focusing on histone H3 dynamics after local UVC irradiation in human cells, we demonstrate that parental histones rapidly redistribute around damaged regions by a dual mechanism combining chromatin opening and histone mobilization on chromatin. Importantly, parental histones almost entirely recover and mix with new histones in repairing chromatin. Our data further define a close coordination of parental histone dynamics with DNA repair progression through the damage sensor DDB2 (DNA damage-binding protein 2). We speculate that this mechanism may contribute to maintaining a memory of the original chromatin landscape and may help preserve epigenome stability in response to DNA damage.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.

BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer.

Disappearance of the Barr body is considered a hallmark of cancer, although whether this corresponds to genetic loss or to epigenetic instability and transcriptional reactivation is unclear. Here we show that breast tumors and cell lines frequently display major epigenetic instability of the inactive X chromosome, with highly abnormal 3D nuclear organization and global perturbations of heterochromatin, including gain of euchromatic marks and aberrant distributions of repressive marks such as H3K27me3 and promoter DNA methylation. Genome-wide profiling of chromatin and transcription reveal modified epigenomic landscapes in cancer cells and a significant degree of aberrant gene activity from the inactive X chromosome, including several genes involved in cancer promotion. We demonstrate that many of these genes are aberrantly reactivated in primary breast tumors, and we further demonstrate that epigenetic instability of the inactive X can lead to perturbed dosage of X-linked factors. Taken together, our study provides the first integrated analysis of the inactive X chromosome in the context of breast cancer and establishes that epigenetic erosion of the inactive X can lead to the disappearance of the Barr body in breast cancer cells. This work offers new insights and opens up the possibility of exploiting the inactive X chromosome as an epigenetic biomarker at the molecular and cytological levels in cancer.

Outcome and prognostic factors of patients with right-sided infective endocarditis requiring intensive care unit admission.

BACKGROUND: Right-sided infective endocarditis (RSIE) is an uncommon diagnosis accounting for less than 10% of cases of infective endocarditis. Optimal management for severely ill patients with RSIE remains challenging because few studies reported on management and outcome. The goal of our study was to determine outcome and associated prognostic factors in a population of ICU patients with a diagnosis of definite, active and severe RSIE. METHODS: We performed a retrospective study in 10 French ICUs between January 2002 and December 2012. Main outcome was mortality at 30 days after ICU admission. Significant variables associated with 30-days mortality in the bivariate analysis were included in a logistic regression analysis. RESULTS: A total of 37 patients were studied. Mean age was 47.9 ± 18.4 years. Mean SAPS II, SOFA score and Charlson comorbidity index were 32.4 ± 17.4, 6.3 ± 4.4 and 3.1 ± 3.4, respectively. Causative pathogens, identified in 34 patients, were mainly staphylococci (n = 29). The source of endocarditis was a catheter related infection in 10 patients, intravenous drug abuse in 8 patients, cutaneous in 7 patients, urinary tract related in one patient and has an unknown origin in 7 patients. Vegetation size was higher than 20 mm for 14 patients. Valve tricuspid regurgitation was classified as severe in 11 patients. All patients received initial appropriate antimicrobial therapy. Aminoglycosides were delivered in combination with ß-lactam antibiotics or vancomycin in 22 patients. Surgical procedure was performed in 14 patients. Eight patients (21.6%) died within 30 days following ICU admission. One independent prognostic factor was identified: use of aminoglycosides was associated with improved outcome (OR = 0.1; 95%CI = 0.0017-0.650; p = 0.007). CONCLUSION: Mortality of patients with RSIE needing ICU admission is high. Aminoglycosides used in combination with ß-lactam or vancomycin could reduce 30 days mortality.

Generation of surface-wave microwave microplasmas in hollow-core photonic crystal fiber based on a split-ring resonator.

We report on a new and highly compact scheme for the generation and sustainment of microwave-driven plasmas inside the core of an inhibited coupling Kagome hollow-core photonic crystal fiber. The microwave plasma generator consists of a split-ring resonator that efficiently couples the microwave field into the gas-filled fiber. This coupling induces the concomitant generation of a microwave surface wave at the fiber core surround and a stable plasma column confined in the fiber core. The scheme allowed the generation of several centimeters long argon microplasma columns with a very low excitation power threshold. This result represents an important step toward highly compact plasma lasers or plasma-based photonic components.

[Representativeness of general practice university lecturers]. / Représentativité des médecins généralistes maîtres de stage universitaires.

OBJECTIVE: In order to develop primary care research by general practice university lecturers, it was necessary to evaluate the representativeness of this group of lecturers at the Angers Faculty of Medicine. METHODS: Declarative study based on self-administered questionnaires filled in by 216 university lecturers. The questionnaire was derived from that of the regional panel of the Research, studies, evaluation and statistics directorate of 2007, investigating the sociodemographic characteristics, professional organization, activities and certain professional practices of general practitioners. University lecturers were compared to the population of the panel by means of a Chi-square test of conformity. RESULTS: A total of 181 university lecturers participated in the survey, comprising 65% of men. The proportion of women was higher among university lecturers and the 45-54years age-group was underrepresented. The university lecturers group was significantly different from the panel in terms of predominantly group practice and shorter weekly working hours. No significant difference was observed for the type of town of practice ahd the continuing medical education participation rate. CONCLUSION: University lecturers present certain specificities, partly related to the reference population used. The development of research based on such a network appears to be feasible in terms ofrepresentativeness, provided these specificities are clearly described.

Intra-abdominal aortic graft infection: prognostic factors associated with in-hospital mortality.

BACKGROUND: Mortality associated with aortic graft infection is considerable. The gold standard for surgical treatment remains explantation of the graft. However, prognostic factors associated with early mortality due to this surgical procedure are not well-known. METHODS: Retrospective analysis of patients admitted in our center between January 2006 and October 2011 for aortic graft infection. The primary endpoint was in-hospital mortality. A bivariate analysis of characteristics of patients associated with in-hospital outcome was performed. RESULTS: Twenty five evaluable patients were studied. All patients were male. Their mean age was 67 ± 8.4 years. Most of them (92%) had severe underlying diseases. An in situ prosthetic graft replacement, mainly using cryopreserved arterial allografts, was performed in all patients, excepted one who underwent extra-anatomic bypass. Causative organisms were identified in 23 patients (92%). The in-hospital mortality rate was 48%. Among pre-operative characteristics, age ≥ 70 years, creatinine ≥ 12 mg/L and C reactive protein ≥ 50 mg/L were significantly associated with in-hospital mortality. Hospital mortality rates increased with the number of risk factor present on ICU admission, and were 0%, 14.3%, 85.7% and 100% for 0, 1, 2 and 3 factors, respectively. The only intra-operative factor associated with prognosis was an associated intestinal procedure due to aorto-enteric fistula. SAPS II, SOFA score and occurrence of medical or surgical complications were postoperative characteristics associated with in-hospital mortality. CONCLUSION: Morbidity and mortality associated with surgical approach of aortic graft infections are considerable. Age and values of creatinine and C Reactive protein on hospital admission appear as the most important determinant of in hospital mortality. They could be taken into account for guiding the surgical strategy.

Factors predictive of treatment failure in staphylococcal prosthetic vascular graft infections: a prospective observational cohort study: impact of rifampin.

BACKGROUND: There exists considerable debate concerning management of prosthetic vascular graft infection (PVGI), especially in terms of antimicrobial treatment. This report studies factors associated with treatment failure in a cohort of patients with staphylococcal PVGI, along with the impact of rifampin (RIF). METHODS: All data on patients with PVGI between 2006 and 2010 were reviewed. Cure was defined as the absence of evidence of infection during the entire post-treatment follow-up for a minimum of one year. Failure was defined as any other outcome. RESULTS: 84 patients (72 M/12 F, median age 64.5 ± 11 y) with diabetes mellitus (n = 25), obesity (n = 48), coronary artery disease (n = 48), renal failure (n = 24) or COPD (n = 22) were treated for PVGI (median follow-up was 470 ± 469 d). PVGI was primarily intracavitary (n = 47). Staphylococcus aureus (n = 65; including 17 methicillin-resistant S. aureus) and coagulase-negative Staphylocococcus (n = 22) were identified. Surgical treatment was performed in 71 patients. In univariate analysis, significant risk factors associated with failure were renal failure (p = 0.04), aortic aneurysm (p = 0.03), fever (p = 0.009), aneurysm disruption (p = 0.02), septic shock in the peri-operative period (p = 0.005) and antibiotic treatment containing RIF (p = 0.03). In multivariate analysis, 2 variables were independently associated with failure:septic shock [OR 4.98: CI 95% 1.45-16.99; p=0.01] and antibiotic containing rifampin [OR: 0.32: CI95% 0.10-0.96; p=0.04]. CONCLUSION: Results of the present study suggest that fever, septic shock and non-use of antibiotic treatment containing RIF are associated with poor outcome.

One-year mortality in patients requiring prolonged mechanical ventilation: multicenter evaluation of the ProVent score.

INTRODUCTION: Current severity-of-illness indexes are unable to assess the long-term prognosis of patients requiring prolonged mechanical ventilation. A prognostic scoring system (Prognosis for Prolonged Ventilation score - ProVent - score) seems able to evaluate one-year mortality of such patients. However, testing of the model outside the developers' centers has not been reported. So, it is unclear how the ProVent score performs in non-US and non-tertiary ICUs. The goal of our study was to evaluate its performances in a French multicenter, community hospital-based setting. METHODS: In three primary ICUs, 201 patients requiring mechanical ventilation for at least 21 days were enrolled in a retrospective cohort study. ICU mortality was abstracted from medical records and, for patients discharged alive from the ICU, one-year mortality was determined by telephone calls to patients' general practitioners. RESULTS: One-year mortality was 60% (n = 120). On day 21 of ventilation, ProVent score value was 0 in 19 patients (9%), 1 in 63 patients (31%), 2 in 64 patients (32%), 3 in 37 patients (18%), and ≥4 in 18 patients (9%), respectively. For ProVent score values ranging from 0 to ≥4, one-year mortality rates were 21%, 43%, 67%, 78%, and 94%, respectively. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve for the ProVent score was 0.74 (95% confidence interval 0.671 to 0.809). Stepwise logistic regression analysis showed that only three variables (age ≥65 years, vasopressors, and hemodialysis) were independently associated with one-year mortality in our population. In assigning one point to each variable, we created a French ProVent score. The Hosmer-Lemeshow goodness-of-fit statistic was 1.36 (DF = 6, P = 0.857) and the AUC of the ROC curve was 0.742 (95% confidence interval 0.673 to 0.810). One-year mortality rates for French ProVent score ranging from 0 to 3 were 34.6%, 70.9%, 83.3% and 100%, respectively (P <0.0001). CONCLUSIONS: The ProVent score is able, even in non-US ICUs and in community hospitals, to accurately identify among patients requiring prolonged mechanical ventilation those who are at high risk of one-year mortality. Its simplification appears possible. However, further validation of this French ProVent score in a larger external sample is indicated.

Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial.

BACKGROUND: Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock. METHODS: APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 µg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209). FINDINGS: Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction). INTERPRETATION: In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.

Improvement in process of care and outcome in patients requiring intensive care unit admission for community acquired pneumonia.

BACKGROUND: The present study was performed to assess the prognosis of patients admitted to the intensive care unit (ICU) for community acquired pneumonia (CAP) after implementation of new processes of care. METHODS: Two groups of patients with CAP were admitted to a 16-bed multidisciplinary ICU in an urban teaching hospital during two different periods: the years 1995-2000, corresponding to the historical group; and 2005-2010, corresponding to the intervention group. New therapeutic procedures were implemented during the period 2005-2010. These procedures included a sepsis management bundle derived from the Surviving Sepsis Campaign, use of a third-generation cephalosporin and levofloxacin as the initial empirical antimicrobial regimen, and noninvasive mechanical ventilation following extubation. RESULTS: A total of 317 patients were studied: 142 (44.8%) during the historical period and 175 (55.2%) during the intervention period. Sequential Organ Failure Assessment scores were higher in patients in the intervention group (7.2 ± 3.7 vs 6.2 ± 2.8; p=0.008). Mortality changed significantly between the two studied periods, decreasing from 43.6% in the historical group to 30.9% in the intervention group (p < 0.02). A restrictive transfusion strategy, use of systematic postextubation noninvasive mechanical ventilation in patients with severe chronic respiratory or cardiac failure patients, less frequent use of dobutamine and/or epinephrine in patients with sepsis or septic shock, and delivery of a third-generation cephalosporin associated with levofloxacin as empirical antimicrobial therapy were independently associated with better outcomes. CONCLUSION: Positive outcomes in ICU patients with CAP have significantly increased in our ICU in recent years. Many new interventions have contributed to this improvement.

Comparison of Anodic and Au-Au Thermocompression Si-Wafer Bonding Methods for High-Pressure Microcooling Devices.

Silicon-based microchannel technology offers unmatched performance in the cooling of silicon pixel detectors in high-energy physics. Although Si-Si direct bonding, used for the fabrication of cooling plates, also meets the stringent requirements of this application (its high-pressure resistance of ~200 bar, in particular), its use is reported to be a challenging and expensive process. In this study, we evaluated two alternative bonding methods, aiming toward a more cost-effective fabrication process: Si-Glass-Si anodic bonding (AB) with a thin-film glass, and Au-Au thermocompression (TC). The bonding strengths of the two methods were evaluated with destructive pressure burst tests (0-690 bar) on test structures, each made of a 1 × 2 cm2 silicon die etched with a tank and an inlet channel and sealed with a plain silicon die using either the AB or TC bonding. The pressure resistance of the structures was measured to be higher for the TC-sealed samples (max. 690 bar) than for the AB samples (max. 530 bar), but less homogeneous. The failure analysis indicated that the AB structure resistance was limited by the adhesion force of the deposited layers. Nevertheless, both the TC and AB methods provided sufficient bond quality to hold the high pressure required for application in high-energy physics pixel detector cooling.

Vascular graft infections.

PURPOSE OF REVIEW: This review provides a focus on infections of prosthetic vascular grafts used to treat peripheral arterial diseases. RECENT FINDINGS: The incidence of infections varies between 1 and 6%. Risk factors of infection are not well identified. Main causative pathogens are Gram-negative bacilli, Staphylococcus aureus, and coagulase-negative staphylococci, without clear differences according to location of graft and time of onset of infection. There is no consensual diagnostic criterion. The basic principles for management of graft infections have been known for many years. A surgical approach combining graft excision, complete debridement, and maintaining distal vascular flow is required. Antimicrobial therapy is always instituted to reduce sepsis and prevent secondary graft infection, but there are no evidence-based data to recommend any regimen. However, antibiotics should have bactericidal activity whatever the bacteria growth phase, reduce the microbial burden, penetrate within the biofilm, and prevent further biofilm formation. Mortality and morbidity from these infections remain significant. SUMMARY: A multidisciplinary approach with a limited number of reference centres, recruiting sufficient numbers of patients to perform controlled trials, and to provide expert recommendations, could be the best way to answer unresolved questions and improve the prognosis.

First initial community-acquired meningitis due to extended-spectrum beta-lactamase producing Escherichia coli complicated with multiple aortic mycotic aneurysms.

We report the first case of extended-spectrum beta-lactamase producing E. coli community-acquired meningitis complicated with multiple aortic mycotic aneurysms. Because of the acute aneurysm expansion with possible impending rupture on 2 abdominal CT scan, the patient underwent prompt vascular surgery and broad spectrum antibiotic therapy but he died of a hemorrhagic shock. Extended-spectrum beta-lactamase producing E. coli was identified from both blood and cerebrospinal fluid culture before vascular treatment. The present case report does not however change the guidelines of Gram negative bacteria meningitis in adults.

Should highly active antiretroviral therapy be prescribed in critically ill HIV-infected patients during the ICU stay? A retrospective cohort study.

BACKGROUND: The impact of highly active antiretroviral therapy (HAART) in HIV-infected patients admitted to the intensive care unit (ICU) remains controversial. We evaluate impact of HAART prescription in HIV-infected patients admitted to the ICU of Tourcoing Hospital from January 2000 to December 2009. RESULTS: There were 91 admissions concerning 85 HIV-infected patients. Reasons for ICU admission were an AIDS-related diagnosis in 46 cases (51%). Fifty two patients (57%) were on HAART at the time of ICU admission, leading to 21 immunovirologic successes (23%). During the ICU stay, HAART was continued in 29 patients (32%), and started in 3 patients (3%). Only one patient experienced an adverse event related to HAART. Mortality rate in ICU and 6 months after ICU admission were respectively 19% and 27%. Kaplan-Meier estimates of the cumulative unajusted survival probability over 6 months were higher in patients treated with HAART during the ICU stay (Log rank: p = 0.04). No benefit of HAART in ICU was seen in the adjusted survival proportion at 6 months or during ICU stay. Prescription of HAART during ICU was associated with a trend to lower incidence of new AIDS-related events at 6 months (respectively 17% and 34% with and without HAART, p = 0.07), and with higher incidence of antiretroviral resistance after ICU stay (respectively 25% and 7% with and without HAART, p = 0.02). CONCLUSIONS: Our results suggest a lower death rate over 6 months in critically ill HIV-infected patients taking HAART during ICU stay. The optimal time to prescribe HAART in critically ill patients needs to be better defined.

Severe secondary peritonitis: impact of inappropriate initial antimicrobial therapy on prognosis and potential carbapenem-sparing.

BACKGROUND: Initiation of antimicrobial therapy (IAT) with broad-spectrum antibiotics is usual in Intensive Care Unit (ICU) patients with secondary peritonitis. Carbapenems are widely proposed by recent guidelines contrasting with current antibiotic stewardship policies of carbapenem-sparing. However, prognosis of inappropriate IAT remains unclear in these patients and broad-spectrum antibiotics are probably overused. We aimed to assess the role of inappropriate IAT in ICU patients with secondary peritonitis and the use of carbapenems in our IAT regimens. METHODS: We performed a retrospective analysis during a six-year period including 131 ICU patients with secondary peritonitis. We collected data concerning comorbidities, source and severity of peritonitis, management of IAT, peritoneal samples and outcome. RESULTS: Forty-one patients presented with community acquired peritonitis (CAP) and 90 with postoperative peritonitis (POP). Thirty-seven (28.2%) patients died during ICU stay. IAT was inappropriate in 35 (26.7%) patients. Inappropriate IAT was not associated with reduced survival with respectively 26 (27%) deaths when IAT was adequate and 11 (31.4%) deaths when IAT was inadequate (P=0.87). Inappropriate IAT was not associated with the need of re-operation and duration of ICU stay. Carbapenems were delivered in 29 patients but were only necessary for eight patients without alternative treatment. CONCLUSIONS: In our study, inappropriate IAT was not associated with a worse prognosis and carbapenems were overused. Extensive delivery of carbapenems proposed by recent guidelines could be reconsidered in the management of these patients.

Continuous Infusion of High Doses of Cefepime in Intensive Care Unit: Assessment of Steady-State Plasma Level and Incidence on Neurotoxicity.

Continuous infusion (CI) with high doses of cefepime is recommended in the empirical antimicrobial regimen of critically ill patients with suspected Gram-negative sepsis. This study aimed to determine factors associated with cefepime overdosing and the incidence of cefepime-induced neurotoxicity (CIN) in these patients. We performed a retrospective study including all patients receiving cefepime treatment between January 2019 and May 2022. The plasma level of cefepime defining overdosing was over 35 mg/L. Neurotoxicity was defined according to strict criteria and correlated with concomitant steady-state concentration of cefepime. Seventy-eight courses of cefepime treatment were analyzed. The mean cefepime plasma level at steady state was 59.8 ± 29.3 mg/L, and overdosing occurred in 80% of patients. Renal failure and a daily dose > 5 g were independently associated with overdosing. CIN was present in 30% of patients. In multivariate analysis, factors associated with CIN were chronic renal failure and a cefepime plasma concentration ≥ 60 mg/L. CIN was not associated with mortality. Overdosing is frequent in patients receiving high doses of cefepime by CI. Steady-state levels are higher than targeted therapeutic pharmacokinetic/pharmacodynamic objectives. The risk of CIN is important when the plasma concentration is ≥60 mg/L.

Severe pneumococcal pneumonia: impact of new quinolones on prognosis.

BACKGROUND: Most guidelines have been proposing, for more than 15 years, a ß-lactam combined with either a quinolone or a macrolide as empirical, first-line therapy of severe community acquired pneumonia (CAP) requiring ICU admission. Our goal was to evaluate the outcome of patients with severe CAP, focusing on the impact of new rather than old fluoroquinolones combined with ß-lactam in the empirical antimicrobial treatments. METHODS: Retrospective study of consecutive patients admitted in a 16-bed general intensive care unit (ICU), between January 1996 and January 2009, for severe (Pneumonia Severity Index > or = 4) community-acquired pneumonia due to non penicillin-resistant Streptococcus pneumoniae and treated with a ß-lactam combined with a fluoroquinolone. RESULTS: We included 70 patients of whom 38 received a ß-lactam combined with ofloxacin or ciprofloxacin and 32 combined with levofloxacin. Twenty six patients (37.1%) died in the ICU. Three independent factors associated with decreased survival in ICU were identified: septic shock on ICU admission (AOR = 10.6; 95% CI 2.87-39.3; p = 0.0004), age > 70 yrs. (AOR = 4.88; 95% CI 1.41-16.9; p = 0.01) and initial treatment with a ß-lactam combined with ofloxacin or ciprofloxacin (AOR = 4.1; 95% CI 1.13-15.13; p = 0.03). CONCLUSION: Our results suggest that, when combined to a ß-lactam, levofloxacin is associated with lower mortality than ofloxacin or ciprofloxacin in severe pneumococcal community-acquired pneumonia.