bluuebunny/crossref_metadata_2025 huggingface dataset:
A case-control association study of NRXN1 polymorphisms with schizophrenia in Chinese Han population
Authors: Yue Weihua , Yang Yongfeng , Zhang Yanling , Lu Tianlan , Hu Xiaofeng , Wang Lifang , Ruan Yanyan , Lv Luxian , Zhang Dai
Published: April 2011

Background

Recent research has implicated that mutations in the neurexin-1 (NRXN1) gene on chromosome 2p16.3 might play a role in schizophrenia, autism, and nicotine dependence. In order to explore the association of NRXN1 polymorphisms with schizophrenia, we made a case-control association study in Chinese Han population.

Methods

We examined six tag single nucleotide polymorphisms (SNPs) spanning 116.7 kb of NRXN1 in 768 schizophrenic patients and 738 healthy control subjects. The association of NRXN1 polymorphisms with schizophrenia and the age-at-onset of this disease were explored.

Results

Our results showed that four SNPs of NRXN1 gene were significantly associated with schizophrenia (rs10490168: G > A, p = 0.017; rs2024513: A > G, p = 0.006; rs13382584: T > C, p = 0.009; and rs1558852: G > A, p = 0.031). Furthermore, the association of SNP rs2024513 with schizophrenia remained significance after the Bonferroni correction. Haplotypes consisting of above six SNPs also showed significantly associated with schizophrenia (global chi-square = 14.725, p = 0.022). A protective haplotype AGTGCA remained associated with schizophrenia, even after 10,000 permutation tests (empirical p-value = 0.043). However, we did not find any association with age-at-onset of schizophrenia with NRXN1 polymorphisms.

Conclusions

Our findings suggest that NRXN1 might represent a major susceptibility gene for schizophrenia in Chinese Han population.
Nutrition and inflammation serum biomarkers are associated with 12‐week mortality among malnourished adults initiating antiretroviral therapy in Zambia
Authors: Koethe John R , Blevins Meridith , Nyirenda Christopher , Kabagambe Edmond K , Shepherd Bryan E , Wester C William , Zulu Isaac , Chiasera Janelle M , Mulenga Lloyd B , Mwango Albert , Heimburger Douglas C
Published: April 2011

Background

A low body mass index (BMI) at antiretroviral therapy (ART) initiation is a strong predictor of mortality among HIV‐infected adults in resource‐constrained settings. The relationship between nutrition and inflammation‐related serum biomarkers and early treatment outcomes (e.g., less than 90 days) in this population is not well described.

Methods

An observational cohort of 142 HIV‐infected adults in Lusaka, Zambia, with BMI under 16 kg/m2or CD4+lymphocyte counts of less than 50 cells/mm3, or both, was followed prospectively during the first 12 weeks of ART. Baseline and serial post‐treatment phosphate, albumin, ferritin and highly sensitive C‐reactive protein (hsCRP) serum levels were measured. The primary outcome was mortality.

Results

Lower baseline phosphate and albumin serum levels, and higher ferritin and hsCRP, were significantly associated with mortality prior to 12 weeks (p < 0.05 for all comparisons), independent of known risk factors for early ART‐associated mortality in sub‐Saharan Africa. The time‐dependent interval change in albumin was associated with mortality after adjusting for the baseline value (AHR 0.62 [0.43, 0.89] per 5 g/L increase), but changes in the other biomarkers were not.

Conclusions

The predictive value of serum biomarkers for early mortality in a cohort of adults with malnutrition and advanced HIV in a resource‐constrained setting was primarily driven by pre‐treatment values, rather than post‐ART changes. Interventions to promote earlier HIV diagnosis and treatment, address nutritional deficiencies, and identify the etiologies of increased systemic inflammation may improve ART outcomes in this vulnerable population.
An evidence-based recommendation on bed head elevation for mechanically ventilated patients
Authors: Niël-Weise Barbara S , Gastmeier Petra , Kola Axel , Vonberg Ralf P , Wille Jan C , van den Broek Peterhans J ,   the Bed Head Elevation Study Group
Published: April 2011

Introduction

A semi-upright position in ventilated patients is recommended to prevent ventilator-associated pneumonia (VAP) and is one of the components in the Ventilator Bundle of the Institute for Health Care Improvement. This recommendation, however, is not an evidence-based one.

Methods

A systematic review on the benefits and disadvantages of semi-upright position in ventilated patients was done according to PRISMA guidelines. Then a European expert panel developed a recommendation based on the results of the systematic review and considerations beyond the scientific evidence in a three-round electronic Delphi procedure.

Results

Three trials (337 patients) were included in the review. The results showed that it was uncertain whether a 45° bed head elevation was effective or harmful with regard to the occurrence of clinically suspected VAP, microbiologically confirmed VAP, decubitus and mortality, and that it was unknown whether 45° elevation for 24 hours a day increased the risk for thromboembolism or hemodynamic instability. A group of 22 experts recommended elevating the head of the bed of mechanically ventilated patients to a 20 to 45° position and preferably to a ≥30° position as long as it does not pose risks or conflicts with other nursing tasks, medical interventions or patients' wishes.

Conclusions

Although the review failed to prove clinical benefits of bed head elevation, experts prefer this position in ventilated patients. They made clear that the position of a ventilated patient in bed depended on many determinants. Therefore, given the scientific uncertainty about the benefits and harms of a semi-upright position, this position could only be recommended as the preferred position with the necessary restrictions.
Impact of ureido/carboxypenicillin resistance on the prognosis of ventilator-associated pneumonia due to Pseudomonas aeruginosa
Authors: Kaminski Catherine , Timsit Jean-François , Dubois Yohann , Zahar Jean-Ralph , Garrouste-Orgeas Maïté , Vesin Aurélien , Azoulay Elie , Feger Céline , Dumenil Anne-Sylvie , Adrie Christophe , Cohen Yves , Allaouchiche Bernard ,   the OUTCOMEREA study group
Published: April 2011

Introduction

Although Pseudomonas aeruginosa is a leading pathogen responsible for ventilator-associated pneumonia (VAP), the excess in mortality associated with multi-resistance in patients with P. aeruginosa VAP (PA-VAP), taking into account confounders such as treatment adequacy and prior length of stay in the ICU, has not yet been adequately estimated.

Methods

A total of 223 episodes of PA-VAP recorded into the Outcomerea database were evaluated. Patients with ureido/carboxy-resistant P. aeruginosa (PRPA) were compared with those with ureido/carboxy-sensitive P. aeruginosa (PSPA) after matching on duration of ICU stay at VAP onset and adjustment for confounders.

Results

Factors associated with onset of PRPA-VAP were as follows: admission to the ICU with septic shock, broad-spectrum antimicrobials at admission, prior use of ureido/carboxypenicillin, and colonization with PRPA before infection. Adequate antimicrobial therapy was more often delayed in the PRPA group. The crude ICU mortality rate and the hospital mortality rate were not different between the PRPA and the PSPA groups. In multivariate analysis, after controlling for time in the ICU before VAP diagnosis, neither ICU death (odds ratio (OR) = 0.73; 95% confidence interval (CI): 0.32 to 1.69; P = 0.46) nor hospital death (OR = 0.87; 95% CI: 0.38 to 1.99; P = 0.74) were increased in the presence of PRPA infection. This result remained unchanged in the subgroup of 87 patients who received adequate antimicrobial treatment on the day of VAP diagnosis.

Conclusions

After adjustment, and despite the more frequent delay in the initiation of an adequate antimicrobial therapy in these patients, resistance to ureido/carboxypenicillin was not associated with ICU or hospital death in patients with PA-VAP.
Linearized AVO and poroelasticity
Authors: Russell Brian H. , Gray David , Hampson Daniel P.
Published: April 2011

The technique of amplitude variation with offset (AVO) allows geoscientists to extract fluid and lithology information from the analysis of prestack seismic amplitudes. Various AVO parameterizations exist, all of which involve the sum of three weighted elastic-constant terms. In present-day AVO approaches, the weighting terms involve either knowledge of the incidence angle only, or knowledge of both the incidence angle and the in situ VP/VS ratio. We have used the theory of poroelasticity to derive a generalized AVO approximation that provides the estimation of fluid, rigidity, and density parameters. We have combined two previously independent AVO formulations, thus reducing, instead of adding to, the total number of formulations. This new approach requires knowledge of a third parameter to compute the weights: the dry-rock VP/VS ratio. We have derived a new equation and applied it to model and real data sets. The new formulation has allowed us to estimate fluid properties of the reservoir in a more direct manner than previous formulations.
Amplitude balancing in separating P- and S-waves in 2D and 3D elastic seismic data
Authors: Sun Robert , McMechan George A. , Chuang Han-Hsiang
Published: April 2011

The reflected P- and S-waves in elastic displacement component data recorded at the earth’s surface are separated by reverse-time (downward) extrapolation of the data in an elastic computational model, followed by calculations to give divergence (dilatation) and curl (rotation) at a selected reference depth. The surface data are then reconstructed by separate forward-time (upward) scalar extrapolations, from the reference depth, of the magnitude of the divergence and curl wavefields, and extraction of the separated P- and S-waves, respectively, at the top of the models. A P-wave amplitude will change by a factor that is inversely proportional to the P-velocity when it is transformed from displacement to divergence, and an S-wave amplitude will change by a factor that is inversely proportional to the S-velocity when it is transformed from displacement to curl. Consequently, the ratio of the P- to the S-wave amplitude (the P-S amplitude ratio) in the form of divergence and curl (postseparation) is different from that in the (preseparation) displacement form. This distortion can be eliminated by multiplying the separated S-wave (curl) by a relative balancing factor (which is the S- to P-velocity ratio); thus, the postseparation P-S amplitude ratio can be returned to that in the preseparation data. The absolute P- and S-wave amplitudes are also recoverable by multiplying them by a factor that depends on frequency, on the P-velocity α, and on the unit of α and is location-dependent if the near-surface P-velocity is not constant.
Exploiting the airwave for time-lapse reservoir monitoring with CSEM on land
Authors: Wirianto Marwan , Mulder Wim A. , Slob Evert C.
Published: April 2011

In the application of controlled source electromagnetics for reservoir monitoring on land, repeatability errors in the source will mask the time-lapse signal due to hydrocarbon production when recording surface data close to the source. We demonstrate that at larger distances, the airwave will still provide sufficient illumination of the target. The primary airwave diffuses downward into the earth and then is scattered back to the surface. The time-lapse difference of its recorded signal reveals the outline on the surface of the resistivity changes in a hydrocarbon reservoir under production. However, repeatability errors in the primary airwave can destroy the signal-to-noise ratio of the time-lapse data. We present a simple and effective method to remove the primary airwave from the data, which we call partial airwave removal. For a homogeneous half space and a delta-function type of source, the surface expression of the airwave does not depend on frequency. For this reason, the primary airwave can be subtracted from the data using recordings at two frequencies, one low enough with a skin depth of the order of the reservoir depth that is sensitive to the reservoir, the other high enough to only sense the near surface. The method does not affect secondary airwave components created by signals that have propagated through the earth and returned to the surface. We show that the method provides a direct indicator of production-related time-lapse changes in the reservoir. We illustrate this for several models, including a general 3D heterogeneous model and one with strong surface topography, for situations where survey repeatability errors are large.
Cave detection using multiple geophysical methods: Unicorn cave, Harz Mountains, Germany
Authors: Kaufmann Georg , Romanov Douchko , Nielbock Ralf
Published: April 2011

Unicorn cave in the southern Harz Mountains of Germany is a show cave in dolomitic rocks of the Zechstein Formation. The cave’s trunk passage is interrupted by larger rooms. The overburden is only around 15 m. The passages are filled with sediments that can be up to 50 m thick. We used gravimetry and electrical resistivity imaging over the cave area to identify the subsurface voids and the extent of the sediment infill of the cave passages. Our choice of methods was based on several conditions unique to the cave: (1) well surveyed, (2) shallow overburden, (3) large air-filled passages, and (4) thick sediment cover, concealing true passage size. Using the cave survey as an initial model for the subsurface structure, we successfully identified the air-filled cave with both methods. We then inferred the thickness of the sediment infill by forward modeling and identified a possible southward continuation beyond the currently explored passages.
Population-Based Study of Treatment Guided by Tumor Marker Decline in Patients With Metastatic Nonseminomatous Germ Cell Tumor: A Report From the Swedish-Norwegian Testicular Cancer Group
Authors: Olofsson Sven-Erik , Tandstad Torgrim , Jerkeman Mats , Dahl Olav , Ståhl Olof , Klepp Olbjørn , Bremnes Roy M. , Cohn-Cedermark Gabriella , Langberg Carl W. , Laurell Anna , Solberg Arne , Stierner Ulrika , Wahlqvist Rolf , Wijkström Hans , Anderson Harald , Cavallin-Ståhl Eva
Published: April 2011

Purpose

From 1995 to 2003, 603 adult patients from Sweden and Norway with metastatic testicular nonseminomatous germ cell tumor (NSGCT) were included prospectively in a population-based protocol with strict guidelines for staging, treatment, and follow-up. Patients with extragonadal primary tumor or previous treatment for contralateral testicular tumor were excluded. The basic strategy was to individualize treatment according to initial tumor marker response.

Methods

Initial treatment for all patients was two courses of standard bleomycin, etoposide, and cisplatin (BEP), with tumor markers analyzed weekly. Good response was defined as a half-life (t1/2) for α-fetoprotein (AFP) of ≤ 7 days and/or for β–human chorionic gonadotropin (β-HCG) of ≤ 3 days. Patients with prolonged marker t1/2 (ie, poor response) received intensification with addition of ifosfamide (BEP-if/PEI) in step 1. If poor response continued, the treatment was intensified with high-dose chemotherapy with stem-cell rescue as step 2.

Results

Overall, 99% of all patients with metastatic testicular NSGCT in the population were included in the protocol. Median follow-up was 8.2 years. Seventy-seven percent of the patients were treated with BEP alone; 18% received intensification step 1%, and 5% received intensification step 2. Grouped according to International Germ Cell Consensus Classification, 10-year overall survival was 94.7% in good-prognosis patients, 90.0% in intermediate-prognosis patients, and 67.4% in poor-prognosis patients.

Conclusion

With detailed treatment protocols and a dedicated collaborative group of specialists, treatment results comparable to those reported from large single institutions can be achieved at national level. With the treatment principles used in Swedish-Norwegian Testicular Cancer Group study SWENOTECA IV, the survival of intermediate-prognosis patients is remarkable and close to that of good-prognosis patients.
Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer
Authors: Mahmoud Sahar M.A. , Paish Emma Claire , Powe Desmond G. , Macmillan R. Douglas , Grainge Matthew J. , Lee Andrew H.S. , Ellis Ian O. , Green Andrew R.
Published: April 2011

Breast carcinomas are often infiltrated by inflammatory cells, particularly macrophages and T lymphocytes, but the significance of these cells remains unclear. One possible role of these inflammatory cells is that they represent a cell-mediated immune response against the carcinoma. CD8+ lymphocytes are a known crucial component of cell-mediated immunity. The purpose of this study was to explore the prognostic value of tumor-infiltrating CD8+ cytotoxic lymphocytes in breast cancer. Tumor-infiltrating CD8+ lymphocytes were assessed by immunohistochemical staining of tissue microarray cores from 1,334 unselected breast tumors from patients with long-term follow-up. The number of CD8+ T cells was counted in tumor nests (intratumoral), in stroma adjacent to tumor cells, and in stroma distant to tumor cells, and their relationship with clinical outcome was determined. The total number of CD8+ cells was positively correlated with tumor grade (rs = 0.20; P < .001) and inversely correlated with patient's age at diagnosis, estrogen receptor–alpha (ER-α), and progesterone receptor (PgR) expression (Mann-Whitney U test, P < .001). The total patient cohort was randomly divided into two separate training and validation sets before performing univariate survival analysis. Total number and distant stromal CD8+ lymphocytes were associated with better patient survival (P = .041 and P < .001, respectively) in the training set. In multivariate analysis, total CD8+ T-cell count was an independent prognostic factor in both training and validation sets. These results suggest that tumor-infiltrating CD8+ T lymphocytes have antitumor activity as judged by their favorable effect on patients' survival and could potentially be exploited in the treatment of breast cancer.
Amyloidosis: Pathogenesis and New Therapeutic Options
Authors: Merlini Giampaolo , Seldin David C. , Gertz Morie A.
Published: April 2011

The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. The most common type, immunoglobulin light chain amyloidosis (AL), is caused by clonal plasma cells that produce misfolded light chains. The purpose of this review is to provide up-to-date information on diagnosis and treatment options for AL amyloidosis. Early, accurate diagnosis is the key to effective therapy, and unequivocal identification of the amyloidogenic protein may require advanced technologies and expertise. Prognosis is dominated by the extent of cardiac involvement, and cardiac staging directs the choice of therapy. Treatment for AL amyloidosis is highly individualized, determined on the basis of age, organ dysfunction, and regimen toxicities, and should be guided by biomarkers of hematologic and cardiac response. Alkylator-based chemotherapy is effective in almost two thirds of patients. Novel agents are also active, and trials are ongoing to establish their optimal use. Treatment algorithms will continue to be refined through controlled trials. Advances in basic research have led to the identification of new drug targets and therapeutic approaches, which will be integrated with chemotherapy in the future.
Novel Therapeutics for Aggressive Non-Hodgkin's Lymphoma
Authors: Mahadevan Daruka , Fisher Richard I.
Published: April 2011

Application of advances in genomic and proteomic technologies has provided molecular insights into distinct types of aggressive B- and T-cell non-Hodgkin's lymphomas (NHLs). This has led to the validation of novel biomarkers of classification, risk-stratification, and druggable targets. The promise of novel treatments from genomic research has been slow to materialize because of the lack of a therapeutic signature for the distinct NHL subtypes. Patients with lymphoma with aggressive disease urgently require the development of novel therapies on the basis of investigation of dysregulated intracellular oncogenic processes that arise during lymphomagenesis. Although monoclonal antibodies have made significant contributions to the armamentarium of B-cell NHL therapy (eg, anti-CD20), parallel development of small-molecule inhibitors (SMIs) to intracellular targets has lagged behind. Despite these deficiencies, several promising anti-NHL therapies are in development that target immune kinases of the B-cell receptor signaling pathway, mammalian target of rapamycin complex, proteasome, DNA/histone epigenetic complex, antiapoptosis, neoangiogenesis, and immune modulation. This review focuses on novel SMI therapeutic strategies that target overlapping core oncogenic pathways in the context of the 10 hallmarks of cancer. Furthermore, we have developed the concept of a therapeutic signature using the 10 hallmarks of cancer, which may be incorporated into novel phase I/II drug development programs.
Allogeneic Transplantation for Lymphoma
Authors: Chakraverty Ronjon , Mackinnon Stephen
Published: April 2011

Historically, high levels of treatment-related mortality restricted the use of standard myeloablative allogeneic stem-cell transplantation to a minority of young and fit patients with lymphoma. Over the last decade, increasing numbers of patients with lymphoma have undergone allogeneic stem-cell transplantation using reduced-intensity protocols that are associated with lower toxicity and reduced transplantation-related mortality. Graft-versus-lymphoma effects contribute to the therapeutic effect in patients with indolent or Hodgkin's lymphoma. However, definitive evidence for efficacy of this strategy is lacking because most patients undergoing transplantation do so after failure of several lines of treatment, leaving no obvious comparator arm for randomized controlled studies. Nevertheless, encouraging results have been reported for selected patients for most lymphoma subtypes, with pretransplantation disease status emerging as the most important predictor of outcome. The major long-term toxicity is chronic graft-versus-host disease that contributes to ill health in a significant minority of survivors. In the future, risk-adapted trials that evaluate reduced-intensity allogeneic transplantation in patients with predicted poor outcomes with immunochemotherapy or autologous transplantation will be important in determining the role of this treatment.
Molecular Heterogeneity of Multiple Myeloma: Pathogenesis, Prognosis, and Therapeutic Implications
Authors: Hervé Avet-Loiseau , Florence Magrangeas , Philippe Moreau , Michel Attal , Thierry Facon , Kenneth Anderson , Jean-Luc Harousseau , Nikhil Munshi , Stéphane Minvielle
Published: April 2011

Multiple myeloma (MM) is characterized by a significant heterogeneity at the molecular level. The first level is the chromosomal one. Although cytogenetics is difficult to assess in MM, patients can be divided into two categories: hyperdiploidy and non-hyperdiploidy (about half in each group). Using molecular cytogenetic techniques, several subgroups of patients are identified, particularly on the basis of 14q32 translocations. This chromosomal heterogeneity is confirmed by genomic techniques (gene expression profiling or single nucleotide polymorphism/comparative genomic hybridization arrays). Unsupervised analyses of gene expression profiles identified several subgroups of patients, essentially on the basis of chromosomal abnormalities such as hyperdiploidy or 14q32 translocations. However, these analyses failed to separate MM into subentities, which could lead to specific therapeutic approaches, as is the case for non-Hodgkin's lymphomas. Nevertheless, these chromosomal/genomic data can be used for prognostication of patients. Specific chromosomal changes, such as loss of the short arm of chromosome 17, or specific gene expression profiles clearly identify patients with short survival. No molecular change so far has been associated with long survival or even cure, probably because of the short follow-up observed in all studies. So far, it is unclear how to use this massive amount of data to treat patients. Because of the complex and heterogeneous picture of the molecular profiles, it is unexpected that targeted therapies might play a role in MM. The only recognized indication is to propose bortezomib-based approaches for the treatment of patients displaying the translocation t(4;14).
Clinical Characteristics of Patients With Lung Adenocarcinomas Harboring BRAF Mutations
Authors: Paik Paul K. , Arcila Maria E. , Fara Michael , Sima Camelia S. , Miller Vincent A. , Kris Mark G. , Ladanyi Marc , Riely Gregory J.
Published: April 2011

Purpose

BRAF mutations occur in non–small-cell lung cancer. Therapies targeting BRAF mutant tumors have recently been identified. We undertook this study to determine the clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations.

Patients and Methods

We reviewed data from consecutive patients with lung adenocarcinoma whose tumors underwent BRAF, EGFR, and KRAS mutation testing as well as fluorescence in situ hybridization for ALK rearrangements. Patient characteristics including age, sex, race, performance status, smoking history, stage, treatment history, and overall survival were collected.

Results

Among 697 patients with lung adenocarcinoma, BRAF mutations were present in 18 patients (3%; 95% CI, 2% to 4%). The BRAF mutations identified were V600E (50%), G469A (39%), and D594G (11%). Mutations in EGFR were present in 24%, KRAS in 25%, and ALK translocations in 6%. In contrast to patients with EGFR mutations and ALK rearrangements who were mostly never smokers, all patients with BRAF mutations were current or former smokers (P < .001). The median overall survival of advanced-stage patients with BRAF mutations was not reached. In comparison, the median overall survival of patients with EGFR mutations was 37 months (P = .73), with KRAS mutations was 18 months (P = .12), and with ALK rearrangements was not reached (P = .64).

Conclusion

BRAF mutations occur in 3% of patients with lung adenocarcinoma and occur more commonly in current and former smokers. The incidence of BRAF mutations other than V600E is significantly higher in lung cancer than in melanoma.
Future Directions of Next-Generation Novel Therapies, Combination Approaches, and the Development of Personalized Medicine in Myeloma
Authors: Mitsiades Constantine S. , Davies Faith E. , Laubach Jacob P. , Joshua Douglas , Miguel Jesus San , Anderson Kenneth C. , Richardson Paul G.
Published: April 2011

Despite tangible progress in recent years, substantial therapeutic challenges remain in multiple myeloma (MM), particularly for patients at high risk for early relapse or death and for those with advanced multi-drug resistant disease and refractoriness to currently available combination regimens. Addressing these challenges requires identification of novel classes of anti-MM agents, their incorporation into safe and more effective combination regimens, and development of efficient algorithms to select the most appropriate therapeutic options for the clinical and molecular features of individual patients at a given time during their disease. Ideally, these goals can be facilitated by preclinical identification of the “driver” molecular lesions on which different myeloma subtypes exquisitely depend, and by informative preclinical models simulating the clinical setting(s) in which trials will be conducted. Large prospective studies of patients treated uniformly with contemporary clinical regimens are essential, but there is also a major need for flexibility in studying new regimens in the future. Long-term patient follow-up and integrated annotation of clinical (safety and efficacy) and correlative (molecular, biochemical, etc) data are also critical. Novel molecular profiling techniques will likely identify more clinically and biologically discrete subsets of patients with recurrent, even if infrequent, lesions. This molecular heterogeneity, combined with the increasing numbers of candidate therapeutic targets and respective investigational agents, may pose formidable challenges for the development and implementation of personalized medicine in MM. This review discusses these challenges, as well as potential strategies to address them, with the aim of making significant improvement in the clinical outcome of patients with MM.
Small RNAs in early mammalian development: from gametes to gastrulation
Authors: Suh Nayoung , Blelloch Robert
Published: April 2011

Small non-coding RNAs, including microRNAs (miRNAs), endogenous small interfering RNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs), play essential roles in mammalian development. The function and timing of expression of these three classes of small RNAs differ greatly. piRNAs are expressed and play a crucial role during male gametogenesis, whereas endo-siRNAs are essential for oocyte meiosis. By contrast, miRNAs are ubiquitously expressed in somatic tissues and function throughout post-implantation development. Surprisingly, however, miRNAs are non-essential during pre-implantation embryonic development and their function is suppressed during oocyte meiosis. Here, we review the roles of small non-coding RNAs during the early stages of mammalian development, from gamete maturation through to gastrulation.
Fabrication of Silica Nanomaterials Reflecting Morphological Transition of DNA Mediated by a Silane-appended Ionic Liquid
Authors: Shimojo Kojiro , Mitamura Hisayoshi , Mouri Tsuyoshi , Naganawa Hirochika
Published: April 2011

A simple fabrication strategy of DNA-transcribed silica materials has been developed. An ionic liquid incorporating an alkoxysilane group is capable of binding with DNA and acts as nuclei for subsequent sol–gel reaction with tetramethoxysilane. Unique silica materials with worm-like, rod-shaped, toroidal, or linearly fibrous structures are created from the same DNA template through the morphological transition of DNA induced by the ionic liquid.
Rapid Access to an Orthogonally Protected Lewis X Derivative: An Important Building Block for Synthesis of Lewis Antigens
Authors: Ohmae Masashi , Takada Junko , Murakami Hiroaki , Kimura Shunsaku
Published: April 2011

A novel Lewis X derivative of 1 with an orthogonal set of protecting groups was systematically prepared. Efficient use of the protecting groups for the amino and the hydroxy groups in lactosamine enabled formation of the diol derivative at C3 and C2′. Glycosidation of 1-thio-l-fucoside donor with the diol derivative progressed preferably at the C3 hydroxy group, resulting in prior production of 1. Compound 1 is a key building block toward easy assemblies of Lewis X-related carbohydrate epitopes.
The Willingness to Pay—Willingness to Accept Gap, the “Endowment Effect,” Subject Misconceptions, and Experimental Procedures for Eliciting Valuations: Reply
Authors: Plott Charles R , Zeiler Kathryn
Published: April 2011

Isoni, Loomes, and Sugden (2011) assert that Plott and Zeiler (2005) reported inaccurate results. Placing ILS's selective quotes into context demonstrates otherwise. Additionally, examining the data closely yields three conclusions. First, all mug data reject endowment effect theory. Second, lottery gaps are associated with unstable attitudes toward uncertainty, a finding consistent with PZ's (2005) lottery data description, explicit warnings about procedure limitations and the data supplement, which reports the lottery data and cautions. Third, lottery outcome beliefs are influenced by whether WTP or WTA is reported, suggesting that changing beliefs, as opposed to the shape of preferences, produce lottery gaps. (JEL C91)
The Rich Domain of Uncertainty: Source Functions and Their Experimental Implementation
Authors: Abdellaoui Mohammed , Baillon Aurélien , Placido Laetitia , Wakker Peter P
Published: April 2011

We often deal with uncertain events for which no probabilities are known. Several normative models have been proposed. Descriptive studies have usually been qualitative, or they estimated ambiguity aversion through one single number. This paper introduces the source method, a tractable method for quantitatively analyzing uncertainty empirically. The theoretical key is the distinction between different sources of uncertainty, within which subjective (choice-based) probabilities can still be defined. Source functions convert those subjective probabilities into willingness to bet. We apply our method in an experiment, where we do not commit to particular ambiguity attitudes but let the data speak. (JEL D81)
Sales and Monetary Policy
Authors: Guimaraes Bernardo , Sheedy Kevin D
Published: April 2011

A striking fact about pricing is the prevalence of “sales”: large temporary price cuts followed by prices returning to exactly their former levels. This paper builds a macroeconomic model with a rationale for sales based on firms facing customers with different price sensitivities. Even if firms can adjust sales without cost, monetary policy has large real effects owing to sales being strategic substitutes: a firm's incentive to have a sale is decreasing in the number of other firms having sales. Thus the flexibility seen in individual prices due to sales does not translate into flexibility of the aggregate price level. (JEL E13, E31, E52, L11, L25, L81, M31)
Real-Time Search in the Laboratory and the Market
Authors: Brown Meta , Flinn Christopher J , Schotter Andrew
Published: April 2011

While widely accepted labor market search models imply a constant reservation wage policy, empirical evidence strongly suggests that reservation wages decline in search duration. This paper reports the results of the first real-time-search laboratory experiment. The controlled environment subjects face is stationary, and the payoff-maximizing reservation wage is constant. Nevertheless, subjects' reservation wages decline sharply over time. We investigate two hypotheses to explain this decline: 1. Searchers respond to the stock of accruing search costs. 2. Searchers experience non-stationary subjective costs of time spent searching. Our data support the latter hypothesis, and we substantiate this conclusion both experimentally and econometrically. (JEL C91, D83, J64)
Checkmate: Exploring Backward Induction among Chess Players
Authors: Levitt Steven D , List John A , Sadoff Sally E
Published: April 2011

Although backward induction is a cornerstone of game theory, most laboratory experiments have found that agents are not able to successfully backward induct. We analyze the play of world-class chess players in the centipede game, which is ill-suited for testing backward induction, and in pure backward induction games—Race to 100 games. We find that chess players almost never play the backward induction equilibrium in the centipede game, but many properly backward induct in the Race to 100 games. We find no systematic within-subject relationship between choices in the centipede game and performance in pure backward induction games. (JEL C73)
Generating Ambiguity in the Laboratory
Authors: Stecher Jack , Shields Timothy , Dickhaut John
Published: April 2011

This article develops a method for drawing samples from a distribution with no finite quantiles or moments. The method provides researchers with a way to give subjects the experience of ambiguity. In any experiment, learning the distribution from experience is impossible for the subjects, essentially because it is impossible for the experimenter. We characterize our method, illustrate it in simulations, and then test it in a laboratory experiment. Our method does not withhold sampling information, does not assume that the subject is incapable of making statistical inferences, is replicable across experiments, and requires no special apparatus. We compare our method to the techniques used in related experiments that attempt to produce an ambiguous experience for the subjects.

This paper was accepted by Peter Wakker, decision analysis.
The Benefits of Competitive Upward Channel Decentralization
Authors: Liu Yunchuan , Tyagi Rajeev K.
Published: April 2011

Upward channel decentralization occurs when firms choose to not manufacture products by themselves and procure products from upstream suppliers. Current voices from marketing scholars and practitioners have predominantly focused on the cost benefits when production is outsourced to lower-cost upstream suppliers. In this paper, we study the effects of upward channel decentralization where competing firms can outsource their production to upstream suppliers who do not have any advantages on production costs. We show how downstream firms can still benefit from upward channel decentralization provided their product positioning is endogenous. Thus, we provide a new theory on the strategic benefits of upward channel decentralization. We also use this framework to show a new benefit to manufacturers selling through downstream retailers rather than directly. We examine the implications of our theory for consumer and social welfare, and also draw managerial implications.

This paper was accepted by Pradeep Chintagunta, marketing.
The Behavioral Genetics of Behavioral Anomalies
Authors: Cesarini David , Johannesson Magnus , Magnusson Patrik K. E. , Wallace Björn
Published: April 2011

A number of recent papers have examined the environmental and genetic sources of individual differences in economic and financial decision making. Here we contribute to this burgeoning literature by extending it to a number of key behavioral anomalies that are thought to be of importance for consumption, savings, and portfolio selection decisions. Using survey-based evidence from more than 11,000 Swedish twins, we demonstrate that a number of anomalies such as, for instance, the conjunction fallacy, default bias, and loss aversion are moderately heritable. In contrast, our estimates imply that variation in common environment explains only a small share of individual differences. We also report suggestive evidence in favor of a shared genetic architecture between cognitive reflection and a subset of the studied anomalies. These results offer some support for the proposition that the heritable variation in behavioral anomalies is partly mediated by genetic variance in cognitive ability. Taken together with previous findings, our results underline the importance of genetic differences as a source of heterogeneity in economic and financial decision making.

This paper was accepted by Brad Barber, Teck Ho, and Terrance Odean, special issue editors.
Why Genius Leads to Adversity: Experimental Evidence on the Reputational Effects of Task Difficulty Choices
Authors: Katok Elena , Siemsen Enno
Published: April 2011

We use a behavioral laboratory experiment to study how agents with reputation concerns select the difficulty of their tasks. Drawing upon existing theory, we subjected participants in our study to a context in which they had to convince a principal of their capability to reap financial benefits. Our results show that participants tended to increase the difficulty of their task to enhance their reputation. In addition, we provide evidence that performance rewards reduce a less capable agent's tendency to choose a more difficult task, whereas a highly capable agent's pattern of choices is unaffected by performance rewards. Although the productivity of agents in our experiment therefore decreased if they had to convince a principal of their capability, we show that these detrimental performance implications can to some degree be overcome for less capable agents through performance rewards or by ensuring that the principal can interpret the agent's choice.

This paper was accepted by Christoph Loch, R&D and product development.
Impact of Growth Opportunities and Competition on Firm-Level Capability Development Trade-offs
Authors: Rahmandad Hazhir
Published: April 2011

How should managers prioritize among production, product development, branding, internationalization, and other capabilities and resources? This question is central to the resource-based view, and the answer depends not only on the direct returns on investment in each capability but also on the trade-offs in using those returns for future growth or survival in a competitive market. Through simulation experiments, this study examines firm-level capability development trade-offs in the context of a firm's market-level competition and growth. It is found that investing in operational capabilities (which enhance short-term performance) gains priority over investing in long-term dynamic capabilities when the operational capability investment strengthens the reinforcing loop between performance, investment flow, and capability development. Such operational capability investment provides growth opportunities and competitive advantage. Moreover, in strategic competition, firms anticipating rivals' focus on short-term growth need to further ignore dynamic (long-term) capability building in order to survive. Testable propositions are offered as to how trade-offs between short-term and long-term investments depend on different firm and industry characteristics. The results may explain why short-term-focused firm behavior persists in firms even in the absence of discounting, short-term managerial incentives, decision biases, or learning failures.
Wall Street vs. Main Street: Firm Strategies for Defending Legitimacy and Their Impact on Different Stakeholders
Authors: Lamin Anna , Zaheer Srilata
Published: April 2011

We assess the effect of firm strategies to defend legitimacy on two different stakeholder groups—the public (“Main Street”) and the investment community (“Wall Street”). We identify four types of firm strategies in response to challenges to their legitimacy—denial, defiance, decoupling, and accommodation— drawing from theory and from case studies of international outsourcing. We then develop and test hypotheses on the effectiveness of these strategies in defending legitimacy across these two stakeholder groups, using data from media reports and press releases on all 126 distinct accusations of the use of international sweatshops by U.S. firms from 1990 through 2002. We find that denial and defiance responses hinder the recovery of legitimacy on Main Street, and none of the responses has a positive effect on public perception, whereas Wall Street is unaffected by denial and defiance but views decoupling favorably. Main Street and Wall Street thus perceive firm actions to defend its legitimacy quite differently, suggesting that these worlds operate by separate moralities in which Main Street appears to privilege fairness as a core value, whereas Wall Street privileges profit.
Advancing the Conceptualization and Operationalization of Novelty in Organizational Research
Authors: Rosenkopf Lori , McGrath Patia
Published: April 2011

The construct of novelty is an important primitive for theories of organization learning, strategic change, and innovation. The organizational pursuit of novelty is generally theorized as necessary for long-term organizational adaptation and survival yet variance increasing in the short term. We argue that the recent explosion of studies of exploration and exploitation tend to conceptualize and operationalize novelty quite narrowly. In contrast, we treat novelty as a multidimensional construct and discuss implications of this approach for future research.
PERSPECTIVE—Toward a Behavioral Theory of Strategy
Authors: Gavetti Giovanni
Published: April 2011

This paper offers an analytical structure to pinpoint the behavioral roots of superior performance, where “behavioral” denotes “being about mental processes.” Such roots are identified in behavioral deviations from market efficiency. The causes of these deviations are behavioral factors that bound firms' ability to pursue and compete for superior opportunities. Because these bounds are systematic and diffused among firms, they ensure that latent opportunities are not competed away. In this setting, the behavioral bases of superior performance stem from a superior ability to overcome focal behavioral bounds. This analytical structure is used to identify the mental processes especially important to firm performance that strategic leaders can reliably manage. Its key insight is that superior opportunities are cognitively distant. They rarely correspond to common ways of thinking. The reason for this is that it is necessary to overcome strong behavioral bounds to pursue these opportunities. This insight contrasts with mainstream behavioral approaches to strategy, which focus on the virtues of local action, and it has two implications: the behavioral essence of superior performance corresponds to strategic leaders' superior ability to manage the mental processes necessary to pursue cognitively distant opportunities; and pursuing the cognitively distant implies a more expansive conception of strategic agency (e.g., the role of strategic leaders) than is acknowledged by mainstream behavioral approaches to strategy. The challenges posed by this conception require a model of human cognition that goes beyond the understanding of bounded rationality that is diffused in current behavioral strategy research. The second part of the paper assesses the traits of a model of human mind that can support the behavioral conception of strategic agency advocated and proposes a unified model of the human mind that centers on associative processes.
PMETB AND Me Or How I Learnt to Stop Worrying and Love Article 14
Authors: Raychowdhury R
Published: April 2011

The Postgraduate Medical Education and Training Board (PMETB) was established by an act of Parliament in 2003, to set standards for postgraduate medical education and training and to ensure that those standards are met. On 30 September 2005 PMETB took over the functions of the Specialist Training Authority and the Joint Committee on Postgraduate Training for General Practice. Under article 14(4) of the regulations governing PMETB, doctors whose training or qualifications and experience, considered together, meet the requirements of a Certificate of Completion of Training (CCT) programme in one of the standard CCT specialties, may apply to PMETB for a statement of eligibility for registration. This in turn allows application to the General Medical Council for admission to the specialist register.
Uganda Hearing Project: Avoiding the Seven Sins
Authors: Clark Matthew PA
Published: April 2011

Humanitarian missions to provide assistance in the developing world are a long-established venture, though varying greatly in their aims and deployment. Certainly within the specialty of otolaryngology there has been increased press on the topic over recent years. There is a recognition that many surgeons, together with their sister specialties, are doing a lot of very useful work as separate groups.
The final surgical examination: then and now
Authors: Marston Adrian
Published: April 2011

John Bishop Harman was the son of Katherine Harman, one of the first woman medical graduates in this country. Born and brought up in Harley Street, he qualified as a doctor in 1923 and immediately, as was permitted in those days, took the primary examination for the fellowship of The Royal College of Surgeons of England. The examination was in anatomy and physiology so that having recently passed his final examinations as a student, he had no difficulty in succeeding in this slightly more advanced test. Acquisition of the primary fellowship entitled him to enter for the final FRCS, which was the defining examination for a surgeon.