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Background and Purpose: Inhibitors of voltage-gated sodium channels (Na V s) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Na v channels as a means of informing the development of improved antiseizure drugs., Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of Na V 1.6 alone or together with Na V 1.2. These novel Na V inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding Na V 1.6) and in wild-type mice., Key Results: Pharmacologic inhibition of Na V 1.6 in Scn8a N1768D/+ mice prevented seizures evoked by a 6-Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. Na V 1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS Na V isoforms., Conclusions and Implications: Our data suggest Na V 1.6 inhibition is a driver of efficacy for Na V inhibitor anti-seizure medicines. Sparing the Na V 1.1 channels of inhibitory interneurons did not compromise efficacy. Selective Na V 1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective analgesics commonly used in fracture management. Although previously associated with delayed fracture healing, multiple studies have demonstrated their safety, with minimal risks of fracture healing. Given the current opioid crisis in the United States, alternate pain control modalities are essential to reduce opioid consumption. This study aims to determine whether the combination of oral acetaminophen and intravenous ketorolac is a viable alternative to opioid-based pain management in closed tibial shaft fractures treated with intramedullary nailing., Methods: We conducted a randomized controlled trial evaluating postoperative pain control and opioid consumption in patients with closed tibial shaft fractures who underwent intramedullary nailing. Patients were randomized into an NSAID-based pain control group (52 patients) and an opioid-based pain control group (44 patients). Visual analog scale (VAS) scores and morphine milligram equivalents (MMEs) were evaluated at 12-hour postoperative intervals during the first 48 hours after surgery. Nonunion and delayed healing rates were recorded for both groups., Results: A statistically significant decrease in MMEs was noted at every measured interval (12, 24, 36, and 48 hours) in the NSAID group compared with the opioid group ( P -value 0.001, 0.001, 0.040, 0.024, respectively). No significant change in visual analog scale scores was observed at 12, 36, and 48 hours between both groups ( P -value 0.215, 0.12, and 0.083, respectively). A significant decrease in VAS scores was observed at the 24-hour interval in the NSAID group compared with the opioid group ( P -value 0.041). No significant differences in union rates were observed between groups ( P -value 0.820)., Discussion: Using an NSAID-based postoperative pain protocol led to a decrease in opioid consumption without affecting pain scores or union rates. Owing to the minimal risk of short-term NSAID use, their role in the perioperative management of tibia shaft fractures is justified, especially when they reduce opioid consumption markedly., Level of Evidence: Therapeutic Level I., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)

Background: Multiple risk assessment scales are available for predicting the development of pressure injuries (PIs) in patients in the intensive care unit (ICU). Most PI risk assessment tools have been validated at the time of admission; however, another time point during treatment could better reflect clinical changes and therefore, the risk of PIs., Aims: The study aimed to examine the predictive validity of PI risk assessment scale designed for ICU patients, the conscious level, mobility, haemodynamic, oxygenation and nutrition (COMHON) index, at several time points or intervals during ICU stay., Study Design: This was an observational prospective study undertaken over a period of 1 year (July 2021-June 2022). Patients admitted to ICU for >3 days were included. The number, location and degree of the PIs were recorded. The level of risk for developing PIs during the stay was determined by calculating the COMHON scores at admission, and 72 h, as well as the highest and mean score. Predictive validity was studied using accuracy parameters and areas under the receiver operating characteristic curve (AUC). The best cutoff point was also determined and used to compare risk between categories., Results: Of the 286 patients included in the study, 160 (59%) were male. The level of severity evaluated using the APACHE II scale was 18.4 ± 5.8 points. Invasive mechanical ventilation was used in 32.1% (n = 92) of the patients and 20.6% (n = 59) received high flow oxygen therapy. The incidence of PI was 15.4% (n = 44), with sacral location in 47.7% (n = 21) and grade II in 75% (n = 33) of the patients. The AUC was 0.907 (0.872-0.942); 0.881 (0.842-0.920); 0.877 (0.835-0.920) and 0.749 (0.667-0.831) at the mean, the highest, 72 h and ICU admission scores, respectively. The best cutoff point was 13 in all patients. The risk of developing a PI was 6.4 times higher in the high-risk group (>13 points)., Conclusions: The best predictive capacity for the COMHON index risk assessment was the mean and highest scores. The predictive accuracy was higher on the third day of the patient's stay than on admission, and this was attributed to the clinical changes observed in some patients over the course of their critical illness., Relevance for Clinical Practice: Patients in ICU are at high risk of developing PIs, therefore, preventive measures should be maximized. Risk assessment should be carried out sequentially owing to the changes that patients present throughout their ICU stay and preventive measures should be used according to the risk level., (© 2024 British Association of Critical Care Nurses.)

Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or β -thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors. Dimeric compounds were made to generate more potent compounds with low systemic exposure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits dietary nonheme iron uptake in both rats and pigs yet has negligible systemic exposure. Efficacy is maintained for >2 weeks in a rat subchronic dosing assay. Doses that lowered iron content in the spleen and liver by >50% had no effect on the tissue content of other divalent cations except for cobalt. XEN602 represents a powerful pharmacological tool for understanding the physiologic function of DMT1 in the gut. SIGNIFICANCE STATEMENT: This report introduces methodology to develop potent, gut-restricted inhibitors of divalent metal transporter 1 (DMT1) and identifies XEN602 as a suitable compound for in vivo studies. We also report novel animal models to quantify the inhibition of dietary uptake of iron in both rodents and pigs. This research shows that inhibition of DMT1 is a promising means to treat iron overload disorders., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Here, we report on our study of plasma lipidomics profiles of patients with type 1 diabetes (T1DM) and explore potential associations. One hundred and seven patients with T1DM were consecutively recruited. Ultrasound imaging of peripheral arteries was performed using a high image resolution B-mode ultrasound system. Untargeted lipidomics analysis was performed using UHPLC coupled to qTOF/MS. The associations were evaluated using machine learning algorithms. SM(32:2) and ether lipid species (PC(O-30:1)/PC(P-30:0)) were significantly and positively associated with subclinical atherosclerosis (SA). This association was further confirmed in patients with overweight/obesity (specifically with SM(40:2)). A negative association between SA and lysophosphatidylcholine species was found among lean subjects. Phosphatidylcholines (PC(40:6) and PC(36:6)) and cholesterol esters (ChoE(20:5)) were associated positively with intima-media thickness both in subjects with and without overweight/obesity. In summary, the plasma antioxidant molecules SM and PC differed according to the presence of SA and/or overweight status in patients with T1DM. This is the first study showing the associations in T1DM, and the findings may be useful in the targeting of a personalized approach aimed at preventing cardiovascular disease in these patients.

Introduction: The current rate of opioid prescription is disquieting because of their high abuse potential, adverse effects, and thousands of overdose deaths. This situation imposes urgency in seeking alternatives for adequate pain management. From this perspective, this study aimed to evaluate the experience and the perceived analgesic efficacy of medical cannabis in managing the pain associated with musculoskeletal conditions., Methods: A 28-question survey was distributed to patients at a major medical cannabis center in Puerto Rico for 2 months. Demographics, medical history, cannabis usage, cannabis use perspective, and analgesic efficacy were assessed in the questionnaire., Results: One hundred eighty-four patients completed our survey. The majority (67%) were males, and the participants' average age was 38 years. This study showed an average pain reduction score of 4.02 points on the Numeric Rating Scale among all the participants. Those with musculoskeletal conditions reported a notable average pain reduction score of 4.47 points. In addition, 89% of the participants considered medical cannabis to be more effective than narcotics for adequate pain management., Conclusions: This study demonstrated that the use of medical cannabis among patients with musculoskeletal conditions effectively reduced pain levels based on their Numeric Rating Scale reported scores., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target Na V 1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A -related epilepsy syndromes ( SCN8A -RES), where gain-of-function (GoF) mutations lead to excess Na V 1.6 sodium current, or other indications where Na V 1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of Na V 1.6 (IC 50 0.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for Na V 1.1, 134 X for Na V 1.2, 276 X for Na V 1.7, and >583 Xfor Na V 1.3, Na V 1.4, and Na V 1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting Na V 1.6 currents, including resurgent and persistent Na V 1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where Na V 1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A- developmental epileptic encephalopathy ( SCN8A -DEE) and adult focal-onset seizures., Competing Interests: JJ, TF, KK, CD, SG, JA, GB, KB, EC, SC, RD, Gd, SD, CD, MF, WG, MG, AH, AH, QJ, SL, JL, SL, AL, VL, JM, RN, KN, NS, LS, SS, MT, MW, DW, SW, AW, MW, ZX, RY, CY, AZ, WZ, AC, RS, SP, RW, CC, JE is employed by Xenon Pharmaceuticals, Inc and may hold equity in Xenon Pharmaceuticals, Inc, PT, DB was previously employed by Xenon Pharmaceuticals, Inc and may hold equity in Xenon Pharmaceuticals, Inc, (© 2022, Johnson et al.)

We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of Na V 1.5. Unlike local anesthetics that are currently used for treatment of Long QT Syndrome 3 (LQT-3), the most potent compound (-)-6 in this series shows high selectivity over hERG and other cardiac ion channels and has a low brain to plasma ratio to minimize CNS side effects. Compound (-)-6 is also effective inshortening prolonged action potential durations (APDs) in a pharmacological model of LQT-3 syndrome in pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Unlike most aryl sulfonamide Na V inhibitors that bind to the channel voltage sensors, these Na V 1.5 inhibitors bind to the local anesthetic binding site in the central pore of the channel., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Case: A 19 year-old male patient presented with testicular dislocation after abdominopelvic trauma. During open reduction and internal fixation, consult to urology was placed after discovering the presence of the intra-abdominal testicle. The testicle was repositioned into the scrotum with orchiopexy, and pelvic fixation was completed with 1 sacroiliac percutaneous screw and pubic symphysis fixation. Postoperative recovery was uneventful, and the patient was discharged home on postoperative day 3., Conclusion: Testicular dislocation is an uncommon finding after blunt abdominopelvic trauma; hence, it may be overlooked. Prompt diagnosis of testicular dislocation given the need for operative management to preserve testicle viability is crucial., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B554)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

The sustained use of intraoperative fluoroscopy has led to increased use of minimally invasive surgical techniques, enhanced surgeon proficiency, improved anatomic corrections, reduced patient morbidity, earlier functional recovery, and decreased length of hospital stay. As a result, orthopedic attending surgeons and residents are exposed to more radiation, increasing the risk of cancer and radiation-induced cataracts compared with the general population and those who work in other surgical specialties. The magnitude of radiation exposure depends on the susceptibility of the tissues affected, medical specialty, the position of the C-arm, distance from the radiation beam, level of difficulty of the surgical procedure, surgeon experience, level of resident training, and level of supervision by the attending surgeon. However, little information is available on the effect of supervision level on radiation exposure for orthopedic senior residents. The goal of this study was to investigate whether level of supervision by the attending surgeon affects the radiation exposure of orthopedic senior residents during surgical treatment of proximal femur fracture with cephalomedullary nail fixation. This retrospective cohort study was performed from January 2019 to March 2019. No significant relationship between supervision level and radiation exposure of senior residents was observed. Supervision level does not significantly affect radiation exposure for senior residents; therefore, the implementation of standardized training in radiation safety may be a more essential measure to decrease radiation exposure. [ Orthopedics . 2021;44(3):e402-e406.].

Na v 1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 ( 1 ) and GDC-0310 ( 2 ), selective Na v 1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3 . This resulted in the discovery of GDC-0276 ( 1 ), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Na v 1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 ( 2 ), which possesses improved Na v selectivity and pharmacokinetic profile over 1 .

Introduction: Demographic and socioeconomic factors are important determinants that may affect patient self-reported outcomes after acetabular fracture surgery. Hispanics, as a minority group, have an increased tendency to suffer demographic and socioeconomic disparities. At the present time, there is scant information regarding their role among Hispanic patients with acetabular fractures. The aim of this study was to investigate whether demographic or socioeconomic factors would affect satisfaction and self-reported functional outcomes in Hispanic patients who endured open reduction and internal fixation (ORIF) of posterior wall fractures of the acetabulum., Methods: A cross-sectional study of 78 patients with posterior wall fracture of the acetabulum treated with ORIF from 2011 to 2017 was performed. Data from demographics (age, sex, and body mass index [BMI]) and socioeconomic factors (household income, highest educational level achieved, employment status, type of medical insurance, workers' compensation involvement, and injury-related litigation process) were obtained and compared with the Short Musculoskeletal Form Assessment-46 (SMFA-46) questionnaire using a multivariable logistic regression analysis., Results: Unemployment was the most significant variable associated with dissatisfaction among 15 of the 46 responses of the SMFA-46 (P < 0.048). Patients who had an overweight or obese BMI and had an age of 41 years or older exhibited significantly worse outcomes in 7 of the 46 questions (P < 0.049). Finally, women were less likely to be satisfied in 1 of the 46 questions (P = 0.028). No notable difference was observed in any of the SMFA-46 responses regarding insurance plan, educational level, workers' compensation involvement, and injury-related litigation process., Discussion: A strong association exists between dissatisfaction after ORIF of posterior wall fractures of the acetabulum and employment status, BMI, and age among the Hispanic population. Addressing socioeconomic factors can be critical to overcome dissatisfaction and improve functional status among Hispanic patients with acetabular fractures., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Nonselective antagonists of voltage-gated sodium (Na V ) channels have been long used for the treatment of epilepsies. The efficacy of these drugs is thought to be due to the block of sodium channels on excitatory neurons, primarily Na V 1.6 and Na V 1.2. However, these currently marketed drugs require high drug exposure and suffer from narrow therapeutic indices. Selective inhibition of Na V 1.6, while sparing Na V 1.1, is anticipated to provide a more effective and better tolerated treatment for epilepsies. In addition, block of Na V 1.2 may complement the anticonvulsant activity of Na V 1.6 inhibition. We discovered a novel series of aryl sulfonamides as CNS-penetrant, isoform-selective Na V 1.6 inhibitors, which also displayed potent block of Na V 1.2. Optimization focused on increasing selectivity over Na V 1.1, improving metabolic stability, reducing active efflux, and addressing a pregnane X-receptor liability. We obtained compounds 30-32 , which produced potent anticonvulsant activity in mouse seizure models, including a direct current maximal electroshock seizure assay.

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide Na V 1.7 inhibitors that are selective for Na V 1.7 over Na V 1.5 and highly efficacious in in vivo models of pain and hNa V 1.7 target engagement. An analysis of the physicochemical properties of literature Na V 1.7 inhibitors suggested that acyl sulfonamides with high f sp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against Na V 1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNa V 1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the Na V 1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious Na V 1.7 inhibitors reported to date.

The sodium channel Na V 1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of Na V 1.7, with high selectivity over the cardiac isoform Na V 1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective Na V 1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of Na V 1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.

The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of over 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. It is once again a 5-day week long event - a full immersion bioanalytical week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations that emerged from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to advance scientific excellence, improve quality and deliver better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 1 covers the recommendations for small molecule bioanalysis using LCMS. Part 2 (hybrid LBA/LCMS and regulatory agencies' inputs) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will also be published in volume 7 of Bioanalysis, issues 23 and 24, respectively.

Endothelial lipase (EL) activity has been implicated in HDL metabolism and in atherosclerotic plaque development; inhibitors are proposed to be efficacious in the treatment of dyslipidemia related cardiovascular disease. We describe here the discovery of a novel class of anthranilic acids EL inhibitors. XEN445 (compound 13) was identified as a potent and selective EL inhibitor, that showed good ADME and PK properties, and demonstrated in vivo efficacy in raising plasma HDLc concentrations in mice., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In this study we demonstrate the use of a multiplexed MRM-based assay to distinguish among normal (NL) and iron-metabolism disorder mouse models, particularly, iron-deficiency anemia (IDA), inflammation (INFL), and inflammation and anemia (INFL+IDA). Our initial panel of potential biomarkers was based on the analysis of 14 proteins expressed by candidate genes involved in iron transport and metabolism. Based on this study, we were able to identify a panel of 8 biomarker proteins: apolipoprotein A4 (APO4), transferrin, transferrin receptor 1, ceruloplasmin, haptoglobin, lactoferrin, hemopexin, and matrix metalloproteinase-8 (MMP8) that clearly distinguish among the normal and disease models. Within this set of proteins, transferrin showed the best individual classification accuracy over all samples (72%) and within the NL group (94%). Compared to the best single-protein biomarker, transferrin, the use of the composite 8-protein biomarker panel improved the classification accuracy from 94% to 100% in the NL group, from 50% to 72% in the INFL group, from 66% to 96% in the IDA group, and from 79% to 83% in the INFL+IDA group. Based on these findings, validation of the utility of this potentially important biomarker panel in human samples in an effort to differentiate IDA, inflammation, and combinations thereof, is now warranted. This article is part of a Special Section entitled: Understanding genome regulation and genetic diversity by mass spectrometry., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: To study the predictors of abnormal fetal growth in diabetic pregnancy, analyzing the role of fetal sex., Study Design: Observational retrospective study was carried out in a University hospital. We studied 2833 newborns of diabetic mothers who attended the Diabetes and Pregnancy Clinic and delivered in the center between 1/1/1982 and 31/12/2006 (2370 born to women with gestational diabetes mellitus, 391 to women with type 1 diabetes mellitus (DM), and 72 to women with type 2 DM). Logistic regression analyses were performed with a backward method to predict large for gestational age (LGA), small for gestational age (SGA) and macrosomic newborns using relevant variables and their interaction with fetal sex. We have used as potential predictors of abnormal birth weight: maternal prepregnancy age, weight, height and body mass index, prior pregnancy, prior macrosomia, smoking habit, weight increase during pregnancy, hypertension, gestational age at delivery, twin pregnancy, fetal sex, diabetes type, third trimester HbA1c and interaction of fetal sex with all these variables., Results: Variables predictive of LGA, SGA and macrosomia were as formerly described. Moreover, some predictors of abnormal growth displayed an interaction with fetal sex. In LGA prediction, male sex displayed a positive interaction with delivery week, prior gestation, diabetes type and twin pregnancy and a negative one with weight increase. In SGA prediction, male sex displayed a positive interaction with delivery week and diabetes type. In macrosomia prediction, male sex displayed a negative interaction with weight increase., Conclusions: In this cohort of diabetic pregnancies, some predictors of abnormal birth weight display interaction with fetal sex. In general, associations were more favorable to female fetuses., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)