bluuebunny/crossref_metadata_2025 huggingface dataset:
Early intra-intensive care unit psychological intervention promotes recovery from post traumatic stress disorders, anxiety and depression symptoms in critically ill patients
Authors: Peris Adriano , Bonizzoli Manuela , Iozzelli Dario , Migliaccio Maria Luisa , Zagli Giovanni , Bacchereti Alberto , Debolini Marta , Vannini Elisetta , Solaro Massimo , Balzi Ilaria , Bendoni Elisa , Bacchi Ilaria , Giovannini Valtere , Belloni Laura
Published: February 2011

Introduction

Critically ill patients who require intensive care unit (ICU) treatment may experience psychological distress with increasing development of psychological disorders and related morbidity. Our aim was to determine whether intra-ICU clinical psychologist interventions decrease the prevalence of anxiety, depression and posttraumatic stress disorder (PTSD) after 12 months from ICU discharge.

Methods

Our observational study included critical patients admitted before clinical psychologist intervention (control group) and patients who were involved in a clinical psychologist program (intervention group). The Hospital Anxiety and Depression Scale (HADS) and Impact of Event Scale-Revised questionnaires were used to assess the level of posttraumatic stress, anxiety and depression symptoms.

Results

The control and intervention groups showed similar demographic and clinical characteristics. Patients in the intervention group showed lower rates of anxiety (8.9% vs. 17.4%) and depression (6.5% vs. 12.8%) than the control group on the basis of HADS scores, even if the differences were not statistically significant. High risk for PTSD was significantly lower in patients receiving early clinical psychologist support than in the control group (21.1% vs. 57%; P < 0.0001). The percentage of patients who needed psychiatric medications at 12 months was significantly higher in the control group than in the patient group (41.7% vs. 8.1%; P < 0.0001).

Conclusions

Our results suggest that that early intra-ICU clinical psychologist intervention may help critically ill trauma patients recover from this stressful experience.
Usefulness of N-terminal pro-brain natriuretic peptide and C-reactive protein to predict ICU mortality in unselected medical ICU patients: a prospective, observational study
Authors: Wang Feilong , Pan Wenzhi , Pan Shuming , Wang Shuyun , Ge Qinmin , Ge Junbo
Published: February 2011

Introduction

The performance of N-terminal pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) to predict clinical outcomes in ICU patients is unimpressive. We aimed to assess the prognostic value of NT-proBNP, CRP or the combination of both in unselected medical ICU patients.

Methods

A total of 576 consecutive patients were screened for eligibility and followed up during the ICU stay. We collected each patient's baseline characteristics including the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, NT-proBNP and CRP levels. The primary outcome was ICU mortality. Potential predictors were analyzed for possible association with outcomes. We also evaluated the ability of NT-proBNP and CRP additive to APACHE-II score to predict ICU mortality by calculation of C-index, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices.

Results

Multiple regression revealed that CRP, NT-proBNP, APACHE-II score and fasting plasma glucose independently predicted ICU mortality (all P < 0.01). The C-index with respect to prediction of ICU mortality of APACHE II score (0.82 ± 0.02; P < 0.01) was greater than that of NT-proBNP (0.71 ± 0.03; P < 0.01) or CRP (0.65 ± 0.03; P < 0.01) (all P < 0.01). As compared with APACHE-II score (0.82 ± 0.02; P < 0.01), combination of CRP (0.83 ± 0.02; P < 0.01) or NT-proBNP (0.83 ± 0.02; P < 0.01) or both (0.84 ± 0.02; P < 0.01) with APACHE-II score did not significantly increase C-index for predicting ICU mortality (all P > 0.05). However, addition of NT-proBNP to APACHE-II score gave IDI of 6.6% (P = 0.003) and NRI of 16.6% (P = 0.007), addition of CRP to APACHE-II score provided IDI of 5.6% (P = 0.026) and NRI of 12.1% (P = 0.023), and addition of both markers to APACHE-II score yielded IDI of 7.5% (P = 0.002) and NRI of 17.9% (P = 0.002). In the cardiac subgroup (N = 213), NT-proBNP but not CRP independently predicted ICU mortality and addition of NT-proBNP to APACHE-II score obviously increased predictive ability (IDI = 10.2%, P = 0.018; NRI = 18.5%, P = 0.028). In the non-cardiac group (N = 363), CRP rather than NT-proBNP was an independent predictor of ICU mortality.

Conclusions

In unselected medical ICU patients, NT-proBNP and CRP can serve as independent predictors of ICU mortality and addition of NT-proBNP or CRP or both to APACHE-II score significantly improves the ability to predict ICU mortality. NT-proBNP appears to be useful for predicting ICU outcomes in cardiac patients.
Hormonal responses upon return of spontaneous circulation after cardiac arrest: a retrospective cohort study
Authors: Kim Jin Joo , Hyun Sung Youl , Hwang Seong Youn , Jung Young Bo , Shin Jong Hwan , Lim Yong Su , Cho Jin Seong , Yang Hyuk Jun , Lee Gun
Published: February 2011

Introduction

Cardiac arrest is often fatal and can be extremely stressful to patients, even if spontaneous rhythm is returned. The purpose of this study was to analyze the hormonal response after return of spontaneous circulation (ROSC).

Methods

This is a retrospective review of the chart and laboratory findings in a single medical facility. The patients admitted to the intensive care unit after successful resuscitation after out-of-hospital cardiac arrest were retrospectively identified and evaluated. Patients with hormonal diseases, patients who received cortisol treatment, those experiencing trauma, and pregnant women were excluded. Serum cortisol, adrenocorticotropic hormone (ACTH), and anti-diuretic hormone (ADH (vasopressin)) were analyzed and a corticotropin-stimulation test was performed. Mortality at one week and one month after admission, and neurologic outcome (cerebral performance category (CPC)) one month after admission were evaluated.

Results

A total of 117 patients, including 84 males (71.8%), were evaluated in this study. One week and one month after admission, 87 (74.4%) and 65 patients (55.6%) survived, respectively. Relative adrenal insufficiency, and higher plasma ACTH and ADH levels were associated with shock-related mortality (P = 0.046, 0.005, and 0.037, respectively), and ACTH and ADH levels were also associated with late mortality (P = 0.002 and 0.004, respectively). Patients with relative adrenal insufficiency, ACTH ≧5 pg/mL, and ADH ≧30 pg/mL, had a two-fold increased risk of a poor outcome (shock-related mortality): (odds ratio (OR), 2.601 and 95% confidence interval (CI), 1.015 to 6.664; OR, 2.759 and 95% CI, 1.060 to 7.185; OR, 2.576 and 95% CI, 1.051 to 6.313, respectively). Thirty-five patients (29.9%) had a good CPC (1 to 2), and 82 patients (70.1%) had a bad CPC (3 to 5). Age ≧50 years and an ADH ≧30 pg/mL were associated with a bad CPC (OR, 4.564 and 95% CI, 1.794 to 11.612; OR, 6.568 and 95% CI, 1.918 to 22.483, respectively).

Conclusions

The patients with relative adrenal insufficiency and higher blood levels of ACTH and ADH upon ROSC after cardiac arrest had a poor outcome. The effectiveness of administration of cortisol and ADH to patients upon ROSC after cardiac arrest is uncertain and additional studies are needed.
Renal replacement therapy is an independent risk factor for mortality in critically ill patients with acute kidney injury
Authors: Elseviers Monique M , Lins Robert L , Van der Niepen Patricia , Hoste Eric , Malbrain Manu L , Damas Pierre , Devriendt Jacques ,   the SHARF investigators
Published: February 2011

Introduction

Outcome studies in patients with acute kidney injury (AKI) have focused on differences between modalities of renal replacement therapy (RRT). The outcome of conservative treatment, however, has never been compared with RRT.

Methods

Nine Belgian intensive care units (ICUs) included all adult patients consecutively admitted with serum creatinine >2 mg/dl. Included treatment options were conservative treatment and intermittent or continuous RRT. Disease severity was determined using the Stuivenberg Hospital Acute Renal Failure (SHARF) score. Outcome parameters studied were mortality, hospital length of stay and renal recovery at hospital discharge.

Results

Out of 1,303 included patients, 650 required RRT (58% intermittent, 42% continuous RRT). Overall results showed a higher mortality (43% versus 58%) as well as a longer ICU and hospital stay in RRT patients compared to conservative treatment. Using the SHARF score for adjustment of disease severity, an increased risk of death for RRT compared to conservative treatment of RR = 1.75 (95% CI: 1.4 to 2.3) was found. Additional correction for other severity parameters (Acute Physiology And Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA)), age, type of AKI and clinical conditions confirmed the higher mortality in the RRT group.

Conclusions

The SHARF study showed that the higher mortality expected in AKI patients receiving RRT versus conservative treatment can not only be explained by a higher disease severity in the RRT group, even after multiple corrections. A more critical approach to the need for RRT in AKI patients seems to be warranted.
Genome-wide transcription profiling of human sepsis: a systematic review
Authors: Tang Benjamin M , Huang Stephen J , McLean Anthony S
Published: February 2011

Introduction

Sepsis is thought to be an abnormal inflammatory response to infection. However, most clinical trials of drugs that modulate the inflammatory response of sepsis have been unsuccessful. Emerging genomic evidence shows that the host response in sepsis does not conform to a simple hyper-inflammatory/hypo-inflammatory model. We, therefore, synthesized current genomic studies that examined the host response of circulating leukocytes to human sepsis.

Methods

Electronic searches were performed in Medline and Embase (1987 to October 2010), supplemented by additional searches in multiple microarray data repositories. We included studies that (1) used microarray, (2) were performed in humans and (3) investigated the host response mediated by circulating leukocytes.

Results

We identified 12 cohorts consisting of 784 individuals providing genome-wide expression data in early and late sepsis. Sepsis elicited an immediate activation of pathogen recognition receptors, accompanied by an increase in the activities of signal transduction cascades. These changes were consistent across most cohorts. However, changes in inflammation related genes were highly variable. Established inflammatory markers, such as tumour necrosis factor-α (TNF-α), interleukin (IL)-1 or interleukin-10, did not show any consistent pattern in their gene-expression across cohorts. The finding remains the same even after the cohorts were stratified by timing (early vs. late sepsis), patient groups (paediatric vs. adult patients) or settings (clinical sepsis vs. endotoxemia model). Neither a distinctive pro/anti-inflammatory phase nor a clear transition from a pro-inflammatory to anti-inflammatory phase could be observed during sepsis.

Conclusions

Sepsis related inflammatory changes are highly variable on a transcriptional level. We did not find strong genomic evidence that supports the classic two phase model of sepsis.
Plasma soluble vascular endothelial growth factor receptor-1 levels predict outcomes of pneumonia-related septic shock patients: a prospective observational study
Authors: Yang Kuang-Yao , Liu Kuan-Ting , Chen Yu-Chun , Chen Chun-Sheng , Lee Yu-Chin , Perng Reury-Perng , Feng Jia-Yih
Published: February 2011

Introduction

Despite recent advances in the management of septic shock, mortality rates are still unacceptably high. Early identification of the high-mortality risk group for early intervention remains an issue under exploration. Vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR1) and urokinase plasminogen activator (uPA) have diverse effects in the pathogenesis of sepsis, which involve pro-inflammation, anti-inflammation, endothelial cell repair, and vascular permeability change. Their roles in predicting mortality and organ dysfunction remain to be clarified.

Methods

Pneumonia-related septic shock patients from medical intensive care units were enrolled for this prospective observational study. We also included 20 patients with pneumonia without organ dysfunction for comparison. Plasma levels of VEGF and sVEGFR1 and uPA activity within 24 hours of shock onset were measured. We compared plasma levels of these biomarkers with APACHE II scores between subgroups of patients, and evaluated their predictive value for 28-day mortality and organ dysfunction.

Results

A total of 101 patients, including 81 with pneumonia-related septic shock and 20 with pneumonia without organ dysfunction, were enrolled. Non-survivors of septic shock had significantly higher plasma sVEGFR1 levels (659.3 ± 1022.8 vs. 221.1 ± 268.9 pg/mL, respectively, P < 0.001) and uPA activity (47.2 ± 40.6 vs. 27.6 ± 17.2 units, respectively, P = 0.001) when compared with those of the survivors. Kaplan-Meier survival analysis demonstrated significantly higher mortality in patients with higher levels of sVEGFR1 (P < 0.001) and uPA activity (P = 0.031). In Cox regression analysis, plasma sVEGFR1 level was independently associated with, and best predicted, the 28-day mortality of septic shock (HR: 1.55, 95% CI: 1.05-2.30). Plasma sVEGFR1 level and uPA activity had good correlation with renal dysfunction, metabolic acidosis, and hematologic dysfunction; their levels significantly increased when the number of organ dysfunctions increased. In multivariate analysis, plasma sVEGFR1 level (HR: 2.82, 95% CI: 1.17-6.81) and uPA activity (HR: 2.75, 95% CI: 1.06-7.13) were independent predictors of the presence of concomitant multi-organ dysfunction. The predictive value of VEGF for mortality and organ dysfunction was limited in pneumonia-related septic shock patients.

Conclusions

High plasma sVEGFR1 level in the early stage of pneumonia-related septic shock independently predicted 28-day mortality and multi-organ dysfunction.
The dynamic pattern of end-tidal carbon dioxide during cardiopulmonary resuscitation: difference between asphyxial cardiac arrest and ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest
Authors: Lah Katja , Križmarić Miljenko , Grmec Štefek
Published: February 2011

Introduction

Partial pressure of end-tidal carbon dioxide (PetCO2) during cardiopulmonary resuscitation (CPR) correlates with cardiac output and consequently has a prognostic value in CPR. In our previous study we confirmed that initial PetCO2 value was significantly higher in asphyxial arrest than in ventricular fibrillation/pulseless ventricular tachycardia (VF/VT) cardiac arrest. In this study we sought to evaluate the pattern of PetCO2 changes in cardiac arrest caused by VF/VT and asphyxial cardiac arrest in patients who were resuscitated according to new 2005 guidelines.

Methods

The study included two cohorts of patients: cardiac arrest due to asphyxia with initial rhythm asystole or pulseless electrical activity (PEA), and cardiac arrest due to arrhythmia with initial rhythm VF or pulseless VT. PetCO2 was measured for both groups immediately after intubation and repeatedly every minute, both for patients with or without return of spontaneous circulation (ROSC). We compared the dynamic pattern of PetCO2 between groups.

Results

Between June 2006 and June 2009 resuscitation was attempted in 325 patients and in this study we included 51 patients with asphyxial cardiac arrest and 63 patients with VF/VT cardiac arrest. The initial values of PetCO2 were significantly higher in the group with asphyxial cardiac arrest (6.74 ± 4.22 kilopascals (kPa) versus 4.51 ± 2.47 kPa; P = 0.004). In the group with asphyxial cardiac arrest, the initial values of PetCO2 did not show a significant difference when we compared patients with and without ROSC (6.96 ± 3.63 kPa versus 5.77 ± 4.64 kPa; P = 0.313). We confirmed significantly higher initial PetCO2 values for those with ROSC in the group with primary cardiac arrest (4.62 ± 2.46 kPa versus 3.29 ± 1.76 kPa; P = 0.041). A significant difference in PetCO2 values for those with and without ROSC was achieved after five minutes of CPR in both groups. In all patients with ROSC the initial PetCO2 was again higher than 1.33 kPa.

Conclusions

The dynamic pattern of PetCO2 values during out-of-hospital CPR showed higher values of PetCO2 in the first two minutes of CPR in asphyxia, and a prognostic value of initial PetCO2 only in primary VF/VT cardiac arrest. A prognostic value of PetCO2 for ROSC was achieved after the fifth minute of CPR in both groups and remained present until final values. This difference seems to be a useful criterion in pre-hospital diagnostic procedures and attendance of cardiac arrest.
Menstrual History and Quality-of-Life Outcomes in Women With Node-Positive Breast Cancer Treated With Adjuvant Therapy on the NSABP B-30 Trial
Authors: Ganz Patricia A. , Land Stephanie R. , Geyer Charles E. , Cecchini Reena S. , Costantino Joseph P. , Pajon Eduardo R. , Fehrenbacher Louis , Atkins James N. , Polikoff Jonathan A. , Vogel Victor G. , Erban John K. , Livingston Robert B. , Perez Edith A. , Mamounas Eleftherios P. , Wolmark Norman , Swain Sandra M.
Published: February 2011

Purpose

Premenopausal women with breast cancer receiving adjuvant chemotherapy are at risk for amenorrhea. The National Surgical Adjuvant Breast and Bowel Project B-30 trial included menstrual history (MH) and quality-of-life (QOL) studies to compare treatments on these outcomes.

Patients and Methods

Patients were randomly assigned to sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T; AC→T), concurrent TAC, or AT, which varied in duration (24, 12, 12 weeks, respectively), and use of C. Endocrine therapy was prescribed for women with hormone receptor–positive tumors. MH and QOL were assessed with standardized questionnaires at baseline; cycle 4, day 1; and every 6 months through 24 months. Prespecified analyses examined rates of amenorrhea by treatment arm, the relationship between amenorrhea and QOL, and QOL by treatment arm.

Results

Amenorrhea 12 months after random assignment was significantly different between treatment groups: 69.8% for AC→T, 57.7% for TAC, and 37.9% for AT (P < .001). The AT group without tamoxifen had the lowest rate of amenorrhea. QOL was poorer for patients receiving AC→T at 6 months but similar to others by 12 months. Post-treatment symptoms were increased above baseline for all treatments. Multivariable repeated measures modeling demonstrated that treatment arm, time point, age, and tamoxifen use were significantly associated with symptom severity (all P values < .002).

Conclusion

Amenorrhea rates differed significantly by treatment arm, with the AT arm having the lowest rate. Patients treated with longer duration therapy (AC→T) had greater symptom severity and poorer QOL at 6 months, but did not differ from shorter duration treatments at 12 months.
Quality of Life of Older Patients With Early-Stage Breast Cancer Receiving Adjuvant Chemotherapy: A Companion Study to Cancer and Leukemia Group B 49907
Authors: Kornblith Alice B. , Lan Lan , Archer Laura , Partridge Ann , Kimmick Gretchen , Hudis Clifford , Winer Eric , Casey Rebecca , Bennett Samantha , Cohen Harvey Jay , Muss Hyman B.
Published: February 2011

Purpose

A phase III trial (Cancer and Leukemia Group B CALGB-49907) was conducted to test whether older patients with early-stage breast cancer would have equivalent relapse-free and overall survival with capecitabine compared with standard chemotherapy. The quality of life (QoL) substudy tested whether capecitabine treatment would be associated with a better QoL than standard chemotherapy.

Patients and Methods

QoL was assessed in 350 patients randomly assigned to either standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin and cyclophosphamide [AC]; n = 182) or capecitabine (n = 168). Patients were interviewed by telephone before treatment (baseline), midtreatment, within 1 month post-treatment, and at 12, 18, and 24 months postbaseline by using questionnaires from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), a breast systemic adverse effects scale (EORTC BR23), and the Hospital Anxiety and Depression Scale (HADS).

Results

Compared with patients who were treated with standard chemotherapy, patients who were treated with capecitabine had significantly better QoL, role function, and social function, fewer systemic adverse effects, less psychological distress, and less fatigue during and at the completion of treatment (P ≤ .005). Capecitabine treatment was associated with less nausea, vomiting, and constipation and with better appetite than standard treatment (P ≤ .004), but worse hand-foot syndrome and diarrhea (P < .005). These differences all resolved by 12 months.

Conclusion

Standard chemotherapy was superior to capecitabine in improving relapse-free and overall survival for older women with early-stage breast cancer. Although capecitabine was associated with better QoL during treatment, QoL was similar for both groups at 1 year. The brief period of poorer QoL with standard treatment is a modest price to pay for a chance at improved survival.
Trajectory of Performance Status and Symptom Scores for Patients With Cancer During the Last Six Months of Life
Authors: Seow Hsien , Barbera Lisa , Sutradhar Rinku , Howell Doris , Dudgeon Deborah , Atzema Clare , Liu Ying , Husain Amna , Sussman Jonathan , Earle Craig
Published: February 2011

Purpose

Ontario's cancer system is unique because it has implemented two standardized assessment tools population-wide to improve care: the Edmonton Symptom Assessment System (ESAS) measures severity of nine symptoms (scale 0 to 10; 10 indicates the worst) and the Palliative Performance Scale (PPS) measures performance status (scale 0 to 100; 0 indicates death). This article describes the trajectory of ESAS and PPS scores 6 months before death.

Patients and Methods

Observational cohort study of cancer decedents between 2007 and 2009. Decedents required ≥1 ESAS or PPS assessment in the 6 months before death for inclusion. Outcomes were the decedents' average ESAS and PPS scores per week before death.

Results

Ten thousand seven hundred fifty-two (ESAS) and 7,882 (PPS) decedents were included. The mean age was 65 years, half were female, and approximately 75% of assessments occurred in cancer clinics. Average PPS score declined slowly over the 6 months before death, starting at approximately 70 and ending at 40, declining more rapidly in the last month. For ESAS symptoms, average pain, nausea, anxiety, and depression scores remained relatively stable over the 6 months. Conversely, shortness of breath, drowsiness, well-being, lack of appetite, and tiredness increased in severity over time, particularly in the month before death. More than one third of the cohort reported moderate to severe scores (ie, 4 to 10) for most symptoms in the last month of life.

Conclusion

In this large outpatient cancer population, trajectories of mean ESAS scores followed two patterns: increasing versus generally flat. The latter was perhaps due to available treatment (eg, prescriptions) for those symptoms. Future research should prioritize addressing symptoms that worsen over time.
Cetuximab Plus Capecitabine and Irinotecan Compared With Cetuximab Plus Capecitabine and Oxaliplatin As First-Line Treatment for Patients With Metastatic Colorectal Cancer: AIO KRK-0104—A Randomized Trial of the German AIO CRC Study Group
Authors: Moosmann Nicolas , von Weikersthal Ludwig Fischer , Vehling-Kaiser Ursula , Stauch Martina , Hass Holger G. , Dietzfelbinger Herrmann , Oruzio Daniel , Klein Stefan , Zellmann Klaus , Decker Thomas , Schulze Mathias , Abenhardt Wolfgang , Puchtler Gerhard , Kappauf Herbert , Mittermüller Johann , Haberl Christopher , Schalhorn Andreas , Jung Andreas , Stintzing Sebastian , Heinemann Volker
Published: February 2011

Purpose

The AIO KRK-0104 randomized phase II trial investigated the efficacy and safety of cetuximab combined with capecitabine and irinotecan (CAPIRI) or capecitabine and oxaliplatin (CAPOX) in the first-line treatment of metastatic colorectal cancer (mCRC).

Patients and Methods

A total of 185 patients with mCRC were randomly assigned to cetuximab (400 mg/m2 day 1, followed by 250 mg/m2 weekly) plus CAPIRI (irinotecan 200 mg/m2, day 1; capecitabine 800 mg/m2 twice daily days 1 through 14, every 3 weeks; or cetuximab plus CAPOX (oxaliplatin 130 mg/m2 day 1; capecitabine 1,000 mg/m2 twice daily day 1 through 14, every 3 weeks). The primary study end point was objective response rate (ORR).

Results

In the intention-to-treat patient population (n = 177), ORR was 46% (95% CI, 35 to 57) for CAPIRI plus cetuximab versus 48% (95% CI, 37 to 59) for CAPOX plus cetuximab. Analysis of the KRAS gene mutation status was performed in 81.4% of the intention to treat population. Patients with KRAS wild-type in the CAPIRI plus cetuximab arm showed an ORR of 50.0%, a PFS of 6.2 months and an OS of 21.1 months. In the CAPOX plus cetuximab arm, an ORR of 44.9%, a PFS of 7.1 months and an OS of 23.5 months were observed. While ORR and PFS were comparable in KRAS wild-type and mutant subgroups, a trend toward longer survival was associated with KRAS wild-type. Both regimens had manageable toxicity profiles and were safe.

Conclusion

This randomized trial demonstrates that the addition of cetuximab to CAPIRI or CAPOX is effective and safe in first-line treatment of mCRC. In the analyzed regimens, ORR and PFS did not differ according to KRAS gene mutation status.
Adverse Prognostic Factors for Testicular Cancer–Specific Survival: A Population-Based Study of 27,948 Patients
Authors: Fosså Sophie D. , Cvancarova Milada , Chen Linlin , Allan Annie L. , Oldenburg Jan , Peterson Derick R. , Travis Lois B.
Published: February 2011

Purpose

The prognostic significance of age at testicular cancer (TC) diagnosis, socioeconomic status (SES), race, and marital status on TC-specific mortality is not well-characterized. In a cancer that is so curable, it is important to identify any influence that confers an increased risk of TC-specific mortality.

Patients and Methods

Using multivariate cause-specific Cox regression models that accounted for competing risks, hazard ratios (HRs) were calculated for 10-year TC-specific mortality among 27,948 patients with TC reported to the Surveillance, Epidemiology and End Results program (1978 to 2006). Independent predictors were age at diagnosis, SES, race, marital status, extent of disease (EOD), calendar year of diagnosis, radiotherapy, and retroperitoneal lymph node dissection (RPLND).

Results

Compared with younger patients, diagnostic age 40+ was associated with increased mortality (seminoma, HR, 2.00, P < .001; nonseminoma, HR, 2.09; P < .001; most evident in metastatic disease, HR, 8.62; P < .001; HR, 6.35; P < .001, respectively). Unmarried men had two-to three-fold excess mortality compared to married men (HR, 2.97; P < .001; HR, 1.54; P < .001, respectively). Among nonseminoma patients, decreasing SES (P trend < .001) and nonwhite race (HR, 2.11; P < .001) increased mortality. Diagnosis after 1987 resulted in reduced mortality compared to earlier calendar years (HR, 0.58; P = .001; HR, 0.74; P = .001, respectively). Lack of RPLND was associated with seven-fold increase in death (P < .001).

Conclusion

TC-specific mortality is doubled among US patients diagnosed with seminoma or nonseminoma after age 40, even when initial treatment and EOD are taken into account. Among men with nonseminoma, nonwhite race and lower SES also significantly increase TC-specific mortality. Additional research is needed, enabling the development of interventional strategies and preventive approaches, as applicable.
Circulating Interleukin (IL)-8, IL-2R, IL-12, and IL-15 Levels Are Independently Prognostic in Primary Myelofibrosis: A Comprehensive Cytokine Profiling Study
Authors: Tefferi Ayalew , Vaidya Rakhee , Caramazza Domenica , Finke Christy , Lasho Terra , Pardanani Animesh
Published: February 2011

Purpose

Abnormal cytokine expression accompanies myelofibrosis and might be a therapeutic target for Janus-associated kinase (JAK) inhibitor drugs. This study describes the spectrum of plasma cytokine abnormalities in primary myelofibrosis (PMF) and examines their phenotypic correlates and prognostic significance.

Patients and Methods

Patients included in this study were required to have archived plasma, bone marrow biopsy, and cytogenetic information available at the time of first referral to the Mayo Clinic. Multiplex biometric sandwich immunoassay was used to measure plasma levels of 30 cytokines.

Results

In total, 127 PMF patients were studied; comparison with normal controls (n = 35) revealed significantly increased interleukin-1β (IL-1β), IL-1RA, IL-2R, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, tumor necrosis factor α (TNF-α), granulocyte colony-stimulating factor (G-CSF), interferon alfa (IFN-α), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, hepatocyte growth factor (HGF), IFN-γ–inducible protein 10 (IP-10), monokine induced by IFN-γ (MIG), monocyte chemotactic protein 1 (MCP-1), and vascular endothelial growth factor (VEGF) levels and decreased IFN-γ levels. In treatment-naive patients (n = 90), increased levels of IL-8 (P < .001), IL-2R (P < .001), IL-12 (P < .001), IL-15 (P = .001), and IP-10 (P = .003) were independently predictive of inferior survival. A similar multivariable analysis that included all 127 study patients confirmed the prognostic value of these five cytokines, and IL-8, IL-2R, IL-12, and IL-15 remained significant when risk stratification, according to the recently revised Dynamic International Prognostic Scoring System (DIPSS plus), was added to the multivariable model. Leukemia-free survival was predicted by IL-8, which was also the only cytokine associated with ≥ 1% circulating blasts. Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP-10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1β, and JAK2V617F. A two-cytokine (IL-8/IL-2R) –based risk categorization delineated prognostically different groups within specific DIPSS plus risk categories.

Conclusion

This study signifies the presence of specific cytokine-phenotype associations in PMF and a prognostically relevant plasma cytokine signature that might prove useful as a laboratory tool for predicting and monitoring treatment response.
Elaborating polarity: PAR proteins and the cytoskeleton
Authors: Nance Jeremy , Zallen Jennifer A.
Published: February 2011

Cell polarity is essential for cells to divide asymmetrically, form spatially restricted subcellular structures and participate in three-dimensional multicellular organization. PAR proteins are conserved polarity regulators that function by generating cortical landmarks that establish dynamic asymmetries in the distribution of effector proteins. Here, we review recent findings on the role of PAR proteins in cell polarity in C. elegans and Drosophila, and emphasize the links that exist between PAR networks and cytoskeletal proteins that both regulate PAR protein localization and act as downstream effectors to elaborate polarity within the cell.
Signaling through BMP receptors promotes respiratory identity in the foregut via repression of Sox2
Authors: Domyan Eric T. , Ferretti Elisabetta , Throckmorton Kurt , Mishina Yuji , Nicolis Silvia K. , Sun Xin
Published: February 2011

The mammalian foregut gives rise to the dorsally located esophagus and stomach and the ventrally located trachea and lung. Proper patterning and morphogenesis of the common foregut tube and its derived organs is essential for viability of the organism at birth. Here, we show that conditional inactivation of BMP type I receptor genes Bmpr1a and Bmpr1b (Bmpr1a;b) in the ventral endoderm leads to tracheal agenesis and ectopic primary bronchi. Molecular analyses of these mutants reveal a reduction of ventral endoderm marker NKX2-1 and an expansion of dorsal markers SOX2 and P63 into the prospective trachea and primary bronchi. Subsequent genetic experiments show that activation of canonical WNT signaling, previously shown to induce ectopic respiratory fate in otherwise wild-type mice, is incapable of promoting respiratory fate in the absence of Bmpr1a;b. Furthermore, we find that inactivation of Sox2 in Bmpr1a;b mutants does not suppress ectopic lung budding but does rescue trachea formation and NKX2-1 expression. Together, our data suggest that signaling through BMPR1A;B performs at least two roles in early respiratory development: first, it promotes tracheal formation through repression of Sox2; and second, it restricts the site of lung bud initiation.
Asymmetric division of cyst stem cells in Drosophila testis is ensured by anaphase spindle repositioning
Authors: Cheng Jun , Tiyaboonchai Amita , Yamashita Yukiko M. , Hunt Alan J.
Published: February 2011

Many stem cells divide asymmetrically to balance self-renewal and differentiation. In Drosophila testes, two stem cell populations, germline stem cells (GSCs) and somatic cyst stem cells (CySCs), cohere and regulate one another. Here, we report that CySCs divide asymmetrically through repositioning the mitotic spindle around anaphase. CySC spindle repositioning requires functional centrosomes, Dynein and the actin-membrane linker Moesin. Anaphase spindle repositioning is required to achieve high-fidelity asymmetric divisions in CySCs, thus maintaining both GSC and CySC numbers. We propose that dynamic spindle repositioning allows CySCs to divide asymmetrically while accommodating the structure of the GSCs they encapsulate.
The control offoxN2/3expression in sea urchin embryos and its function in the skeletogenic gene regulatory network
Authors: Rho Ho Kyung , McClay David R.
Published: February 2011

Early development requires well-organized temporal and spatial regulation of transcription factors that are assembled into gene regulatory networks (GRNs). In the sea urchin, an endomesoderm GRN model explains much of the specification in the endoderm and mesoderm prior to gastrulation, yet some GRN connections remain incomplete. Here, we characterize FoxN2/3 in the primary mesenchyme cell (PMC) GRN state. Expression of foxN2/3 mRNA begins in micromeres at the hatched blastula stage and then is lost from micromeres at the mesenchyme blastula stage. foxN2/3 expression then shifts to the non-skeletogenic mesoderm and, later, to the endoderm. Here, we show that Pmar1, Ets1 and Tbr are necessary for activation of foxN2/3 in micromeres. The later endomesoderm expression of foxN2/3 is independent of the earlier expression of foxN2/3 in micromeres and is independent of signals from PMCs. FoxN2/3 is necessary for several steps in the formation of the larval skeleton. Early expression of genes for the skeletal matrix is dependent on FoxN2/3, but only until the mesenchyme blastula stage as foxN2/3 mRNA disappears from PMCs at that time and we assume that the protein is not abnormally long-lived. Knockdown of FoxN2/3 inhibits normal PMC ingression and foxN2/3 morphant PMCs do not organize in the blastocoel and fail to join the PMC syncytium. In addition, without FoxN2/3, the PMCs fail to repress the transfating of other mesodermal cells into the skeletogenic lineage. Thus, FoxN2/3 is necessary for normal ingression, for expression of several skeletal matrix genes, for preventing transfating and for fusion of the PMC syncytium.
Neuronal subtype specification in the spinal cord of a protovertebrate
Authors: Stolfi Alberto , Levine Michael
Published: February 2011

The visceral ganglion (VG) comprises the basic motor pool of the swimming ascidian tadpole and has been proposed to be homologous to the spinal cord of vertebrates. Here, we use cis-regulatory modules, or enhancers, from transcription factor genes expressed in single VG neuronal precursors to label and identify morphologically distinct moto- and interneuron subtypes in the Ciona intestinalis tadpole larva. We also show that the transcription factor complement present in each differentiating neuron correlates with its unique morphology. Forced expression of putative interneuron markers Dmbx and Vsx results in ectopic interneuron-like cells at the expense of motoneurons. Furthermore, by perturbing upstream signaling events, we can change the transcription factor expression profile and subsequent identity of the different precursors. Perturbation of FGF signaling transforms the entire VG into Vsx+/Pitx+ putative cholinergic interneurons, while perturbation of Notch signaling results in duplication of Dmbx+ decussating interneurons. These experiments demonstrate the connection between transcriptional regulation and the neuronal subtype diversity underlying swimming behavior in a simple chordate.
Two Illustrations of the Quantity Theory of Money: Breakdowns and Revivals
Authors: Sargent Thomas J , Surico Paolo
Published: February 2011

By extending his data, we document the instability of low-frequency regression coefficients that Lucas (1980) used to express the quantity theory of money. We impute the differences in these regression coefficients to differences in monetary policies across periods. A DSGE model estimated over a subsample like Lucas's implies values of the regression coefficients that confirm Lucas's results for his sample period. But perturbing monetary policy rule parameters away from the values estimated over Lucas's subsample alters the regression coefficients in ways that reproduce their instability over our longer sample. (JEL C51, E23, E31, E43, E51, E52)
Growing Like China
Authors: Song Zheng , Storesletten Kjetil , Zilibotti Fabrizio
Published: February 2011

We construct a growth model consistent with China's economic transition: high output growth, sustained returns on capital, reallocation within the manufacturing sector, and a large trade surplus. Entrepreneurial firms use more productive technologies, but due to financial imperfections they must finance investments through internal savings. State-owned firms have low productivity but survive because of better access to credit markets. High-productivity firms outgrow low-productivity firms if entrepreneurs have sufficiently high savings. The downsizing of financially integrated firms forces domestic savings to be invested abroad, generating a foreign surplus. A calibrated version of the theory accounts quantitatively for China's economic transition. (JEL E21, E22, E23, F43, L60, O16, O53, P23, P24, P31).
Reference Prices, Costs, and Nominal Rigidities
Authors: Eichenbaum Martin , Jaimovich Nir , Rebelo Sergio
Published: February 2011

We assess the importance of nominal rigidities using a new weekly scanner dataset. We find that nominal rigidities take the form of inertia in reference prices and costs, defined as the most common prices and costs within a given quarter. Reference prices are particularly inertial and have an average duration of roughly one year, even though weekly prices change roughly once every two weeks. We document the relation between prices and costs and find sharp evidence of state dependence in prices. We use a simple model to argue that reference prices and costs are useful statistics for macroeconomic analysis. (JEL L11, L25, L81).
Bundle-Size Pricing as an Approximation to Mixed Bundling
Authors: Chu Chenghuan Sean , Leslie Phillip , Sorensen Alan
Published: February 2011

Multiproduct firms can set separate prices for all possible bundled combinations of its products (“mixed bundling”). However, this is impractical for firms with more than a few products, because the number of prices increases exponentially with the number of products. We find that simple pricing strategies are often nearly optimal. Specifically, we show that bundle-size pricing—setting prices that depend only on the size of bundle purchased—tends to be more profitable than offering the individual products priced separately and tends to closely approximate the profits from mixed bundling. (JEL D24, D42, L11, L13, L25).
Some Unsettled Problems of Irrigation
Authors: Coman Katharine
Published: February 2011

The lead article in the inaugural issue of the AER examines the common property resource problem as applied to water in the Western United States.
Inflation and Unemployment in the Long Run
Authors: Berentsen Aleksander , Menzio Guido , Wright Randall
Published: February 2011

We study the long-run relation between money (inflation or interest rates) and unemployment. We document positive relationships between these variables at low frequencies. We develop a framework where money and unemployment are modeled using explicit microfoundations, providing a unified theory to analyze labor and goods markets. We calibrate the model and ask how monetary factors account for labor market behavior. We can account for a sizable fraction of the increase in unemployment rates during the 1970s. We show how it matters whether one uses monetary theory based on the search-and-bargaining approach or on an ad hoc cash-in-advance constraint. (JEL E24, E31, E41, E43, E52)
The Evolution of Cooperation in Infinitely Repeated Games: Experimental Evidence
Authors: Dal Bó Pedro , Fréchette Guillaume R
Published: February 2011

A usual criticism of the theory of infinitely repeated games is that it does not provide sharp predictions since there may be a multiplicity of equilibria. To address this issue, we present experimental evidence on the evolution of cooperation in infinitely repeated prisoner's dilemma games as subjects gain experience. We show that cooperation may prevail in infinitely repeated games, but the conditions under which this occurs are more stringent than the subgame perfect conditions usually considered or even a condition based on risk dominance. (JEL C71, C73)
Reflections on “Some Unsettled Problems of Irrigation”
Authors: Ostrom Elinor
Published: February 2011

It is instructive to read the article that Katharine Coman published in the first issue of the American Economic Review to gain insight into the problems of collective action related to irrigation in the American West. One gains further understanding of the problems Coman identifies by using a social-ecological system (Ostrom 2007, 2009) to organize the diverse variables identified by Coman. One gains a general lesson from this analysis that changing the formal governance structure of irrigation is not sufficient to ensure efficient investment in facilities or that farmers are able to acquire property and make a reasonable living. Building knowledge and trust are, however, essential for solving collective-action problems. (JEL B31, N51, Q15, Q25)
Institutional Path Dependence in Climate Adaptation: Coman's “Some Unsettled Problems of Irrigation”
Authors: Libecap Gary D
Published: February 2011

Katharine Coman's “Some Unsettled Problems of Irrigation,” published in March 1911 in the first issue of the American Economic Review, addressed issues of water supply, rights, and organization. These same issues have relevance today, in the face of growing concern about the availability of fresh water worldwide. The central point of this article is that appropriative water rights and irrigation districts that emerged in the American West in the late nineteenth and early twentieth centuries in response to aridity to facilitate agricultural water delivery, use, and trade raise the transaction costs today of water markets. These markets are vital for smooth reallocation of water to higher-valued uses elsewhere in the economy and for flexible response to greater hydrological uncertainty. This institutional path dependence illustrates how past arrangements to meet conditions of the time constrain contemporary economic opportunities. They cannot be easily significantly modified or replaced ex post. (JEL N51, Q15, Q25, Q54)
The Journey to Regulation of Protein-Based Multiplex Quantitative Assays
Authors: Boja Emily S , Jortani Saeed A , Ritchie James , Hoofnagle Andrew N , Težak Živana , Mansfield Elizabeth , Keller Penny , Rivers Robert C , Rahbar Amir , Anderson N Leigh , Srinivas Pothur , Rodriguez Henry
Published: February 2011

BACKGROUND

Clinical proteomics presents great promise in biology and medicine because of its potential for improving our understanding of diseases at the molecular level and for detecting disease-related biomarkers for diagnosis, prognosis, and prediction of therapeutic responses. To realize its full potential to improve clinical outcome for patients, proteomic studies have to be well designed, from biosample cohorts to data and statistical analyses. One key component in the biomarker development pipeline is the understanding of the regulatory science that evaluates diagnostic assay performance through rigorous analytical and clinical review criteria.

CONTENT

The National Cancer Institute's Clinical Proteomic Technologies for Cancer (CPTC) initiative has proposed an intermediate preclinical “verification” step to close the gap between protein-based biomarker discovery and clinical qualification. In collaboration with the US Food and Drug Administration (FDA), the CPTC network investigators recently published 2 mock submission review documents, first-of-their-kind educational materials that may help the scientific community interested in developing products for the clinic in understanding the likely analytical evaluation requirements for multiplex protein technology–based diagnostic tests.

CONCLUSIONS

Building on this momentum, the CPTC continues with this report its collaboration with the FDA, as well as its interactions with the AACC and the Centers for Medicare and Medicaid Services, to further the understanding of regulatory requirements for approving multiplex proteomic platform–based tests and analytically validating multiple analytes.
Application of Statistical Methods in Evaluating Asphalt Mixture Homogeneity
Authors: Peng Y. , Sun L. J.
Published: February 2011

Homogeneity is one of the most important factors affecting the performance-related properties of asphalt mixtures. Pavement condition surveys have shown various patterns of distress due to segregation and other types of non-uniformity. Using digital image processing, a statistical method was developed to evaluate asphalt mixture homogeneity quantitatively. Aggregate particle distribution in asphalt mixtures was described and analyzed by aggregate particle frequency statistic and distance statistic. The index of homogeneity was presented through aggregate particle distribution. The relevance of homogeneity to some mixture performance properties was also investigated. Results show that asphalt mixture homogeneity can be assessed quantitatively by the values of aggregate particle frequency statistic and distance statistic. Moreover, homogeneity dominates variations in mixture performance properties.