bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic utility and characterization of cell-free DNA in patients with severe sepsis
Authors: Dwivedi Dhruva J , Toltl Lisa J , Swystun Laura L , Pogue Janice , Liaw Kao-Lee , Weitz Jeffrey I , Cook Deborah J , Fox-Robichaud Alison E , Liaw Patricia C ,   the Canadian Critical Care Translational Biology Group
Published: August 2012

Abstract
Introduction
Although sepsis is the leading cause of death in noncoronary critically ill patients, identification of patients at high risk of death remains a challenge. In this study, we examined the incremental usefulness of adding multiple biomarkers to clinical scoring systems for predicting intensive care unit (ICU) mortality in patients with severe sepsis.

Methods
This retrospective observational study used stored plasma samples obtained from 80 severe sepsis patients recruited at three tertiary hospital ICUs in Hamilton, Ontario, Canada. Clinical data and plasma samples were obtained at study inclusion for all 80 patients, and then daily for 1 week, and weekly thereafter for a subset of 50 patients. Plasma levels of cell-free DNA (cfDNA), interleukin 6 (IL-6), thrombin, and protein C were measured and compared with clinical characteristics, including the primary outcome of ICU mortality and morbidity measured with the Multiple Organ Dysfunction (MODS) score and Acute Physiology and Chronic Health Evaluation (APACHE) II scores.

Results
The level of cfDNA in plasma at study inclusion had better prognostic utility than did MODS or APACHE II scores, or the biomarkers measured. The area under the receiver operating characteristic (ROC) curves for cfDNA to predict ICU mortality is 0.97 (95% CI, 0.93 to 1.00) and to predict hospital mortality is 0.84 (95% CI, 0.75 to 0.94). We found that a cfDNA cutoff value of 2.35 ng/μl had a sensitivity of 87.9% and specificity of 93.5% for predicting ICU mortality. Sequential measurements of cfDNA suggested that ICU mortality may be predicted within 24 hours of study inclusion, and that the predictive power of cfDNA may be enhanced by combining it with protein C levels or MODS scores. DNA-sequence analyses and studies with Toll-like receptor 9 (TLR9) reporter cells suggests that the cfDNA from sepsis patients is host derived.

Conclusions
These studies suggest that cfDNA provides high prognostic accuracy in patients with severe sepsis. The serial data suggest that the combination of cfDNA with protein C and MODS scores may yield even stronger predictive power. Incorporation of cfDNA in sepsis risk-stratification systems may be valuable for clinical decision making or for inclusion into sepsis trials.
Vasopressin and terlipressin in adult vasodilatory shock: a systematic review and meta-analysis of nine randomized controlled trials
Authors: Serpa Neto Ary , Nassar Antônio P , Cardoso Sérgio O , Manetta José A , Pereira Victor GM , Espósito Daniel C , Damasceno Maria CT , Russell James A 
Published: August 2012

Abstract
Introduction
Catecholamines are the most used vasopressors in vasodilatory shock. However, the development of adrenergic hyposensitivity and the subsequent loss of catecholamine pressor activity necessitate the search for other options. Our aim was to evaluate the effects of vasopressin and its analog terlipressin compared with catecholamine infusion alone in vasodilatory shock.

Methods
A systematic review and meta-analysis of publications between 1966 and 2011 was performed. The Medline and CENTRAL databases were searched for studies on vasopressin and terlipressin in critically ill patients. The meta-analysis was limited to randomized controlled trials evaluating the use of vasopressin and/or terlipressin compared with catecholamine in adult patients with vasodilatory shock. The assessed outcomes were: overall survival, changes in the hemodynamic and biochemical variables, a decrease of catecholamine requirements, and adverse events.

Results
Nine trials covering 998 participants were included. A meta-analysis using a fixed-effect model showed a reduction in norepinephrine requirement among patients receiving terlipressin or vasopressin infusion compared with control (standardized mean difference, -1.58 (95% confidence interval, -1.73 to -1.44); P < 0.0001). Overall, vasopressin and terlipressin, as compared with norepinephrine, reduced mortality (relative risk (RR), 0.87 (0.77 to 0.99); P = 0.04). Vasopressin compared with norepinephrine decreased mortality in adult patients (RR, 0.87 (0.76 to 1.00); P = 0.05) and in patients with septic shock (42.5% vs. 49.2%, respectively; RR, 0.87 (0.75 to 1.00); P = 0.05; number needed to treat, 1 to 15). There was no difference in adverse events between the vasopressin and control groups (RR, 0.98 (0.65 to 1.47); P = 0.92).

Conclusions
Vasopressin use in vasodilatory shock is safe, associated with reduced mortality, and facilitates weaning of catecholamines. In patients with septic shock, use of vasopressin compared with norepinephrine may also decrease mortality.
Anti-inflammatory treatment induced regenerative oligodendrogenesis in parkinsonian mice
Authors: Worlitzer Maik MA , Bunk Eva C , Hemmer Kathrin , Schwamborn Jens C 
Published: August 2012

Abstract
Introduction
The adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. However, it is barely established how chronic neuroinflammation, as it occurs in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, affects adult neurogenesis and, therefore, modulates the brain's potential for self-regeneration.

Methods
Neural stem cell culture techniques, intraventricular tumor necrosis factor (TNF)-α infusion and the 6-hydroxydopamine mouse model were used to investigate the influence of neuroinflammation on adult neurogenesis in the Parkinson's disease background. Microscopic methods and behavioral tests were used to analyze samples.

Results
Here, we demonstrate that differences in the chronicity of TNF-α application to cultured NSCs result in opposed effects on their proliferation. However, chronic TNF-α treatment, mimicking Parkinson's disease associated neuroinflammation, shows detrimental effects on neural progenitor cell activity. Inversely, pharmacological inhibition of neuroinflammation in a 6-hydroxydopamine mouse model led to increased neural progenitor cell proliferation in the subventricular zone and neuroblast migration into the lesioned striatum. Four months after surgery, we measured improved Parkinson's disease-associated behavior, which was correlated with long-term anti-inflammatory treatment. But surprisingly, instead of newly generated striatal neurons, oligodendrogenesis in the striatum of treated mice was enhanced.

Conclusions
We conclude that anti-inflammatory treatment, in a 6-hydroxydopamine mouse model for Parkinson's disease, leads to activation of adult neural stem cells. These adult neural stem cells generate striatal oligodendrocytes. The higher numbers of newborn oligodendrocytes possibly contribute to axonal stability and function in this mouse model of Parkinson's disease and thereby attenuate dysfunctions of basalganglian motor-control.
Myeloid-derived suppressor cells from tumor-bearing mice impair TGF-β-induced differentiation of CD4+CD25+FoxP3+ Tregs from CD4+CD25−FoxP3− T cells
Authors: Centuori Sara M , Trad Malika , LaCasse Collin J , Alizadeh Darya , Larmonier Claire B , Hanke Neale T , Kartchner Jessica , Janikashvili Nona , Bonnotte Bernard , Larmonier Nicolas , Katsanis Emmanuel 
Published: August 2012

Abstract
Granulocytic myeloid-derived suppressor cells from tumorbearing mice inhibit the differentiation of iTreg.
MDSCs and Tregs play an essential role in the immunosuppressive networks that contribute to tumor-immune evasion. The mechanisms by which tumors promote the expansion and/or function of these suppressive cells and the cross-talk between MDSC and Treg remain incompletely defined. Previous reports have suggested that MDSC may contribute to Treg induction in cancer. Herein, we provide evidence that tumor-induced gr-MDSCs, endowed with the potential of suppressing conventional T Lc, surprisingly impair TGF-β1-mediated generation of CD4+CD25+FoxP3+ iTregs. Furthermore, gr-MDSCs impede the proliferation of nTregs without, however, affecting FoxP3 expression. Suppression of iTreg differentiation from naïve CD4+ cells by gr-MDSC occurs early in the polarization process, requires inhibition of early T cell activation, and depends on ROS and IDO but does not require arginase 1, iNOS, NO, cystine/cysteine depletion, PD-1 and PD-L1 signaling, or COX-2. These findings thus indicate that gr-MDSCs from TB hosts have the unanticipated ability to restrict immunosuppressive Tregs.
Serum Lactate Dehydrogenase Predicts for Overall Survival Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Inhibition of Mammalian Target of Rapamycin
Authors: Armstrong Andrew J. , George Daniel J. , Halabi Susan 
Published: August 2012

Purpose Lactate dehydrogenase (LDH) is an enzyme involved in anaerobic glycolysis and regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR)–containing complex 1 (PI3K/Akt/TORC1) pathway as well as tumor hypoxia/necrosis. High serum LDH levels are associated with poor prognosis in patients with cancer, including renal cell carcinoma (RCC). We tested whether serum LDH is prognostic and has predictive value in patients with metastatic RCC receiving an mTOR inhibitor. Patients and Methods We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk patients with RCC treated with the TORC1 inhibitor temsirolimus or interferon alfa in an international phase III randomized trial. The proportional hazards model was used to test for the prognostic and predictive association of LDH in predicting overall survival (OS). Results Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (ULN; range, 0.05 to 28.5 × ULN). The multivariable hazard ratio for death was 2.81 (95% CI, 2.01 to 3.94; P < .001) for patients with LDH more than 1 × ULN versus patients with LDH ≤ 1 × ULN. The LDH-treatment interaction term was statistically significant for OS (P = .016). Among 140 patients with LDH above the ULN, OS was significantly improved with temsirolimus (6.9 v 4.2 months; P < .002). Among 264 patients with normal LDH, OS was not significantly improved with temsirolimus as compared with interferon therapy (11.7 v 10.4 months; P = .514). Conclusion Serum LDH is a prognostic and a predictive biomarker for the survival benefit conferred by TORC1 inhibition in poor-risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with PI3K/TORC1 pathway inhibition in other RCC risk groups and other tumor types is warranted.
The Maximalist Novel
Authors: Ercolino Stefano 
Published: August 2012

This article seeks to define a new genre of the contemporary novel: the maximalist novel. It is an aesthetically hybrid genre that developed in the United States in the early 1970s and then spread to Europe at the beginning of the twenty-first century. The aim of this article is to stake out a new conceptual territory that will contribute to a re-shaping of both the traditional view of the literary postmodern and the understanding of the development of the novel in the second half of the twentieth century. The maximalist novel has a strong symbolic and morphological identity, with ten elements that define and structure it as a highly complex literary form: length, encyclopedic mode, dissonant chorality, diegetic exuberance, completeness, narrratorial omniscience, paranoid imagination, inter-semiocity, ethical commitment, and hybrid realism. These ten categories are common to the seven novels discussed in this essay: Gravity's Rainbow by Thomas Pynchon, Infinite Jest by David Foster Wallace, Underworld by Don DeLillo, White Teeth by Zadie Smith, The Corrections by Jonathan Franzen, 2666 by Roberto Bolaño, and 2005 dopo Cristo by the Babette Factory.
Although these ten features are not all present in the same form or intensity in each of these texts, they are decisive in defining them as maximalist novels, insofar as they are systematically co-present. These elements can individually be found in modernist and postmodern novels that are not maximalist; however, it is their co-presence and their reciprocal articulation that make them fundamental in demarcating the maximalist novel as a genre. The essay shows both the peculiar significance these elements have and the function some of the categories play within the internal dialectic of the genre. It discusses chaos-function and cosmos-function and argues that categories such as “length,” “encyclopedic mode,” “dissonant chorality,” and “diegetic exuberance,” beyond their strong specificity and irreducibility to one another, play a common role against categories such as “completeness,” “narratorial omniscience,” and “paranoia,” thus creating a centrifugal/centripetal dialectic within the representation. The remaining three categories—“inter-semiocity,” “ethical commitment,” and “hybrid realism”—do not play a specific role within the internal dialectic of the genre, but are crucial—to the same extent as the other seven—to understanding the ethical and aesthetical project of the maximalist novel, which strives to relate the complexity of the world we live in and to give a synthetic and totalizing representation of it.
Failure to increase insulin secretory capacity during pregnancy-induced insulin resistance is associated with ethnicity and gestational diabetes
Authors: Mørkrid Kjersti , Jenum Anne K , Sletner Line , Vårdal Mari H , Waage Christin W , Nakstad Britt , Vangen Siri , Birkeland Kåre I 
Published: August 2012

ObjectiveTo assess changes in insulin resistance and β-cell function in a multiethnic cohort of women in Oslo, Norway, from early to 28 weeks' gestation and 3 monthspost partumand relate the findings to gestational diabetes mellitus (GDM).MethodPopulation-based cohort study of 695 healthy pregnant women from Western Europe (41%), South Asia (25%), Middle East (15%), East Asia (6%) and elsewhere (13%). Blood samples and demographics were recorded at mean 15 (V1) and 28 (V2) weeks' gestation and 3 monthspost partum(V3). Universal screening was by 75 g oral glucose tolerance test at V2, GDM with modified IADPSG criteria (no 1-h measurement): fasting plasma glucose (PG) ≥5.1 or 2-h PG ≥8.5 mmol/l. Homeostatic model assessment (HOMA)-β (β-cell function) and HOMA-IR (insulin resistance) were calculated from fasting glucose and C-peptide.ResultCharacteristics were comparable across ethnic groups, except age (South Asians: younger,P<0.001) and prepregnant BMI (East Asians: lower,P=0.040). East and South Asians were more insulin resistant than Western Europeans at V1. From V1 to V2, the increase in insulin resistance was similar across the ethnic groups, but the increase in β-cell function was significantly lower for the East and South Asians compared with Western Europeans. GDM women compared with non-GDM women were more insulin resistant at V1; from V1 to V2, their β-cell function increased significantly less and the percentage increase in β-cell function did not match the change in insulin resistance.ConclusionPregnant women from East Asia and South Asia were more insulin resistant and showed poorer HOMA-β-cell function than Western Europeans.
Mortality and Clinical Outcomes in HIV-Infected Children on Antiretroviral Therapy in Malawi, Lesotho, and Swaziland
Authors: Kabue Mark M. , Buck W. Chris , Wanless Sebastian R. , Cox Carrie M. , McCollum Eric D. , Caviness A. Chantal , Ahmed Saeed , Kim Maria H. , Thahane Lineo , Devlin Andrew , Kochelani Duncan , Kazembe Peter N. , Calles Nancy R. , Mizwa Michael B. , Schutze Gordon E. , Kline Mark W. 
Published: August 2012

OBJECTIVE:
To determine mortality and immune status improvement in HIV-infected pediatric patients on antiretroviral treatment (ART) in Malawi, Lesotho, and Swaziland.

METHODS:
We conducted a retrospective cohort study of patients aged &lt;12 years at ART initiation at 3 sites in sub-Saharan Africa between 2004 and 2009. Twelve-month and overall mortality were estimated, and factors associated with mortality and immune status improvement were evaluated.

RESULTS:
Included in the study were 2306 patients with an average follow-up time on ART of 2.3 years (interquartile range 1.5–3.1 years). One hundred four patients (4.5%) died, 9.0% were lost to follow-up, and 1.3% discontinued ART. Of the 104 deaths, 77.9% occurred in the first year of treatment with a 12-month mortality rate of 3.5%. The overall mortality rate was 2.25 deaths/100 person-years (95% confidence interval [CI] 1.84–2.71). Increased 12-month mortality was associated with younger age; &lt;6 months (hazard ratio [HR] = 8.11, CI 4.51–14.58), 6 to &lt;12 months (HR = 3.43, CI 1.96–6.02), and 12 to &lt;36 months (HR = 1.92, CI 1.16–3.19), and World Health Organization stage IV (HR = 4.35, CI 2.19–8.67). Immune status improvement at 12 months was less likely in patients with advanced disease and age &lt;12 months.

CONCLUSIONS:
Despite challenges associated with pediatric ART in developing countries, low mortality and good treatment outcomes can be achieved. However, outcomes are worse in younger patients and those with advanced disease at the time of ART initiation, highlighting the importance of early diagnosis and treatment.
Efficacy of Fat-Soluble Vitamin Supplementation in Infants With Biliary Atresia
Authors: Shneider Benjamin L. , Magee John C. , Bezerra Jorge A. , Haber Barbara , Karpen Saul J. , Raghunathan Trivellore , Rosenthal Philip , Schwarz Kathleen , Suchy Frederick J. , Kerkar Nanda , Turmelle Yumirle , Whitington Peter F. , Robuck Patricia R. , Sokol Ronald J. 
Published: August 2012

OBJECTIVE:
Cholestasis predisposes to fat-soluble vitamin (FSV) deficiencies. A liquid multiple FSV preparation made with tocopheryl polyethylene glycol-1000 succinate (TPGS) is frequently used in infants with biliary atresia (BA) because of ease of administration and presumed efficacy. In this prospective multicenter study, we assessed the prevalence of FSV deficiency in infants with BA who received this FSV/TPGS preparation.

METHODS:
Infants received FSV/TPGS coadministered with additional vitamin K as routine clinical care in a randomized double-blinded, placebo-controlled trial of corticosteroid therapy after hepatoportoenterostomy (HPE) for BA (identifier NCT 00294684). Levels of FSV, retinol binding protein, total serum lipids, and total bilirubin (TB) were measured 1, 3, and 6 months after HPE.

RESULTS:
Ninety-two infants with BA were enrolled in this study. Biochemical evidence of FSV insufficiency was common at all time points for vitamin A (29%–36% of patients), vitamin D (21%–37%), vitamin K (10%–22%), and vitamin E (16%–18%). Vitamin levels were inversely correlated with serum TB levels. Biochemical FSV insufficiency was much more common (15%–100% for the different vitamins) in infants whose TB was ≥2 mg/dL. At 3 and 6 months post HPE, only 3 of 24 and 0 of 23 infants, respectively, with TB &gt;2 mg/dL were sufficient in all FSV.

CONCLUSIONS:
Biochemical FSV insufficiency is commonly observed in infants with BA and persistent cholestasis despite administration of a TPGS containing liquid multiple FSV preparation. Individual vitamin supplementation and careful monitoring are warranted in infants with BA, especially those with TB &gt;2 mg/dL.
Preterm Birth and Body Composition at Term Equivalent Age: A Systematic Review and Meta-analysis
Authors: Johnson Mark J. , Wootton Stephen A. , Leaf Alison A. , Jackson Alan A. 
Published: August 2012

BACKGROUND AND OBJECTIVE:Infants born preterm are significantly lighter and shorter on reaching term equivalent age (TEA) than are those born at term, but the relation with body composition is less clear. We conducted a systematic review to assess the body composition at TEA of infants born preterm.METHODS:The databases MEDLINE, Embase, CINAHL, HMIC, “Web of Science,” and “CSA Conference Papers Index” were searched between 1947 and June 2011, with selective citation and reference searching. Included studies had to have directly compared measures of body composition at TEA in preterm infants and infants born full-term. Data on body composition, anthropometry, and birth details were extracted from each article.RESULTS:Eight studies (733 infants) fulfilled the inclusion criteria. Mean gestational age and weight at birth were 30.0 weeks and 1.18 kg in the preterm group and 39.6 weeks and 3.41 kg in the term group, respectively. Meta-analysis showed that the preterm infants had a greater percentage total body fat at TEA than those born full-term (mean difference, 3%; P = .03), less fat mass (mean difference, 50 g; P = .03), and much less fat-free mass (mean difference, 460 g; P &lt; .0001).CONCLUSIONS:The body composition at TEA of infants born preterm is different than that of infants born at term. Preterm infants have less lean tissue but more similar fat mass. There is a need to determine whether improved nutritional management can enhance lean tissue acquisition, which indicates a need for measures of body composition in addition to routine anthropometry.
Effects of CPOE on Provider Cognitive Workload: A Randomized Crossover Trial
Authors: Avansino Jeffrey , Leu Michael G. 
Published: August 2012

OBJECTIVE:
To evaluate whether systematically developed clinical decision supports provide usability benefit or decreased cognitive workload with their use.

METHODS:
Seven surgeons at a pediatric hospital at different levels of training (3 residents, 3 fellows, and 1 attending) were randomized to use either a historical control (ad hoc developed order set) or a systematically developed order set for postoperative management of appendicitis in children. After a washout period, they were crossed over to the other order set. Participants were videorecorded and completed postsurveys, including the System Usability Scale and the National Aeronautic and Space Administration–Task Load Index.

RESULTS:
Participants unanimously preferred using systematically developed order sets. These order sets resulted in higher usability scores (75 ± 10 vs 60 ± 19; P &lt; .05) and lower cognitive workload scores (37.7 ± 15 vs 52.2 ± 12; P &lt; .05), with comparable amounts of time spent, mouse clicks, and free text entry. Orders generated were more likely to conform to established clinical guidelines.

CONCLUSIONS:
Systematically designed order sets provide a reduction in cognitive workload and order variation in the context of improved system usability and improved guideline adherence. The systematically designed order set did not improve time spent, reduce mouse clicks, or reduce free text entry.