bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple Self-Controlled Case Series for Large-Scale Longitudinal Observational Databases
Authors: Simpson Shawn E. , Madigan David , Zorych Ivan , Schuemie Martijn J. , Ryan Patrick B. , Suchard Marc A.
Published: October 2013

Characterization of relationships between time-varying drug exposures and adverse events (AEs) related to health outcomes represents the primary objective in postmarketing drug safety surveillance. Such surveillance increasingly utilizes large-scale longitudinal observational databases (LODs), containing time-stamped patient-level medical information including periods of drug exposure and dates of diagnoses for millions of patients. Statistical methods for LODs must confront computational challenges related to the scale of the data, and must also address confounding and other biases that can undermine efforts to estimate effect sizes. Methods that compare on-drug with off-drug periods within patient offer specific advantages over between patient analysis on both counts. To accomplish these aims, we extend the self-controlled case series (SCCS) for LODs. SCCS implicitly controls for fixed multiplicative baseline covariates since each individual acts as their own control. In addition, only exposed cases are required for the analysis, which is computationally advantageous. The standard SCCS approach is usually used to assess single drugs and therefore estimates marginal associations between individual drugs and particular AEs. Such analyses ignore confounding drugs and interactions and have the potential to give misleading results. In order to avoid these difficulties, we propose a regularized multiple SCCS approach that incorporates potentially thousands or more of time-varying confounders such as other drugs. The approach successfully handles the high dimensionality and can provide a sparse solution via an regularizer. We present details of the model and the associated optimization procedure, as well as results of empirical investigations.
Nail Assessment in Psoriasis and Psoriatic Arthritis (NAPPA): development and validation of a tool for assessment of nail psoriasis outcomes
Authors: Augustin M. , Blome C. , Costanzo A. , Dauden E. , Ferrandiz C. , Girolomoni G. , Gniadecki R. , Iversen L. , Menter A. , Michaelis-Wittern K. , Morita A. , Nakagawa H. , Reich K.
Published: October 2013

Background

Existing tools for nail psoriasis are complex and may not adequately measure outcomes that are important to patients.

Objectives

We have developed and validated a new tool, the Nail Assessment in Psoriasis and Psoriatic Arthritis (NAPPA), with three components: a questionnaire assessing quality of life (NAPPA-QoL), a two-part questionnaire assessing patient-relevant treatment benefits (the Patient Benefit Index, NAPPA-PBI) and a psoriasis Clinical Assessment of Severity (NAPPA-CLIN).

Methods

Development of the questionnaires involved multiple steps: (i) collection of items about nail psoriasis-related impairments and treatment goals; (ii) selection of 48 items by an expert panel, including patients; (iii) translation into eight languages; (iv) feasibility testing and (v) longitudinal validation in six countries.

Results

Patients found the questionnaires clear (84%) and comprehensible (95%). NAPPA-QoL and NAPPA-PBI scores correlated moderately with clinical outcomes [e.g. Nail Psoriasis Severity Index (NAPSI)] and markedly with other quality-of-life questionnaires (e.g. EQ-5D™). Both questionnaires were sensitive to change. Internal consistency was good (Cronbach α ≥ 0·88 for all scales). The NAPPA-CLIN, a brief version of NAPSI that involves assessment of only four digits rather than all 20, was found to correlate highly with total NAPSI score (r =0·97, P <0·001).

Conclusions

Overall, the three-component NAPPA tool is a valid, reliable and practical instrument to assess patient-relevant nail psoriasis outcomes.
Prevalence and risk factors of cataract after chemotherapy with or without central nervous system irradiation for childhood acute lymphoblastic leukaemia: an LEA study
Authors: Alloin Anne‐Lise , Barlogis Vincent , Auquier Pascal , Contet Audrey , Poiree Maryline , Demeocq François , Herrmann Iris , Villes Virginie , Bertrand Yves , Plantaz Dominique , Kanold Justyna , Chastagner Pascal , Chambost Hervé , Sirvent Nicolas , Michel Gérard
Published: October 2013

Corticosteroid and central nervous system (CNS) irradiation can induce cataract in childhood lymphoblastic leukaemia survivors. Few prospective studies with systematic ophthalmological evaluation have been published. Cataract was prospectively assessed by serial slip lamp tests in 517 patients. All had acute lymphoblastic leukaemia, all had been treated by chemotherapy with or without CNS irradiation, and none had received haematopoietic stem cell transplantation. Median ages at last evaluation and follow‐up duration from leukaemia diagnosis were 16·8 and 10·9 years, respectively. Cataract was observed in 21/517 patients (4·1%). Cumulative incidence was 4·5 ± 1·2% at 15 years and reached 26 ± 8·1% at 25 years. CNS irradiation was the only risk factor: prevalence was 11·1% in patients who had received irradiation and 2·8% in those who did not. We did not detect any steroid dose effect: cumulative dose was 5133 and 5190 mg/m2 in patients with and without cataract, respectively. Cataract occurrence did not significantly impact quality of life. We conclude that, in the range of steroid dose reported here, the cataract risk proves very low 15 years after treatment without CNS irradiation but an even more prolonged follow‐up is required because of potential very late occurrence.
Unionization, Inequality and Redistribution
Authors: Pontusson Jonas
Published: October 2013

This article explores the implications of the OECD‐wide decline of union density for earnings inequality and income redistribution by looking at aggregate (country‐level) data. Over the period 1975–95, countries that experienced relatively large declines in union density also experienced relatively large increases in earnings inequality. In addition, governments apparently became less willing to engage in ‘compensatory redistribution’ in these countries. Since the early 1990s, however, union decline has become less closely associated with rising earnings inequality and redistributive policy changes. I argue that the declining relevance of unionization has to do with changes in the position of union members in the income distribution. In most OECD countries, the average union member has become relatively better off as union density has declined and union members have probably become less supportive of wage solidarity and redistributive government policies.
Small renal mass biopsy – how, what and when: report from an international consensus panel
Authors: Tsivian Matvey , Rampersaud Edward N. , del Pilar Laguna Pes Maria , Joniau Steven , Leveillee Raymond J. , Shingleton William B. , Aron Monish , Kim Charles Y. , DeMarzo Angelo M. , Desai Mihir M. , Meler James D. , Donovan James F. , Klingler Hans Christoph , Sopko David R. , Madden John F. , Marberger Michael , Ferrandino Michael N. , Polascik Thomas J.
Published: October 2013

To discuss the use of renal mass biopsy (RMB) for small renal masses (SRMs), formulate technical aspects, outline potential pitfalls and provide recommendations for the practicing clinician.

The meeting was conducted as an informal consensus process and no scoring system was used to measure the levels of agreement on the different topics.

A moderated general discussion was used as the basis for consensus and arising issues were resolved at this point.

A consensus was established and lack of agreement to topics or specific items was noted at this point.

Recommended biopsy technique: at least two cores, sampling different tumour regions with ultrasonography being the preferred method of image guidance.

Pathological interpretation: ‘non‐diagnostic samples’ should refer to insufficient material, inconclusive and normal renal parenchyma. For non‐diagnostic samples, a repeat biopsy is recommended. Fine‐needle aspiration may provide additional information but cannot substitute for core biopsy.

Indications for RMB: biopsy is recommended in most cases except in patients with imaging or clinical characteristics indicative of pathology (syndromes, imaging characteristics) and cases whereby conservative management is not contemplated. RMB is recommended for active surveillance but not for watchful‐waiting candidates.

We report the results of an international consensus meeting on the use of RMB for SRMs, defining the technique, pathological interpretation and indications.
Mechanism and regulation of kinesin‐5, an essential motor for the mitotic spindle
Authors: Waitzman Joshua S. , Rice Sarah E.
Published: October 2013

Mitotic cell division is the most fundamental task of all living cells. Cells have intricate and tightly regulated machinery to ensure that mitosis occurs with appropriate frequency and high fidelity. A core element of this machinery is the kinesin‐5 motor protein, which plays essential roles in spindle formation and maintenance. In this review, we discuss how the structural and mechanical properties of kinesin‐5 motors uniquely suit them to their mitotic role. We describe some of the small molecule inhibitors and regulatory proteins that act on kinesin‐5, and discuss how these regulators may influence the process of cell division. Finally, we touch on some more recently described functions of kinesin‐5 motors in non‐dividing cells. Throughout, we highlight a number of open questions that impede our understanding of both this motor's function and the potential utility of kinesin‐5 inhibitors.
Aquaporin‐4 Antibodies (NMO‐IgG) as a Serological Marker of Neuromyelitis Optica: A Critical Review of the Literature
Authors: Jarius Sven , Wildemann Brigitte
Published: October 2013

Antibodies to aquaporin‐4 (called NMO‐IgG or AQP4‐Ab) constitute a sensitive and highly specific serum marker of neuromyelitis optica (NMO) that can facilitate the differential diagnosis of NMO and classic multiple sclerosis. NMO‐IgG/AQP4‐Ab seropositive status has also important prognostic and therapeutic implications in patients with isolated longitudinally extensive myelitis (LETM) or optic neuritis (ON). In this article, we comprehensively review and critically appraise the existing literature on NMO‐IgG/AQP4‐Ab testing. All available immunoassays—including tissue‐based (IHC), cell‐based (ICC, FACS) and protein‐based (RIPA, FIPA, ELISA, Western blotting) assays—and their differential advantages and disadvantages are discussed. Estimates for sensitivity, specificity, and positive and negative likelihood ratios are calculated for all published studies and accuracies of the various immunoassay techniques compared. Subgroup analyses are provided for NMO, LETM and ON, for relapsing vs. monophasic disease, and for various control groups (eg, MS vs. other controls). Numerous aspects of NMO‐IgG/AQP4‐Ab testing relevant for clinicians (eg, impact of antibody titers and longitudinal testing, indications for repeat testing, relevance of CSF testing and subclass analysis, NMO‐IgG/AQP4‐Ab in patients with rheumatic diseases) as well as technical aspects (eg, AQP4‐M1 vs. AQP4‐M23‐based assays, intact AQP4 vs. peptide substrates, effect of storage conditions and freeze/thaw cycles) and pitfalls are discussed. Finally, recommendations for the clinical application of NMO‐IgG/AQP4‐Ab serology are given.
The midkine family of growth factors: diverse roles in nervous system formation and maintenance
Authors: Winkler C , Yao S
Published: October 2013

Midkines are heparin‐binding growth factors involved in a wide range of biological processes. Originally identified as retinoic acid inducible genes, midkines are widely expressed during embryogenesis with particularly high levels in the developing nervous system. During postnatal stages, midkine expression generally ceases but is often up‐regulated under disease conditions, most notably those affecting the nervous system. Midkines are known as neurotrophic factors, as they promote neurite outgrowth and neuron survival in cell culture. Surprisingly, however, mouse embryos deficient for midkine (knockout mice) are phenotypically normal, which suggests functional redundancy by related growth factors. During adult stages, on the other hand, midkine knockout mice develop striking deficits in neuroprotection and regeneration after drug‐induced neurotoxicity and injury. The detailed mechanisms by which midkine controls neuron formation, differentiation and maintenance remain unclear. Recent studies in zebrafish and chick have provided important insight into the role of midkine and its putative receptor, anaplastic lymphoma kinase, in cell cycle control in the central and peripheral nervous systems. A recent structural analysis of zebrafish midkine furthermore revealed essential protein domains required for biological activity that serve as promising novel targets for future drug designs. This review will summarize latest findings in the field that help to better understand the diverse roles of midkine in nervous system formation and maintenance.

Linked Articles

This article is part of a themed section on Midkine. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2014.171.issue‐4
Andrographolide suppresses RANKL‐induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo
Authors: Zhai Z J , Li H W , Liu G W , Qu X H , Tian B , Yan W , Lin Z , Tang T T , Qin A , Dai K R
Published: October 2013

Background and Purpose

Osteoclasts play a pivotal role in diseases such as osteoporosis, rheumatoid arthritis and tumour bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast‐related diseases. Here, we examined changes in osteoclastogenesis and LPS‐induced osteolysis in response to andrographolide (AP), a diterpenoid lactone isolated from the traditional Chinese and Indian medicinal plant Andrographis paniculata.

Experimental Approach

Effects of AP on osteoclast differentiation and bone resorption were measured in vitro. Western blots and RT‐PCR techniques were used to examine the underlying molecular mechanisms. The bone protective activity of AP in vivo was assessed in a mouse model of osteolysis.

Key Results

AP concentration‐dependently suppressed RANKL‐mediated osteoclast differentiation and bone resorption in vitro and reduced the expression of osteoclast‐specific markers, including tartrate‐resistant acid phosphatase, calcitonin receptors and cathepsin K. Further molecular analysis revealed that AP impaired RANKL‐induced NF‐κB signalling by inhibiting the phosphorylation of TGF‐β‐activated kinase 1, suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the nuclear translocation of the NF‐κB p65 subunit. AP also inhibited the ERK/MAPK signalling pathway without affecting p38 or JNK signalling.

Conclusions and Implications

AP suppressed RANKL‐induced osteoclastogenesis through attenuating NF‐κB and ERK/MAPK signalling pathways in vitro, thus preventing bone loss in vivo. These data indicated that AP is a promising natural compound for the treatment of osteoclast‐related bone diseases.
Design, Synthesis and Biological Evaluation of Pazopanib Derivatives as Antitumor Agents
Authors: Jia Yuping , Zhang Jian , Feng Jinhong , Xu Fuming , Pan Huili , Xu Wenfang
Published: October 2013

A novel series of pazopanib derivatives were designed, synthesized, and evaluated for their inhibitory activity against a series of kinases including VEGFR‐2, EGFR, AKT1, ALK1, and ABL1. The anti‐angiogenic activities ex vivo of some compounds were also investigated. Compounds P2d and P2e demonstrated outstanding inhibitory activity against VEGFR‐2 and ABL1 and higher anti‐angiogenic activity compared with Pazopanib, the reference standard. These two compounds (P2d and P2e) could be used as novel lead compounds for further development of anticancer agents.
Oral health‐related quality of life and traumatic dental injuries in Brazilian adolescents
Authors: Bendo Cristiane B. , Paiva Saul M. , Varni James W. , Vale Miriam P.
Published: October 2013

Objectives

To evaluate the impact of traumatic dental injuries (TDI) on oral health‐related quality of life (OHRQoL) among Brazilian adolescents.

Methods

A population‐based case–control study was carried out, which was nested to a cross‐sectional study with a sample of 1215 adolescents aged 11–14 years from Belo Horizonte, Brazil. OHRQoL was measured using the Brazilian version of the Child Perceptions Questionnaire (CPQ11–14) – Impact Short Form (ISF:16). Two‐step cluster analysis was performed to define cases and controls based on CPQ11–14‐ISF:16 scores. This method considers the pattern of responses for each item separately and how important each item is to the formation of clusters. The case group included those adolescents who presented higher negative impact on OHRQoL (n = 405), while the control group included those with lower negative impact (n = 810). Two controls for each case were individually matched from the same school and gender. The main independent variable was TDI, diagnosed by the Andreasen's classification. Untreated dental caries, malocclusion, and age were confounding variables. Conditional logistic regression analysis was performed with the significance level set at 5%.

Results

A multiple conditional logistic regression model demonstrates that adolescents diagnosed with fracture involving dentin and/or pulp had a 2.40‐fold greater chance of presenting high negative impact on QHRQoL [95% CI = 1.26–4.58; P = 0.008] than those without evidence of fractures. Enamel fracture only [P = 0.065] and restored fractures [P = 0.072] were not statistically associated with OHRQoL.

Conclusions

Adolescents with more severe untreated TDI, such as fractures involving dentin and/or pulp, were more likely to self‐report a higher negative impact on their OHRQoL than those without TDI.
Neuroprotective effects of argatroban and C5a receptor antagonist (PMX53) following intracerebral haemorrhage
Authors: Li G , Fan R-M , Chen J-L , Wang C-M , Zeng Y-C , Han C , Jiao S , Xia X-P , Chen W , Yao S-T
Published: October 2013

Intracerebral haemorrhage (ICH) is a subtype of stroke that associated with neurological dysfunction and inflammation, which may be ameliorated by a neuroprotective strategy targeting the complement cascade. The protective effect of C5a-receptor antagonist (PMX53) solely and in combination with thrombin antagonist (argatroban) was investigated in the ICH mouse model, respectively. Adult male C57BL/6J wild-type (WT) mice and C3–/– mice were randomized to receive PMX53/argatroban 1, 3 and 5 days after ICH. A double injection technique was used to infuse 25 μl of autologous whole blood into the right striatum. Mice in the sham group received only needle insertion. Brain water content and mRNA of inflammatory factors were measured on the first, third and fifth days after ICH, respectively. Neurological dysfunction was assessed using a 28-point neurological scoring system in the three cohorts, namely, on days 1, 3 and 5 following ICH. Animals treated with PMX53/argatroban demonstrated significant improvements in neurological function and fewer neurological apoptosis detected by TUNEL [terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labelling] and βIII-tubulin dual-staining compared with vehicle-treated animals. Compared with sham-treated mice, the brain water content in argatroban/PMX53-treated mice was decreased significantly in both the ipsilateral cortex and ipsilateral striatum. Administration of PMX53/argatroban provided a synergistic neuroprotective effect via reducing inflammatory factors and brain oedema, leading to improvements in neurofunctional outcome. The results of this study indicated that simultaneous blockade of the thrombin and C5a receptors represent a promising neuroprotective strategy in haemorrhagic stroke.
Effects of Intravenous and Intrathecal Dexmedetomidine in Spinal Anesthesia: A Meta‐Analysis
Authors: Niu Xiao‐Yin , Ding Xi‐Bing , Guo Ting , Chen Ming‐Hui , Fu Shu‐Kun , Li Quan
Published: October 2013

Purpose

To assess the effects of dexmedetomidine on the duration of sensory and motor block, postoperative analgesia, hypotension, bradycardia, and side effects in patients undergoing spinal anesthesia.

Methods

Two researchers searched MEDLINE, EMBASE, and the Cochrane controlled trial register independently for randomized controlled trials comparing dexmedetomidine with a placebo without any language restrictions.

Results

A total of 412 patients from eight trials were included in this study. The results revealed that dexmedetomidine was statistically significant in prolonging the duration of sensory block (mean difference, MD = 73.55; 95% CI, [55.69, 91.40] P < 0.00001, I2 = 89%) and motor block (MD = 59.11; 95% CI, [29.58, 88.65] P < 0.00001, I2 = 91%) and the time to first request for postoperative analgesia (MD = 245.77, 95% CI, [143.53, 348.00] P < 0.00001, I2 = 98%). The occurrence of hypotension (OR = 0.60, 95% CI, [0.3–1.23], P = 0.40, I2 = 3%) and side effects (OR = 0.9, 95% CI, [0.36–2.22], P = 0.88, I2 = 0%) was not significantly different between dexmedetomidine and placebo. However, dexmedetomidine was associated with more frequent bradycardia requiring atropine (OR = 7.55; 95% CI, [2.76–20.63], P = 0.63, I2 = 0%).

Conclusions

This meta‐analysis has shown that dexmedetomidine prolonged the duration of spinal anesthesia and improved postoperative analgesia and did not increase the incidence of hypotension and adverse events, but needs more atropine to reverse bradycardia.
Tumour budding is a reproducible index for risk stratification of patients with Stage II colon cancer
Authors: Lai Y.‐H. , Wu L.‐C. , Li P.‐S. , Wu W.‐H. , Yang S.‐B. , Xia P. , He X.‐X. , Xiao L.‐B.
Published: October 2013

Aim

High‐risk patients with Stage II colon cancer may benefit from adjuvant chemotherapy, but it is difficult to identify such a patient group. A robust and reproducible index would be helpful to select the subset of Stage II colon cancer patients at high risk. This study investigated the potential prognostic significance of tumour budding in Stage II colon cancer.

Method

In all, 135 Stage II colon cancer patients with known outcome were identified. The degree of tumour budding was assessed by two individual observers and was classified, according to the number of tumour buds in the area with the greatest budding intensity on haematoxylin and eosin slides, as high‐grade budding (10 or more tumour buds) and low‐grade budding (0–9 buds). Inter‐observer agreement for two observers was assessed by using the kappa test. Progression‐free and cancer‐specific survivals were analysed using the Kaplan–Meier method and Cox regression.

Results

The 5‐year progression‐free survival rates for patients with high‐grade tumour budding (n = 36) and those with low‐grade budding (n = 99) were 57.6% and 89.0% (P < 0.001). The 5‐year cancer‐specific survival rates were 66.7% vs 92.0% (P < 0.001). Cox regression analyses demonstrated tumour budding as an independent predictor of disease progression (hazard ratio 4.982, P < 0.001) and cancer‐related death (hazard ratio 4.142, P = 0.003). The two observers agreed on the classification of tumour budding in 118 cases (87.4%) and the inter‐observer agreement was good (κ = 0.692).

Conclusion

Tumour budding is a strong and reproducible prognostic factor for adverse outcome in Stage II colon cancer, which may serve as a prognostic marker to identify patients with a high risk of recurrence who may benefit from adjuvant therapy.
Incidence and long‐term outcomes of squamous cell bladder cancer after deceased donor renal transplantation
Authors: Davis N. F. , McLoughlin L. C. , Dowling C. , Power R. , Mohan P. , Hickey D. , Smyth G. , Eng M. , Little D. M.
Published: October 2013

Objective

To review the incidence and long‐term outcomes of squamous cell carcinoma (SCC) of the bladder in patients after kidney transplantation.

Methods

Between January 1976 and March 2013, five patients from one center (0.0013%) developed SCC of the bladder after undergoing a deceased donor kidney transplant. Their relevant risk factors included long‐term self‐intermittent catheterization/indwelling catheter (n = 2), smoking history (n = 2), and a prior history of cyclophosphamide treatment for vasculitis (n = 1). Primary outcome variables were overall patient survival and latency period between transplantation and SCC diagnosis.

Results

The duration of long‐term follow‐up was 94 ± 89 (range: 4–239) months. The latency period between transplantation and bladder SCC was 87 ± 87 (range: 2–228) months, and all five patients were immunosuppressed with tacrolimus, mycophenolate mofetil, and prednisone. Four patients had suspected metastases upon presentation, and one patient presented with organ‐confined disease. This patient underwent a radical cystectomy and remains disease free eight months post‐operatively. Despite radical treatment, the remaining four patients died from metastatic disease 7 ± 4.4 (range: 2–11) months after their initial diagnosis.

Conclusion

SCC of the bladder has a poor prognosis particularly in renal transplant patients. Early detection with flexible cystourethroscopy in patients with risk factors for SCC may improve long‐term outcomes in this patient cohort.
A randomized, crossover pharmacokinetic study comparing generic tacrolimus vs. the reference formulation in subpopulations of kidney transplant patients
Authors: Bloom R. D. , Trofe‐Clark J. , Wiland A. , Alloway R. R.
Published: October 2013

An exploratory, post hoc analysis was performed using data from a prospective, multicenter, open‐label, randomized, two‐period (14 d per period), two‐sequence, crossover, steady‐state pharmacokinetic study comparing generic tacrolimus (Sandoz) vs. reference tacrolimus in stable renal transplant patients receiving their pre‐study twice‐daily dose. Pharmacokinetic parameters were compared in 68 patients according to gender, African American ethnicity, the presence or absence of diabetes, and use of steroids. The ratios of tacrolimus AUC0–12 h, Cmax, and C12 with generic vs. reference tacrolimus were calculated using the geometric mean (GM) of dose‐normalized values at days 14 and 28. Mean (SD) tacrolimus dose at baseline was 5.7 (4.2) mg/d. There were no consistent differences in dose‐normalized AUC0–12 h, C12, Cmax, or tmax between the generic and reference preparations within subpopulations. The 90% confidence intervals (CI) for the ratios of dose‐normalized AUC0–12 h and C12 with generic vs. reference tacrolimus were within 80–125% for all subpopulations, as were 90% CIs for Cmax other than for females, African Americans, and non‐diabetics, which is not unexpected given the wide variability of tacrolimus Cmax and the small subpopulation sizes. These exploratory results suggest that this generic tacrolimus preparation would be expected to offer comparable bioavailability to the reference drug in these patient subpopulations.
Decision Support System of Truck Routing and Refueling: A Dual‐Objective Approach
Authors: Suzuki Yoshinori , Dai Jing
Published: October 2013

The variable‐route vehicle‐refueling problem (VRVRP) is a variant of the network‐flow problem which seeks, for a vehicle traveling from origin s to destination d, both the route and the refueling policy (sequence of fuel stations to use between s and d) that jointly minimize the fuel cost of operating the vehicle. Commercial‐grade decision support systems that solve the VRVRP are widely used by motor carriers, but they provide heuristic solutions only. Exact methods are available from the academic side, but because they focus on minimizing costs, they tend to cut fuel costs in exchange for increased vehicle miles (which can increase fuel consumptions and pollutants emission). We propose a new approach to the VRVRP that allows carriers to jointly seek the two possibly conflicting goals; minimizing fuel cost and vehicle miles. Computational testing shows that our approach (i) outperforms the commercial software products in both goals, and (ii) finds solutions that require significantly less vehicle miles than those given by the exact method proposed in the academic literature, without incurring unacceptable increases in fuel cost.
Efficiency Evaluation in Search Advertising
Authors: Ayanso Anteneh , Mokaya Brian
Published: October 2013

In this article, we use data envelopment analysis combined with principal component analysis to evaluate the efficiency of online retailers in search advertising. We examine various efficiency model specifications involving several resource and performance‐related variables in search advertising. Our analysis based on 200 retailers suggests different efficiency patterns for multichannel and Web‐only retailers. The results of our efficiency pattern analysis indicate that the performance metrics, impressions, online sales, click‐through rate, and conversion rate together reveal differences in efficiency mainly for multichannel retailers. On the other hand, ad positions in sponsored and organic links reveal differences in efficiency for Web‐only retailers. In terms of overall efficiency, we find that multichannel retailers occupy relatively most of the top positions. These results contribute to organizational level understanding of search advertising practices in online retailing and offer insights into keyword management, resource utilization, and performance metrics in search advertising campaigns.
Supply Chain Knowledge and Performance: A Meta‐Analysis
Authors: Wowak Kaitlin D. , Craighead Christopher W. , Ketchen David J. , Hult G. Tomas M.
Published: October 2013

Many firms make significant investments into developing and managing knowledge within their supply chains. Such investments are often prudent because studies indicate that supply chain knowledge (SCK) has a positive influence on performance. Key questions still surround the SCK–performance relationship, however. First, what is the overall relationship between SCK and performance? Second, under what conditions is the relationship stronger or weaker? To address these questions, we applied meta‐analysis to 35 studies of the SCK–performance relationship that collectively include more than 8,400 firms. Our conservative estimate is that the effect size of the overall relationship is  = .39. We also find that the SCK–performance relationship is stronger when (i) examining operational performance, (ii) gathering data from more than one supply chain node, (iii) gathering data from multiple countries, (iv) examining service industries, and (v) among more recently published studies. We also found that studies that embraced a single theory base (as opposed to using multiple ones) had a stronger SCK–performance relationship. Looking to the future, our meta‐analysis highlights the need for studies to (i) include lags between the measurement of SCK and performance, (ii) gather upstream data when examining innovation, (iii) examine SCK within emerging countries, and (iv) provide much more information relative to the nuances of the SCK examined.
Distribution Channel Network and Relational Performance: The Intervening Mechanism of Adaptive Distribution Flexibility
Authors: Yu Kangkang , Cadeaux Jack , Song Hua
Published: October 2013

Network theories argue that organizations can enjoy information and control benefits from the network in which they are embedded. Focusing on distribution channel networks with strong, prominent, and central ties, this article argues that distribution flexibility, composed of logistics and relationship flexibility, is a response to environmental uncertainty that mediates the effect of channel network embeddedness on relationship performance. Results show that logistics flexibility and relationship flexibility fully mediate the effect of channel network embeddedness on relationship satisfaction, but that only relationship flexibility mediates the effect of channel network embeddedness on long‐term relationship orientation. Furthermore, not only is the effect of tie strength on logistics flexibility stronger in an uncertain environment, but relationship flexibility also decreases as the congruence between uncertainty and tie strength increases, suggesting a complex higher‐order contingency model.
The contribution of sex to clinical picture variability
Authors: Brossard‐Racine Marie
Published: October 2013

This commentary is on the original article by Kikkert et al. on pages 1023–1029 of this issue.
Randomized, 1‐year comparison of three ways to initiate and advance insulin for type 2 diabetes: twice‐daily premixed insulin versus basal insulin with either basal‐plus one prandial insulin or basal‐bolus up to three prandial injections
Authors: Riddle M. C. , Rosenstock J. , Vlajnic A. , Gao L.
Published: October 2013

Aim

Many patients with type 2 diabetes mellitus (T2DM) initiate insulin therapy when other treatments fail; how best to do this is poorly defined.

Methods

People with T2DM [n = 588; glycated haemoglobin A1C (A1C) >7.0%, mean baseline 9.4%] were randomized to twice‐daily premixed protamine‐aspart/aspart insulin (PM − 2), once‐daily insulin glargine plus zero to one prandial insulin glulisine injection (G + 1), or insulin glargine plus zero to three prandial injections (G + 3). Insulin was titrated for 60 weeks. Efficacy and safety outcomes were assessed.

Results

Discontinuation rates were 53 of the 194 (27%), 44 of the 194 (23%) and 38 of the 194 (20%), for PM − 2, G + 1 and G + 3. Glycaemic control improved in all groups (A1C 7.2 ± 1.37, 7.1 ± 1.68 and 7.0 ± 1.21% at 60 weeks; 7.5 ± 1.29, 7.2 ± 1.62 and 7.2 ± 1.63% at endpoint). G + 1 was statistically non‐inferior to PM − 2 in reducing A1C. G + 3 was slightly superior to PM − 2 in attaining <7.0% at 60 weeks, but only when the analysis included Good Clinical Practice non‐adherent sites. Hypoglycaemia with plasma glucose <2.8 mmol/l was more frequent with PM − 2 versus G + 1 and G + 3; [adjusted incidence: 46 (p = 0.0087) vs. 33 (p = 0.0045) and 31.5%; events per patient‐year: 1.9 vs. 0.8 and 0.9, p ≤ 0.0001]. Insulin dosage and weight‐gain were similar.

Conclusion

Basal insulin plus a single prandial injection is as effective in improving glycaemic control as premixed insulin. Full basal‐prandial therapy is only slightly more effective than premixed insulin. Stepwise basal‐prandial regimens improve glycaemic control with less hypoglycaemia than twice‐daily premixed insulin.
Value of the Mitral Valve Resistance in Evaluation of Symptomatic Patients with Mild and Moderate Mitral Stenosis – A Dobutamine Stress Echocardiographic Study
Authors: Roshdy Hisham S. , Meshrif Amir M. , El‐Dosouky Ibtesam I.
Published: October 2013

Background

Conventional stenosis indexes poorly reflect the major hemodynamic consequence of mitral stenosis (MS). Valve resistance (VR) is a physiologic expression of stenosis.

Objectives

This study aimed to demonstrate whether the mitral valve resistance (MVR) and its changes, relate to restricted exercise capacity in patients with mild and moderate mitral stenosis.

Methods

Twenty‐four patients with rheumatic mild‐to‐moderateMSunderwent transthoracic echocardiographic study (resting and dobutamine stress echocardiography [DSE]), divided into two groups; group I: symptomatic (12 patients) and groupII: asymptomatic (12 patients). Mitral valve area (MVA), mean transmitral diastolic pressure gradient (TMPG), cardiac output (CO), andMVRwere measured in all patients at rest and at peakDSE. Changes (∆) inMVA,TMPG,CO, andMVRwere calculated. Data underwent statistical analysis.

Results

From resting to peak dobutamine infusion, theMVRsignificantly decreased from 111.4 ± 28.2 to 83.6 ± 27.0 dynes sec/cm5in groupII(P < 0.001). The increase inMVRin group I (13.8 ± 10.3 dynes sec/cm5) compared with its reduction (−27.8 ± 15.6 dynes sec/cm5) in groupIIwere highly significant different (P < 0.001). A reduction inMVRby less than 21.5 dynes sec/cm5at peak dobutamine infusion reflect a cutoff value considered to detect the hemodynamic significance of mild‐to‐moderateMSwith a sensitivity of 92% and a specificity of 73%.

Conclusion

The changes in theMVRcan be used as aDSEparameter for expression of stenosis severity and to describe discrepancy in symptom status in patients with mild‐to‐moderate mitral stenosis.
Addition of thalidomide to melphalan and prednisone treatment prolongs survival in multiple myeloma – a retrospective population based study of 1162 patients
Authors: Lund Johan , Uttervall Katarina , Liwing Johan , Gahrton Gösta , Alici Evren , Aschan Johan , Holmberg Erik , Nahi Hareth
Published: October 2013

The combination of melphalan and prednisone (MP) has been the standard treatment of multiple myeloma (MM). Since the introduction of novel agents, the clinical outcome in MM has improved. Six randomized prospective studies with thalidomide combined with melphalan and prednisone (MPT) compared to MP have been performed, most of them showing that MPT gives a better response rate and median overall survival (OS). Amongst 1843 MM patients admitted to 15 Swedish centres, we selected all patients treated with MP and MPT in first, second, third or fourth line of therapy, in total 888 patients treated with MP and 274 with MPT. Patients were evaluated for response rate, OS and Time to Next Treatment. Multivariate Cox model analysis was made to adjust for different criteria at time for MM‐diagnosis. The median OS from beginning of first line of treatment was 2.2/4.2 yrs after MP/MPT respectively, and in second, third and fourth line of treatment 1.8/2.9, 1.4/1.6 and 1.1/1.9 yrs (P < 0.0001, 0.003, 0.74 and 0.235). The relative risk for death in the MPT group vs. the MP group was 0.61 (95% CI: 0.45–0.84) in first and 0.55 (0.38–0.83), P < 0.01) in second line. Treatment with MPT gave a significantly better OS rate after both first and second line of therapy when compared with treatment with MP only.
Effects of transcranial direct current stimulation on risky decision making are mediated by ‘hot’ and ‘cold’ decisions, personality, and hemisphere
Authors: Pripfl Jürgen , Neumann Renate , Köhler Ulla , Lamm Claus
Published: October 2013

Previous results point towards a lateralization of dorsolateral prefrontal cortex (DLPFC) function in risky decision making. While the right hemisphere seems involved in inhibitory cognitive control of affective impulses, the left DLPFC is crucial in the deliberative processing of information relevant for the decision. However, a lack of empirical evidence precludes definitive conclusions. The aim of our study was to determine whether anodal transcranial direct current stimulation (tDCS) over the right DLPFC with cathodal tDCS over the lDLPFC (anodal right/cathodal left) or vice versa (anodal left/cathodal right) differentially modulates risk‐taking in a task [the Columbia Card Task (CCT)] specifically engaging affect‐charged (Hot CCT) vs. deliberative (Cold CCT) decision making. The facilitating effect of the anodal stimulation on neuronal activity was emphasized by the use of a small anode and a big cathode. To investigate the role of individual differences in risk‐taking, participants were either smokers or non‐smokers. Anodal left/cathodal right stimulation decreased risk‐taking in the ‘cold’ cognition version of the task, in both groups, probably by modulating deliberative processing. In the ‘hot’ version, anodal right/cathodal left stimulation led to opposite effects in smokers and non‐smokers, which might be explained by the engagement of the same inhibitory control mechanism: in smokers, improved controllability of risk‐seeking impulsivity led to more conservative decisions, while inhibition of risk‐aversion in non‐smokers resulted in riskier choices. These results provide evidence for a hemispheric asymmetry and personality‐dependent tDCS effects in risky decision making, and may be important for clinical research on addiction and depression.
Gap junction networks can generate both ripple‐like and fast ripple‐like oscillations
Authors: Simon Anna , Traub Roger D. , Vladimirov Nikita , Jenkins Alistair , Nicholson Claire , Whittaker Roger G. , Schofield Ian , Clowry Gavin J. , Cunningham Mark O. , Whittington Miles A.
Published: October 2013

Fast ripples (FRs) are network oscillations, defined variously as having frequencies of > 150 to > 250 Hz, with a controversial mechanism. FRs appear to indicate a propensity of cortical tissue to originate seizures. Here, we demonstrate field oscillations, at up to 400 Hz, in spontaneously epileptic human cortical tissue in vitro, and present a network model that could explain FRs themselves, and their relation to ‘ordinary’ (slower) ripples. We performed network simulations with model pyramidal neurons, having axons electrically coupled. Ripples (< 250 Hz) were favored when conduction of action potentials, axon to axon, was reliable. Whereas ripple population activity was periodic, firing of individual axons varied in relative phase. A switch from ripples to FRs took place when an ectopic spike occurred in a cell coupled to another cell, itself multiply coupled to others. Propagation could then start in one direction only, a condition suitable for re‐entry. The resulting oscillations were > 250 Hz, were sustained or interrupted, and had little jitter in the firing of individual axons. The form of model FR was similar to spontaneously occurring FRs in excised human epileptic tissue. In vitro, FRs were suppressed by a gap junction blocker. Our data suggest that a given network can produce ripples, FRs, or both, via gap junctions, and that FRs are favored by clusters of axonal gap junctions. If axonal gap junctions indeed occur in epileptic tissue, and are mediated by connexin 26 (recently shown to mediate coupling between immature neocortical pyramidal cells), then this prediction is testable.
Climate change in the oceans: evolutionary versus phenotypically plastic responses of marine animals and plants
Authors: Reusch Thorsten B. H.
Published: October 2013

I summarize marine studies on plastic versus adaptive responses to global change. Due to the lack of time series, this review focuses largely on thepotentialfor adaptive evolution in marine animals and plants. The approaches were mainly synchronic comparisons of phenotypically divergent populations, substituting spatial contrasts in temperature orCO2environments for temporal changes, or in assessments of adaptive genetic diversity within populations for traits important under global change. The available literature is biased towards gastropods, crustaceans, cnidarians and macroalgae. Focal traits were mostly environmental tolerances, which correspond to phenotypic buffering, a plasticity type that maintains a functional phenotype despite external disturbance. Almost all studies address coastal species that are already today exposed to fluctuations in temperature, pHand oxygen levels. Recommendations for future research include (i) initiation and analyses of observational and experimental temporal studies encompassing diverse phenotypic traits (including diapausing cues, dispersal traits, reproductive timing, morphology) (ii) quantification of nongenetic trans‐generational effects along with components of additive genetic variance (iii) adaptive changes in microbe–host associations under the holobiont model in response to global change (iv) evolution of plasticity patterns under increasingly fluctuating environments and extreme conditions and (v) joint consideration of demography and evolutionary adaptation in evolutionary rescue approaches.
Genomic selection for recovery of original genetic background from hybrids of endangered and common breeds
Authors: Amador Carmen , Hayes Ben J. , Daetwyler Hans D.
Published: October 2013

Critically endangered breeds and populations are often crossed with more common breeds or subspecies. This results in genetic admixture that can be undesirable when it challenges the genetic integrity of wild and domestic populations, causing a loss in special characteristics or unique genetic material and ultimately extinction. Here, we present two genomic selection strategies, using genome‐wide DNA markers, to recover the genomic content of the original endangered population from admixtures. Each strategy relies on the estimation of the proportion of nonintrogressed genome in individuals based on a different method: either genomic prediction or identification of breed‐specific haplotypes. Then, breeding programs that remove introgressed genomic information can be designed. To test these strategies, we used empirical 50K SNP array data from two pure sheep breeds, Merino (used as target breed), Poll Dorset and an existing admixed population of both breeds. Sheep populations with varying degrees of introgression and admixture were simulated starting from these real genotypes. Both strategies were capable of identifying segment origin, and both removed up to the 100% of the Poll Dorset segments. While the selection process led to substantial inbreeding, we controlled it by imposing a minimum number of individuals contributing to the next generation.
Plastic limit load and its application to the fracture toughness testing for heterogeneous single edge notch tension specimens
Authors: Paredes M.
Published: October 2013

The current investigation pursues the confirmation of the applicability of the limit load solutions in determination of the η factors necessary for fracture toughness testing protocols. The procedure begins with the correct calculation of limit load values in welded single edge notch tension (SE(T)) fracture specimens containing centreline cracks. Hence, the η factor is inferred through the principle of potential energy. Additionally, such results are compared with those obtained from finite element analyses, including strain hardening effects available in the literature. SE(T) specimens subject to pin‐loading display that the η factors are insensitive to the configurational effects and hardening properties. On the other hand, in clamped SE(T) specimens, such effects become meaningful, making its usage in fracture toughness experiments questionable. This work provides an alternative methodology to compute fully plastic proportionality coefficients (η) based on limit load solutions for heterogeneous cracked SE(T) specimens. These analyses also consider the limitations and potentialities of such an approach in experimental measurements of ductile crack growth.
In‐plane progressive matrix cracking analysis of symmetric cross‐ply laminates with holes
Authors: Sadeghi G. , Hosseini‐Toudeshky H. , Mohammadi B.
Published: October 2013

Most of the previously performed damage analyses in composite laminates have been restricted to model the plain laminates without geometry discontinuities. In this study, a micromechanical damage model is combined with the finite element formulation and is implemented in the integration points to perform progressive damage analyses of composite laminates. A micromechanical damage model based on the stress transfer method is used to find the degradation of mechanical properties of composite laminates. Crack density is also used as an only state variable representing the damage in each Gauss point of every layer of the laminate. The strain energy and critical energy release rate criterion is also used to predict the damage initiation and evolution in each layer. A finite element discretization is used in conjunction with the user element definition capability of ABAQUS commercial software. To verify the developed procedure, a single element is analysed, and the obtained results are compared with available results in the literature. Progressive damage analyses are also performed for several symmetric cross‐ply laminates with and without geometry discontinuity subjected to matrix cracking damage mechanism under in‐plane loading conditions. The obtained mechanical response and variations of matrix crack density versus the applied load are also discussed.