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1.  Long-Term Mortality of Coronary Artery Bypass Graft Surgery and Stenting with Drug-Eluting Stents 
The Annals of thoracic surgery  2013;95(4):1297-1305.
Background
Few studies have examined differences in long-term mortality between coronary artery bypass graft surgery and stenting with drug-eluting stents (DES) for multivessel disease without left main coronary artery stenosis. This study compares the risks of long-term mortality between these 2 procedures during a follow-up of up to 5 years.
Methods
Patients who underwent isolated bypass surgery (n=13,212) and stenting with DES (n=20,161) between October 2003 and December 2005 in New York State were followed for their vital status through 2008. To control for treatment selection bias, bypass and stenting patients were matched on age, number of diseased coronary vessels, presence of proximal or nonproximal left anterior descending (LAD) artery disease, and propensity of undergoing bypass surgery. Five-year survival rates for the 2 procedures were compared and hazard ratios for death of bypass surgery compared to stenting were obtained.
Results
The respective 5-year survival rates in the 8,121 pairs of matched bypass and stenting patients were 80.4%and 73.6% (P<0.001), and the risk of death following bypass surgery was 29% lower than for stenting (hazard ratio=0.71, 95% confidence interval: 0.67-0.77, P<0.001). Significantly lower risks of death for bypass surgery were observed in patients with LAD artery disease but not in patients without LAD artery disease. Significantly lower risks of death for bypass surgery were also found in all patient subgroups defined by the presence of selected baseline risk factors.
Conclusions
Bypass surgery is associated with lower risk of death than stenting with DES for multivessel disease without left main stenosis.
doi:10.1016/j.athoracsur.2012.11.073
PMCID: PMC3756666  PMID: 23391171
CABG; stents; outcomes
2.  Temperature Variability during Delirium in ICU Patients: An Observational Study 
PLoS ONE  2013;8(10):e78923.
Introduction
Delirium is an acute disturbance of consciousness and cognition. It is a common disorder in the intensive care unit (ICU) and associated with impaired long-term outcome. Despite its frequency and impact, delirium is poorly recognized by ICU-physicians and –nurses using delirium screening tools. A completely new approach to detect delirium is to use monitoring of physiological alterations. Temperature variability, a measure for temperature regulation, could be an interesting component to monitor delirium, but whether temperature regulation is different during ICU delirium has not yet been investigated. The aim of this study was to investigate whether ICU delirium is related to temperature variability. Furthermore, we investigated whether ICU delirium is related to absolute body temperature.
Methods
We included patients who experienced both delirium and delirium free days during ICU stay, based on the Confusion Assessment method for the ICU conducted by a research- physician or –nurse, in combination with inspection of medical records. We excluded patients with conditions affecting thermal regulation or therapies affecting body temperature. Daily temperature variability was determined by computing the mean absolute second derivative of the temperature signal. Temperature variability (primary outcome) and absolute body temperature (secondary outcome) were compared between delirium- and non-delirium days with a linear mixed model and adjusted for daily mean Richmond Agitation and Sedation Scale scores and daily maximum Sequential Organ Failure Assessment scores.
Results
Temperature variability was increased during delirium-days compared to days without delirium (βunadjusted=0.007, 95% confidence interval (CI)=0.004 to 0.011, p<0.001). Adjustment for confounders did not alter this result (βadjusted=0.005, 95% CI=0.002 to 0.008, p<0.001). Delirium was not associated with absolute body temperature (βunadjusted=-0.03, 95% CI=-0.17 to 0.10, p=0.61). This did not change after adjusting for confounders (βadjusted=-0.03, 95% CI=-0.17 to 0.10, p=0.63).
Conclusions
Our study suggests that temperature variability is increased during ICU delirium.
doi:10.1371/journal.pone.0078923
PMCID: PMC3806845  PMID: 24194955
3.  The Role of Cyclooxygenase-2 in Mechanical Ventilation–Induced Lung Injury 
Mechanical ventilation is necessary for patients with acute respiratory failure, but can cause or propagate lung injury. We previously identified cyclooxygenase-2 as a candidate gene in mechanical ventilation–induced lung injury. Our objective was to determine the role of cyclooxygenase-2 in mechanical ventilation–induced lung injury and the effects of cyclooxygenase-2 inhibition on lung inflammation and barrier disruption. Mice were mechanically ventilated at low and high tidal volumes, in the presence or absence of pharmacologic cyclooxygenase-2–specific inhibition with 3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole (CAY10404). Lung injury was assessed using markers of alveolar–capillary leakage and lung inflammation. Cyclooxygenase-2 expression and activity were measured by Western blotting, real-time PCR, and lung/plasma prostanoid analysis, and tissue sections were analyzed for cyclooxygenase-2 staining by immunohistochemistry. High tidal volume ventilation induced lung injury, significantly increasing both lung leakage and lung inflammation relative to control and low tidal volume ventilation. High tidal volume mechanical ventilation significantly induced cyclooxygenase-2 expression and activity, both in the lungs and systemically, compared with control mice and low tidal volume mice. The immunohistochemical analysis of lung sections localized cyclooxygenase-2 expression to monocytes and macrophages in the alveoli. The pharmacologic inhibition of cyclooxygenase-2 with CAY10404 significantly decreased cyclooxygenase activity and attenuated lung injury in mice ventilated at high tidal volume, attenuating barrier disruption, tissue inflammation, and inflammatory cell signaling. This study demonstrates the induction of cyclooxygenase-2 by mechanical ventilation, and suggests that the therapeutic inhibition of cyclooxygenase-2 may attenuate ventilator-induced acute lung injury.
doi:10.1165/rcmb.2011-0005OC
PMCID: PMC3488687  PMID: 22556158
cyclooxygenase-2; mechanical ventilation; lung injury
4.  Interleukin 5 Is Protective during Sepsis in an Eosinophil-Independent Manner 
Rationale: The immune response in sepsis is characterized by overt immune dysfunction. Studies indicate immunostimulation represents a viable therapy for patients. One study suggests a potentially protective role for interleukin 5 (IL-5) in sepsis; however, the loss of eosinophils in this disease presents a paradox.
Objectives: To assess the protective and eosinophil-independent effects of IL-5 in sepsis.
Methods: We assessed the effects of IL-5 administration on survival, bacterial burden, and cytokine production after polymicrobial sepsis. In addition, we examined the effects on macrophage phagocytosis and survival using fluorescence microscopy and flow cytometry.
Measurements and Main Results: Loss of IL-5 increased mortality and tissue damage in the lung, IL-6 and IL-10 production, and bacterial burden during sepsis. Therapeutic administration of IL-5 improved mortality in sepsis. Interestingly, IL-5 administration resulted in neutrophil recruitment in vivo. IL-5 overexpression in the absence of eosinophils resulted in decreased mortality from sepsis and increased circulating neutrophils and monocytes, suggesting their importance in the protective effects of IL-5. Furthermore, novel data demonstrate IL-5 receptor expression on neutrophils and monocytes in sepsis. IL-5 augmented cytokine secretion, activation, phagocytosis, and survival of macrophages. Importantly, macrophage depletion before the onset of sepsis eliminated IL-5–mediated protection. The protective effects of IL-5 were confirmed in humans, where IL-5 levels were elevated in patients with sepsis. Moreover, neutrophils and monocytes from patients expressed the IL-5 receptor.
Conclusions: Taken together, these data support a novel role for IL-5 on noneosinophilic myeloid populations, and suggest treatment with IL-5 may be a viable therapy for sepsis.
doi:10.1164/rccm.201201-0134OC
PMCID: PMC3423456  PMID: 22652030
macrophages; neutrophils; innate immunity; immunotherapy
5.  A Risk Score for Predicting Long-Term Mortality Following Coronary Artery Bypass Graft Surgery 
Circulation  2012;125(20):2423-2430.
Background
No simplified bedside risk scores have been created to predict long-term mortality after coronary artery bypass graft (CABG) surgery.
Methods and Results
The New York State’s Cardiac Surgery Reporting System was used to identify 8,597 patients who underwent isolated CABG surgery in July-December 2000. The National Death Index was used to ascertain patients’ vital status through December 31, 2007. A Cox proportional hazards model was fit to predict death following CABG surgery using pre-procedural risk factors. Then points were assigned to significant predictors of death based on the values of their regression coefficients. For each possible point total, the predicted risks of death at years 1, 3, 5, and 7 were calculated. It was found that the 7-year mortality rate was 24.2% in the study population. Significant predictors of death included age, body mass index, ejection fraction, unstable hemodynamic state or shock, left main coronary artery disease, cerebrovascular disease, peripheral arterial disease, congestive heart failure, malignant ventricular arrhythmia, chronic obstructive pulmonary disease, diabetes, renal failure, and history of open heart surgery. The points assigned to these risk factors ranged from 1 to 7; and possible point totals for each patient ranged from 0 to 28. The observed and predicted risks of death at years 1, 3, 5, and 7 across patient groups stratified by point totals were highly correlated.
Conclusions
The simplified risk score accurately predicted the risk of mortality following CABG surgery, and can be used for informed consent and as an aid in determining treatment choice.
doi:10.1161/CIRCULATIONAHA.111.055939
PMCID: PMC3422677  PMID: 22547673
CABG; follow-up studies; mortality; risk score
6.  OX40L Regulates Inflammation and Mortality in the Innate Immune Response to Sepsis 
The initial phase of sepsis is characterized by massive inflammatory cytokine production which contributes to multisystem organ failure and death. Costimulatory molecules are a class of receptors capable of regulating cytokine production in adaptive immunity and recent studies describe their presence on neutrophils and monocytes, suggesting a potential role for regulating cytokine production in innate immunity. The purpose of this study is to determine the role for OX40-OX40L interaction in the innate immune response to polymicrobial sepsis. Humans with sepsis demonstrated upregulation of OX40L on both monocytes and neutrophils, with mortality and ICU stay correlating with expression levels. In an animal model of polymicrobial sepsis, a direct role for OX40L in regulating inflammation was evidenced by improved survival, decreased cytokine production and a decrease in remote organ damage in OX40L−/− mice. The finding of similar results with an OX40L antibody suggests a potential future therapeutic role for OX40L blockade in sepsis. The inability of α-OX40L to provide significant protection in macrophage-depleted mice establishes macrophages as an indispensible cell type within the OX40/OX40L axis that helps to mediate the clinical signs of disease in sepsis. Conversely, the protective effect of α-OX40L antibody in RAG1−/− mice, further confirms a T-cell independent role for OX40L stimulation in sepsis. In conclusion, our data provide a novel in vivo role for OX40-OX40L system in the innate immune response during polymicrobial sepsis and suggests a potential beneficial role for therapeutic blockade of OX40L in this devastating disorder.
doi:10.4049/jimmunol.1000404
PMCID: PMC3622718  PMID: 20844189
7.  A Comparison of Long-Term Mortality for Off-Pump and On-Pump Coronary Artery Bypass Graft Surgery 
Background
The survival difference between off-pump and on-pump coronary artery bypass graft (CABG) surgery for follow-up longer than 5 years is not well understood. The objective of this study is to examine the difference in 7-year mortality after these two procedures.
Methods and Results
New York State’s Cardiac Surgery Reporting System was used to identify the 2,640 off-pump and 5,940 on-pump isolated CABG patients discharged from July through December, 2000. The National Death Index was used to ascertain patients’ vital statuses through 2007. A logistic regression model was fit to predict the probability of receiving an off-pump procedure using baseline patient characteristics. Off-pump and on-pump patients were matched with a 1:1 ratio based on the probability of receiving an off-pump procedure. Kaplan-Meier survival curves for the 2 procedures were compared using the propensity-matched data, and the hazard ratio for death for off-pump in comparison to on-pump procedures was obtained. In subgroup analyses, the significance of interactions between type of surgery and baseline risk factors was tested. In this study, 2,631 pairs of off-pump and on-pump patients were propensity matched. The 7-year Kaplan-Meier survival rates were 71.2% and 73.4% (P=0.07) for off-pump and on-pump surgery, respectively. The hazard ratio for death (off-pump vs. on-pump) was 1.10 (95% confidence interval: 0.99-1.21, P=0.07). No statistical significance was detected for the interaction terms between type of surgery and a number of different baseline risk factors.
Conclusions
The difference in long-term morality between on-pump and off-pump CABG surgery is not statistically significant.
doi:10.1161/CIRCOUTCOMES.111.963124
PMCID: PMC3277259  PMID: 22235063
CABG; coronary artery disease; follow-up studies; mortality; off-pump surgery
8.  Posttraumatic stress symptoms following pregnancy complicated by hyperemesis gravidarum 
Objective
Hyperemesis gravidarum (HG) can be accompanied by severe physical and emotional distress. Most studies have focused on the physical and psychological stress associated with this condition during the affected pregnancy. This study explores posttraumatic stress symptoms (PTSS) and negative life outcomes following HG pregnancies.
Methods
A total of 610 women (HG = 377 and control = 233) were recruited and completed an online survey. χ-square analyses were used to compare the HG and control groups on various life outcome variables.
Results
Eighteen percent of women with HG reported full criteria PTSS (n = 68). Negative life outcomes regarding financial and marital status, career, as well as psychological and physical well-being differed significantly for the HG groups compared to the control group (0.001 < p < 0.05).
Conclusions
PTSS is common following HG pregnancies and is associated with negative life outcomes including inability to breastfeed, marital problems, financial problems, and inability of self care.
doi:10.3109/14767058.2011.582904
PMCID: PMC3514078  PMID: 21635201
Nausea; pregnancy; posttraumatic stress disorder
9.  Long-Term Mortality of Coronary Artery Bypass Graft Surgery and Bare-Metal Stenting 
The Annals of Thoracic Surgery  2011;92(6):2132-2138.
Background
There is little information on the relative survival of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention with stenting with follow-up longer than 5 years. This study tested the hypothesis that CABG surgery is associated with lower risk of long-term (8-year) mortality than stenting with bare-metal stents for multivessel coronary disease.
Methods
We identified 18,359 patients with multivessel disease who underwent isolated CABG surgery and 13,377 patients who received BMS in 1999–2000 in New York, and followed their vital status through 2007 using the National Death Index. We matched CABG and stent patients on the number of diseased coronary vessels, proximal left anterior descending (LAD) artery disease, and propensity of undergoing CABG surgery based on numerous patient characteristics, and compared the survival after the two procedures.
Results
In the 7,235 pairs of matched patients, the overall 8-year survival rates were 78.0% for CABG surgery and 71.2% for stenting (hazard ratio = 0.68, 95% confidence interval: 0.64 to 0.74, P<0.001). For anatomic groups classified by the number of diseased vessels and proximal LAD involvement, the hazard ratios ranged from 0.53 (P<0.001) for patients with 3-vessel disease involving proximal LAD artery disease to 0.78 (P=0.05) for patients with 2-vessel disease but no disease in the LAD artery. A lower risk of death after CABG surgery was observed in all subgroups stratified by a number of baseline risk factors.
Conclusions
CABG surgery is associated with lower risk of death than stenting with bare-metal stents for multivessel coronary disease.
doi:10.1016/j.athoracsur.2011.06.061
PMCID: PMC3271851  PMID: 22014747
Coronary artery bypass grafts; Coronary percutaneous interventions; Outcomes
10.  Chronic Medical Conditions and Risk of Sepsis 
PLoS ONE  2012;7(10):e48307.
Background
We sought to determine the associations between baseline chronic medical conditions and future risk of sepsis.
Methods
Longitudinal cohort study using the 30,239 community-dwelling participants of the REGARDS cohort. We determined associations between baseline chronic medical conditions and incident sepsis episodes, defined as hospitalization for an infection with the presence of infection plus two or more systemic inflammatory response syndrome criteria.
Results
Over the mean observation time of 4.6 years (February 5, 2003 through October 14, 2011), there were 975 incident cases of sepsis. Incident sepsis episodes were associated with older age (p<0.001), white race (HR 1.39; 95% CI: 1.22–1.59), lower education (p<0.001) and income (p<0.001), tobacco use (p<0.001), and alcohol use (p = 0.02). Incident sepsis episodes were associated with baseline chronic lung disease (adjusted HR 2.43; 95% CI: 2.05–2.86), peripheral artery disease (2.16; 1.58–2.95), chronic kidney disease (1.99; 1.73–2.29), myocardial infarction 1.79 (1.49–2.15), diabetes 1.78 (1.53–2.07), stroke 1.67 (1.34–2.07), deep vein thrombosis 1.63 (1.29–2.06), coronary artery disease 1.61 (1.38–1.87), hypertension 1.49 (1.29–1.74), atrial fibrillation 1.48 (1.21–1.81) and dyslipidemia 1.16 (1.01–1.34). Sepsis risk increased with the number of chronic medical conditions (p<0.001).
Conclusions
Individuals with chronic medical conditions are at increased risk of future sepsis events.
doi:10.1371/journal.pone.0048307
PMCID: PMC3485139  PMID: 23118977
11.  A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens 
Critical care medicine  2007;35(3):724-730.
Objective
Patients with severe alcohol withdrawal and delirium tremens are frequently resistant to standard doses of benzodiazepines. Case reports suggest that these patients have a high incidence of requiring intensive care and many require mechanical ventilation. However, few data exist on treatment strategies and outcomes for these subjects in the medical intensive care unit (ICU). Our goal was a) to describe the outcomes of patients admitted to the medical ICU solely for treatment of severe alcohol withdrawal and b) to determine whether a strategy of escalating doses of benzodiazepines in combination with phenobarbital would improve outcomes.
Design
Retrospective cohort study.
Setting
Inner-city municipal hospital.
Patients
Subjects admitted to the medical ICU solely for the treatment of severe alcohol withdrawal.
Interventions
Institution of guidelines emphasizing escalating doses of diazepam in combination with phenobarbital.
Measurements and Main Results
Preguideline (n = 54) all subjects were treated with intermittent boluses of diazepam with an average total and maximal individual dose of 248 mg and 32 mg, respectively; 17% were treated with phenobarbital. Forty-seven percent required intubation due to inability to achieve adequate sedation and need for constant infusion of sedative-hypnotics. Intubated subjects had longer length of stay (5.6 vs. 3.4 days; p = .09) and higher incidence of nosocomial pneumonia (42 vs. 21% p = .08). Postguideline (n = 41) there were increases in maximum individual dose of diazepam (32 vs. 86 mg; p = .001), total amount of diazepam (248 vs. 562 mg; p = .001), and phenobarbital use (17 vs. 58%; p = .01). This was associated with a reduction in the need for mechanical ventilation (47 vs. 22%; p = .008), with trends toward reductions in ICU length of stay and nosocomial pneumonia.
Conclusions
Patients admitted to a medical ICU solely for treatment of severe alcohol withdrawal have a high incidence of requiring mechanical ventilation. Guidelines emphasizing escalating bolus doses of diazepam, and barbiturates if necessary, significantly reduced the need for mechanical ventilation and showed trends toward reductions in ICU length of stay and nosocomial infections.
doi:10.1097/01.CCM.0000256841.28351.80
PMCID: PMC3417045  PMID: 17255852
alcohol withdrawal; benzodiazepines; phenobarbital; intensive care unit
12.  Vascular Endothelial Growth Factor Blockade Reduces Plasma Cytokines in a Murine Model of Polymicrobial Sepsis 
Inflammation  2004;28(5):271-278.
Numerous cytokines, including vascular endothelial growth factor (VEGF), are implicated in the pathogenesis of sepsis. While overexpression of VEGF produces pulmonary capillary leak, the role of VEGF in sepsis is less clear. We investigated VEGF in sepsis, utilizing a VEGF trap (VEGFT). Polymicrobial sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP) and resulted in significantly increased plasma VEGF levels (234 vs. 46 pg/mL; p = 0.03). Inhibition of VEGF had no effect on mortality or lung leak but did attenuate plasma IL-6 (120 vs. 236 ng/mL; p = 0.02) and IL-10 (16 vs. 41 ng/mL; p = 0.03). These alterations in inflammatory cytokines were associated with increased levels of the dominant negative inhibitory C/EBPβ. In vitro, VEGF stimulated IL-6, IL-10 and reduced the inhibitory isoform of C/EBPβ in cultured macrophages. Together these data suggest VEGF can regulate inflammatory cytokine production in murine polymicrobial sepsis, via regulation of C/EBPβ.
doi:10.1007/s10753-004-6050-3
PMCID: PMC3417046  PMID: 16134000
VEGF; sepsis; IL-6; IL-10; C/EBPβ
13.  CD40 BUT NOT CD154 KNOCKOUT MICE HAVE REDUCED INFLAMMATORY RESPONSE IN POLYMICROBIAL SEPSIS: A POTENTIAL ROLE FOR ESCHERICHIA COLI HEAT SHOCK PROTEIN 70 IN CD40-MEDIATED INFLAMMATION IN VIVO 
Shock (Augusta, Ga.)  2004;22(6):538-542.
The CD40-CD154 system controls various aspects of the host inflammatory response in models of cellular and humoral immunity. Recently, we described a role for CD40 in the innate immune response in polymicrobial sepsis. However, recent data suggests that CD40 maybe activated by CD154 or directly via bacterial heat shock protein (HSP) 70. Therefore, we decided to test the mechanism of CD40 activation in murine polymicrobial sepsis. Wild-type (WT), CD40–/–, and CD154–/– underwent cecal ligation and puncture (CLP). Compared with WT mice, CD40–/– had improved survival in association with attenuated production of IL-12, TNF-α, and IL-6. In contrast, CD154–/– mice behaved similar to WT mice with regard to mortality and cytokine production. The differential response of CD40–/– and CD154–/– mice to CLP was not due to a general attenuated response to inflammatory stimuli, as all three strains had similar survival after LPS administration, and CD40–/– macrophages had normal production of IL-12 in response to lipopolysaccharide. In contrast, CD40–/– macrophages had attenuated IL-12 production in response to Escherichia coli HSP70 (DnaK). Furthermore, intraperitoneal administration of DnaK resulted in a 4-fold increase in IL-12 in WT mice, which was absent in CD40–/– mice. This data demonstrates CD154-independent CD40 activation in polymicrobial sepsis and suggests that bacterial HSP70 is capable of stimulating CD40 in vitro and in vivo.
PMCID: PMC3404132  PMID: 15545825
DnaK; cecal ligation and puncture; IL-12; LPS; macrophage
14.  Virtual reality and pain management: current trends and future directions 
Pain management  2011;1(2):147-157.
SUMMARY
Virtual reality (VR) has been used to manage pain and distress associated with a wide variety of known painful medical procedures. In clinical settings and experimental studies, participants immersed in VR experience reduced levels of pain, general distress/unpleasantness and report a desire to use VR again during painful medical procedures. Investigators hypothesize that VR acts as a nonpharmacologic form of analgesia by exerting an array of emotional affective, emotion-based cognitive and attentional processes on the body’s intricate pain modulation system. While the exact neurobiological mechanisms behind VR’s action remain unclear, investigations are currently underway to examine the complex interplay of cortical activity associated with immersive VR. Recently, new applications, including VR, have been developed to augment evidenced-based interventions, such as hypnosis and biofeedback, for the treatment of chronic pain. This article provides a comprehensive review of the literature, exploring clinical and experimental applications of VR for acute and chronic pain management, focusing specifically on current trends and recent developments. In addition, we propose mechanistic theories highlighting VR distraction and neurobiological explanations, and conclude with new directions in VR research, implications and clinical significance.
doi:10.2217/pmt.10.15
PMCID: PMC3138477  PMID: 21779307
15.  Decreasing Mortality in Severe Sepsis and Septic Shock Patients by Implementing a Sepsis Bundle in a Hospital Setting 
PLoS ONE  2011;6(11):e26790.
Background
The Surviving Sepsis Campaign (SSC) guidelines for the management of severe sepsis (SS) and septic shock (SSh) have been recommended to reduce morbidity and mortality.
Materials and Methods
A quasi-experimental study was conducted in a medical-surgical ICU. Multiple interventions to optimize SS and SSh shock patients' clinical outcomes were performed by applying sepsis bundles (6- and 24-hour) in May 2006. We compared bundle compliance and patient outcomes before (July 2005-April 2006) and after (May 2006-December 2009) implementation of the interventions.
Results
A total of 564 SS and SSh patients were identified. Prior to the intervention, compliance with the 6 hour-sepsis resuscitation bundle was only 6%. After the intervention, compliance was as follows: 8.2% from May to December 2006, 9.3% in 2007, 21.1% in 2008 and 13.7% in 2009. For the 24 hour-management bundle, baseline compliance was 15.0%. After the intervention, compliance was 15.1% from May to December 2006, 21.4% in 2007, 27.8% in 2008 and 44.4% in 2009. The in-hospital mortality was 54.0% from July 2005 to April 2006, 41.1% from May to December 2006, 39.3% in 2007, 41.4% in 2008 and 16.2% in 2009.
Conclusion
These results suggest reducing SS and SSh patient mortality is a complex process that involves multiple performance measures and interventions.
doi:10.1371/journal.pone.0026790
PMCID: PMC3207817  PMID: 22073193
16.  Very Low Tidal Volume Ventilation with Associated Hypercapnia - Effects on Lung Injury in a Model for Acute Respiratory Distress Syndrome 
PLoS ONE  2011;6(8):e23816.
Background
Ventilation using low tidal volumes with permission of hypercapnia is recommended to protect the lung in acute respiratory distress syndrome. However, the most lung protective tidal volume in association with hypercapnia is unknown. The aim of this study was to assess the effects of different tidal volumes with associated hypercapnia on lung injury and gas exchange in a model for acute respiratory distress syndrome.
Methodology/Principal Findings
In this randomized controlled experiment sixty-four surfactant-depleted rabbits were exposed to 6 hours of mechanical ventilation with the following targets: Group 1: tidal volume = 8–10 ml/kg/PaCO2 = 40 mm Hg; Group 2: tidal volume = 4–5 ml/kg/PaCO2 = 80 mm Hg; Group 3: tidal volume = 3–4 ml/kg/PaCO2 = 120 mm Hg; Group 4: tidal volume = 2–3 ml/kg/PaCO2 = 160 mm Hg. Decreased wet-dry weight ratios of the lungs, lower histological lung injury scores and higher PaO2 were found in all low tidal volume/hypercapnia groups (group 2, 3, 4) as compared to the group with conventional tidal volume/normocapnia (group 1). The reduction of the tidal volume below 4–5 ml/kg did not enhance lung protection. However, oxygenation and lung protection were maintained at extremely low tidal volumes in association with very severe hypercapnia and no adverse hemodynamic effects were observed with this strategy.
Conclusion
Ventilation with low tidal volumes and associated hypercapnia was lung protective. A tidal volume below 4–5 ml/kg/PaCO2 80 mm Hg with concomitant more severe hypercapnic acidosis did not increase lung protection in this surfactant deficiency model. However, even at extremely low tidal volumes in association with severe hypercapnia lung protection and oxygenation were maintained.
doi:10.1371/journal.pone.0023816
PMCID: PMC3158784  PMID: 21886825
17.  Management of Metformin-Associated Lactic Acidosis by Continuous Renal Replacement Therapy 
PLoS ONE  2011;6(8):e23200.
Background
Metformin-associated lactic acidosis (MALA) is a severe metabolic failure with high related mortality. Although its use is controversial, intermittent hemodialysis is reported to be the most frequently used treatment in conjunction with nonspecific supportive measures. Our aim was to report the evolution and outcome of cases managed by continuous renal replacement therapy (CRRT).
Methodology and Principal Findings
Over a 3-year period, we retrospectively identified patients admitted to the intensive care unit for severe lactic acidosis caused by metformin. We included patients in our study who were treated with CRRT because of shock. We describe their clinical and biological features at admission and during renal support, as well as their evolution. We enrolled six patients with severe lactic acidosis; the mean pH and mean lactate was 6.92±0.20 and 14.4±5.1 mmol/l, respectively. Patients had high illness severity scores, including the Simplified Acute Physiology Score II (SAPS II) (average score 63±12 points). Early CRRT comprised either venovenous hemofiltration (n = 3) or hemodiafiltration (n = 3) with a mean effluent flow rate of 34±6 ml/kg/h. Metabolic acidosis control and metformin elimination was rapid and there was no rebound. Outcome was favorable in all cases.
Conclusions and Significance
Standard use of CRRT efficiently treated MALA in association with symptomatic organ supportive therapies.
doi:10.1371/journal.pone.0023200
PMCID: PMC3154925  PMID: 21853087
18.  Gene expression profiles of bronchoalveolar cells in Pulmonary TB 
The host response to Mycobacterium tuberculosis includes macrophage activation, inflammation with increased immune effector cells, tissue necrosis and cavity formation, and fibrosis, distortion, and bronchiectasis. To evaluate the molecular basis of the immune response in the lungs of patients with active pulmonary tuberculosis (TB), we used bronchoalveolar lavage to obtain cells at the site of infection. Affymetrix Genechip micro-arrays and cDNA nylon filter microarrays interrogated gene expression in BAL cells from 11 healthy controls and 17 patients with active pulmonary TB. We found altered gene expression for 69 genes in TB versus normal controls that included cell surface markers, cytokines, chemokines, receptors, transcription factors, and complement components. In addition, TB BAL cell gene expression patternssegregated into 2 groups: one suggestive of a T helper type 1 (Th1) cellular immune response with increased STAT-4, IFN-γ receptor, and MIG expression with increased IFN-γ protein levels in BAL fluid; the other group displayed characteristics of Th2 immunity with increased STAT-6, CD81, and IL-10 receptor expression. We were able to demonstrate that a Th2 presentation could change to a Th1 pattern after anti-tuberculous treatment in one TB patient studied serially. These gene expression data support the conclusion that pulmonary TB produces a global change in the BAL cell transcriptome with manifestations of either Th1 or Th2 immunity.
doi:10.1016/j.tube.2007.07.003
PMCID: PMC3151146  PMID: 17921069
Human; tuberculosis; bronchoalveolar lavage; functional genomics; immunity
19.  Fatty Acid Binding Protein 1 Is Related with Development of Aspirin-Exacerbated Respiratory Disease 
PLoS ONE  2011;6(8):e22711.
Background
Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in asthmatics following the ingestion of aspirin. Although alterations in eicosanoid metabolites play a role in AERD, other immune or inflammatory mechanisms may be involved. We aimed to identify proteins that were differentially expressed in nasal polyps between patients with AERD and aspirin-tolerant asthma (ATA).
Methodology/Principal Findings
Two-dimensional electrophoresis was adopted for differential display proteomics. Proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS). Western blotting and immunohistochemical staining were performed to compare the amount of fatty acid-binding protein 1 (FABP1) in the nasal polyps of patients with AERD and ATA. Fifteen proteins were significantly up- (seven spots) or down-regulated in the nasal polyps of patients with AERD (n = 5) compared to those with ATA (n = 8). LC-MS revealed an increase in seven proteins expression and a decrease in eight proteins expression in patients with AERD compared to those with ATA (P = 0.003–0.045). FABP1-expression based on immunoblotting and immunohistochemical analysis was significantly higher in the nasal polyps of patients with AERD compared to that in patients with ATA. FABP1 was observed in epithelial, eosinophils, macrophages, and the smooth-muscle cells of blood vessels in the polyps.
Conclusions/Significance
Our results indicate that alterations in 15 proteins, including FABP1, may be related to the development of AERD.
doi:10.1371/journal.pone.0022711
PMCID: PMC3150373  PMID: 21829647
20.  Gp130-Dependent Release of Acute Phase Proteins Is Linked to the Activation of Innate Immune Signaling Pathways 
PLoS ONE  2011;6(5):e19427.
Background
Elevated levels of acute phase proteins (APP) are often found in patients with cardiovascular diseases. In a previous study, we demonstrated the importance of the IL-6-gp130 axis -as a key regulator of inflammatory acute phase signaling in hepatocytes-for the development of atherosclerosis.
Background/Principal Findings
Gp130-dependent gene expression was analyzed in a previously established hepatocyte-specific gp130 knockout mouse model. We performed whole transcriptome analysis in isolated hepatocytes to measure tissue specific responses after proinflammatory stimulus with IL-6 across different time points. Our analyses revealed an unexpected small gene cluster that requires IL-6 stimulus for early activation. Several of the genes in this cluster are involved in different cell defense mechanisms. Thus, stressors that trigger both general stress and inflammatory responses lead to activation of a stereotypic innate cellular defense response. Furthermore, we identified a potential biomarker Lipocalin (LCN) 2 for the gp130 dependent early inflammatory response.
Conclusions/Significance
Our findings suggest a complex network of tightly linked genes involved in the early activation of different parts of the innate immune response including acute phase proteins, complement and coagulation cascade.
doi:10.1371/journal.pone.0019427
PMCID: PMC3087798  PMID: 21573245
21.  Revisiting the Sham: Is It all Smoke and Mirrors? 
The misuse of sham controls in examining the efficacy or effectiveness of Complementary and Alternative Medicine has created numerous problems. The theoretical justification for incorporating a sham is questionable. The sham does not improve our control of bias and leads to relativistic data that, in most instances, has no appropriate interpretation with regards to treatment efficacy. Even the concept of a sham or placebo control in an efficacy trial is inherently paradoxical. Therefore, it is prudent to re-examine how we view sham controls in the context of medical research. Extreme caution should be used in giving weight to any sham-controlled study claiming to establish efficacy or safety.
doi:10.1093/ecam/neq074
PMCID: PMC3137704  PMID: 21785635
22.  TLR3 and TLR7 Modulate IgE Production in Antigen Induced Pulmonary Inflammation via Influencing IL-4 Expression in Immune Organs 
PLoS ONE  2011;6(2):e17252.
Background
Toll-like receptors (TLRs) as pattern recognition receptors, participate in both innate and adaptive immune responses, and seem to play an important role in the pathogenesis of asthma. This study aimed to identify key TLRs involved in antigen induced pulmonary inflammation (AIPI), a rat model for asthma, and to explore the role of TLRs in the disease development.
Methods and Findings
E3 rats were sensitized with ovalbumin (OVA)/alum intraperitoneally and intranasally challenged with OVA to induce AIPI model. TLR1-9 and cytokine mRNA expression in spleen, lung and mediastinal lymph node (mLN) tissues were screened by quantitative real-time polymerase chain reaction. TLR7 expression was found to be significantly down-regulated in spleen while TLR3 and TLR8 expression was up-regulated in mLN of AIPI rats. Furthermore, imiquimod (a ligand of TLR7) and TLR3 specific short-hairpin RNA plasmid for RNA interference were administrated, respectively, in vivo to AIPI rats to observe their effects on the disease by assessing various asthmatic parameters. The numbers of total cells, eosinophils, macrophages and lymphocytes were counted according to differential morphology in bronchoalveolar lavage fluid. Serum IgE and OVA specific IgG1 concentration was detected by enzyme-linked immunosorbent assay. The results showed that both TLR7 ligand treatment and TLR3 RNAi in vivo decreased serum IgE level and interleukin-4 mRNA expression.
Conclusion/Significance
TLR3 in mLN and TLR7 in spleen both systemically modulate disease development in AIPI rats via altering serum IgE concentration relevant to Th2 responses. And these findings may provide an important clue for further research in the asthma pathogenesis and suggest a new remedy for asthma treatment.
doi:10.1371/journal.pone.0017252
PMCID: PMC3045401  PMID: 21364926
23.  Pressure and Volume Limited Ventilation for the Ventilatory Management of Patients with Acute Lung Injury: A Systematic Review and Meta-Analysis 
PLoS ONE  2011;6(1):e14623.
Background
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life threatening clinical conditions seen in critically ill patients with diverse underlying illnesses. Lung injury may be perpetuated by ventilation strategies that do not limit lung volumes and airway pressures. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing pressure and volume-limited (PVL) ventilation strategies with more traditional mechanical ventilation in adults with ALI and ARDS.
Methods and Findings
We searched Medline, EMBASE, HEALTHSTAR and CENTRAL, related articles on PubMed™, conference proceedings and bibliographies of identified articles for randomized trials comparing PVL ventilation with traditional approaches to ventilation in critically ill adults with ALI and ARDS. Two reviewers independently selected trials, assessed trial quality, and abstracted data. We identified ten trials (n = 1,749) meeting study inclusion criteria. Tidal volumes achieved in control groups were at the lower end of the traditional range of 10–15 mL/kg. We found a clinically important but borderline statistically significant reduction in hospital mortality with PVL [relative risk (RR) 0.84; 95% CI 0.70, 1.00; p = 0.05]. This reduction in risk was attenuated (RR 0.90; 95% CI 0.74, 1.09, p = 0.27) in a sensitivity analysis which excluded 2 trials that combined PVL with open-lung strategies and stopped early for benefit. We found no effect of PVL on barotrauma; however, use of paralytic agents increased significantly with PVL (RR 1.37; 95% CI, 1.04, 1.82; p = 0.03).
Conclusions
This systematic review suggests that PVL strategies for mechanical ventilation in ALI and ARDS reduce mortality and are associated with increased use of paralytic agents.
doi:10.1371/journal.pone.0014623
PMCID: PMC3030554  PMID: 21298026
24.  Neuropsychological Dysfunction and Neuroimaging Abnormalities in Neurologically Intact Adults With Sickle Cell Anemia 
Context
Sickle cell anemia (SCA) is a chronic illness causing progressive deterioration in quality of life. Brain dysfunction may be the most important and least studied problem affecting individuals with this disease.
Objective
To measure neurocognitive dysfunction in neurologically asymptomatic adults with SCA vs healthy control individuals.
Design, Setting, and Participants
Cross-sectional study comparing neuropsychological function and neuroimaging findings in neurologically asymptomatic adults with SCA and controls from 12 SCA centers, conducted between December 2004 and May 2008. Participants were patients with SCA (hemoglobin [Hb] SS and hemoglobin level ≤10 mg/dL) aged 19 to 55 years and of African descent (n=149) or community controls (Hb AA and normal hemoglobin level) (n=47). Participants were stratified on age, sex, and education.
Main Outcome Measures
The primary outcome measure was nonverbal function assessed by the Wechsler Adult Intelligence Scale, third edition (WAIS-III) Performance IQ Index. Secondary exploratory outcomes included performance on neurocognitive tests of executive function, memory, attention, and language and magnetic resonance imaging measurement of total intracranial and hippocampal volume, cortical gray and white matter, and lacunae.
Results
The mean WAIS-III Performance IQ score of patients with SCA was significantly lower than that of controls (adjusted mean, 86.69 for patients with SCA vs 95.19 for controls [mean difference, −5.50; 95% confidence interval {CI}, −9.55 to −1.44]; P =.008), with 33% performing more than 1 SD (<85) below the population mean. Among secondary measures, differences were observed in adjusted mean values for global cognitive function (full-scale IQ) (90.47 for patients with SCA vs 95.66 for controls [mean difference, −5.19; 95% CI, −9.24 to −1.13]; P =.01), working memory (90.75 vs 95.25 [mean difference, −4.50; 95% CI, −8.55 to −0.45]; P =.03), processing speed (86.50 vs 97.95 [mean difference, −11.46; 95% CI, −15.51 to −7.40]; P <.001), and measures of executive function. Anemia was associated with poorer neurocognitive function in older patients. No differences in total gray matter or hippocampal volume were observed. Lacunae were more frequent in patients with SCA but not independently related to neurocognitive function.
Conclusion
Compared with healthy controls, adults with SCA had poorer cognitive performance, which was associated with anemia and age.
doi:10.1001/jama.2010.562
PMCID: PMC2892214  PMID: 20460621
25.  Pain, fatigue and health-related quality of life in children and adolescents with chronic pain 
The Clinical journal of pain  2009;25(5):407-412.
OBJECTIVES
Chronic pain and fatigue are common physical complaints among children and adolescents. Both symptoms can interfere considerably with daily life by affecting sleep and eating habits, engagement in physical and social activities, and school participation. The aim of this study was to examine the potential mediational role of fatigue in the relationship between pain and children’s school functioning and overall health-related quality of life (HRQOL). METHODS: Children seeking outpatient pain management services at two urban children’s hospitals were recruited for this study. The combined sample includes 80 children and adolescents between the ages of 8 and 18 (M = 13.89, SD = 2.57), 72.5% female, and their caregivers. The Pediatric Quality of Life Inventory (PedsQL™ 4.0) was used to assess HRQOL and the related PedsQL™ Multidimensional Fatigue Scale provided a comprehensive measure of fatigue.
RESULTS
Based on Preacher and Hayes’ mediation model (2004), fatigue functioned as a mediator between pain and overall HRQOL based on both self and proxy reports. Fatigue functioned as a mediator between pain and school functioning based on the caregiver proxy report only. Additionally, moderate relationships were found between self and caregiver proxy reports of HRQOL and fatigue, although children self-reported less fatigue, better school functioning, and greater quality of life than did their caregivers via proxy report.
DISCUSSION
Findings demonstrated that fatigue is a significant problem for many youth with chronic pain and may be an important target for clinical intervention.
doi:10.1097/AJP.0b013e318192bfb1
PMCID: PMC2844257  PMID: 19454874
fatigue; chronic pain; health-related quality of life; school functioning; children

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