bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonal variations of the thermohaline structure in the Magdalena-Almejas Bay lagoon system and adjacent sea
Authors: Zaitsev O , Sánchez-Montante O , Saldivar-Reyes M
Published: September 2012

The seasonal variability of sea surface temperature (SST) in the Magdalena-Almejas Bay lagoon system (Mexico) and adjacent oceanic region was characterized in terms of the averaged monthly SST distributions obtained from AVHRR satellite images during the period 1996–2001. Additionally, oceanographic data obtained during five sampling campaigns were analyzed. A regional subdivision of the study area was made in relation to the main physical processes affecting the thermohaline structure, such as upwelling, tidal transport, and surface heat fluxes. Annual cycles of monthly mean SST for these subregions showed that during the period from April to September the inner lagoon water was warmer than the adjacent oceanic water, with a maximum difference of 1.3ºC in June. During the period from October to February, the SST inside the lagoon system was lower than in the adjacent ocean (by up to –1.5ºC in December). These results are discussed in terms of upwelling activity in the adjacent oceanic region and winter cooling effects on the surface, particularly in Almejas Bay. Most of the system (about 70% of its surface) is characterized by vertical homogeneity. Thermohaline stratification modulated by coastal upwelling activity in the adjacent oceanic region is observed in the deepest part of the lagoon system (greater than 15 m), especially during the spring and summer. The oceanic conditions frequently observed in this subregion of Magdalena Bay are hypothetically explained by the combined action of coastal upwelling and horizontal tidal transport. These local effects were more evident during the flood, when a strong tidal flow (up to 1.1 m s–1) produced intense vertical mixing of near-bottom cold water with upper layer water leading to reduced SST values.
Micropatterning Different Cell Types with Microarray Amplification of Natural Directional Persistence
Authors: Mun Kyu‐Shik , Kumar Girish , Co Carlos C. , Ho Chia‐Chi
Published: September 2012

In vivo, different cell types assemble in specific patterns to form functional tissues. Reproducing this process in vitro by designing scaffold materials to direct cells precisely to the right locations at the right time is important for the next generation of biomaterials. Here, using microarray amplification of natural directional persistence (MANDIP), simultaneous assembly of fibroblasts and endothelial cells is demonstrated by directing their long‐range migration. Amplification of the directional persistence occurs through morphology‐induced polarity and the asymmetric positioning of individual microsized adhesive islands that restrict lamellipodia attachment, and thus migration, to one preset direction. Quantitative analysis of cell migration on different MANDIP designs yields insight to the relative importance of the asymmetric island shapes and their arrangement. The approach enables spatial patterning of different cell types with micrometer‐scale precision over large areas for investigation of cell‐cell interactions within complex tissue architectures.
Simulation of the Tape‐Laying Process for Thermoplastic Matrix Composites
Authors: Narnhofer M. , Schledjewski R. , Mitschang P. , Perko L.
Published: September 2012

The paper presents an overview of the tape‐laying process for thermoplastic matrix composites and the current state‐of‐the‐art simulation of this process. As the current mathematical description of the process is partly based on a Newtonian shear flow and thermoplastics normally show a shear thinning behavior at higher shear rates, the assumption of a Newtonian shear flow has been verified. Therefore, the occurring shear rates have been calculated and compared with the data of a viscosity plot for a polyether ether ketone material. As a result of this analysis, the assumption of Newtonian shear flow is shown to be an oversimplification. © 2012 Wiley Periodicals, Inc. Adv Polym Techn 32: E705–E713, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/adv.21312
Layered double hydroxide platelets exfoliation into a water‐based polyester
Authors: Swanson C.H. , Stimpfling T. , Troutier‐Thulliez A.‐L. , Hintze‐Bruening H. , Leroux F.
Published: September 2012

Nitrate layered double hydroxide (LDH) phase Zn2Al(OH)6(NO3)·2H2O is successfully exfoliated in the presence of polyester under mild conditions using water as essential solvent and at room temperature under air. From small angle X‐ray scattering spectroscopy a total exfoliation is found to be achieved using up to 10 wt % LDH, while intercalated polymer nanocomposite structures largely extended up to 14 nm are observed for loading ranging from 10 to 20 wt %. The process is found to be explained by the diffusion of the polymer chain into the interlayer host structure. Starting from an initial value of 0.89 nm, ≈3, 7, 10, 14, and 20 nm transient interleaved nanostructures are formed without any carbonate uptake. The collective gap distance is certainly due to a defined number of polymer chains diffusing into the LDH interstices. Similarly, starting from an aqueous polyester solution highly concentrated in LDH nitrate phase up to 50% w.w, successive dilutions yield platelet exfoliation, thus rendering a smooth chemistry process attractive for potential applications. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Should Y stay or should Y go: The evolution of non‐recombining sex chromosomes
Authors: Sun Sheng , Heitman Joseph
Published: September 2012

Gradual degradation seems inevitable for non‐recombining sex chromosomes. This has been supported by the observation of degenerated non‐recombining sex chromosomes in a variety of species. The human Y chromosome has also degenerated significantly during its evolution, and theories have been advanced that the Y chromosome could disappear within the next ∼5 million years, if the degeneration rate it has experienced continues. However, recent studies suggest that this is unlikely. Conservative evolutionary forces such as strong purifying selection and intrachromosomal repair through gene conversion balance the degeneration tendency of the Y chromosome and maintain its integrity after an initial period of faster degeneration. We discuss the evidence both for and against the extinction of the Y chromosome. We also discuss potential insights gained on the evolution of sex‐determining chromosomes by studying simpler sex‐determining chromosomal regions of unicellular and multicellular microorganisms.
Anion exchange membrane adsorbers for flow‐through polishing steps: Part II. Virus, host cell protein, DNA clearance, and antibody recovery
Authors: Weaver Justin , Husson Scott M. , Murphy Louise , Wickramasinghe S. Ranil
Published: September 2012

Anion exchange membrane adsorbers are used for contaminant removal in flow‐through polishing steps in the manufacture of biopharmaceuticals. This contribution describes the clearance of minute virus of mice, DNA, and host cell proteins by three commercially available anion‐exchange membranes: Sartobind Q, Mustang Q, and ChromaSorb. The Sartobind Q and Mustang Q products contain quaternary amine ligands; whereas, ChromaSorb contains primary amine based ligands. Performance was evaluated over a range of solution conditions: 0–200 mM NaCl, pH 6.0–9.0, and flow rates of 4–20 membrane volumes/min in the presence and absence of up to 50 mM phosphate and acetate. In addition contaminant clearance was determined in the presence and absence of 5 g/L monoclonal antibody. The quaternary amine based ligands depend mainly on Coulombic interactions for removal of negatively charged contaminants. Consequently, performance of Sartobind Q and Mustang Q was compromised at high ionic strength. Primary amine based ligands in ChromaSorb enable high capacities at high ionic strength due to the presence of secondary, hydrogen bonding interactions. However, the presence of hydrogen phosphate ions leads to reduced capacity. Monoclonal antibody recovery using primary amine based anion‐exchange ligands may be lower if significant binding occurs due to secondary interactions. The removal of a specific contaminant is affected by the level of removal of the other contaminants. The results of this study may be used to help guide selection of commercially available membrane absorbers for flow‐through polishing steps. Biotechnol. Bioeng. 2013; 110: 500–510. © 2012 Wiley Periodicals, Inc.
Cardiac myocytes' dynamic contractile behavior differs depending on heart segment
Authors: De Souza Emerson J. , Ahmed Wylie , Chan Vincent , Bashir Rashid , Saif Taher
Published: September 2012

Cardiac myocytes originating from different parts of the heart exhibit varying morphology and ultrastructure. However, the difference in their dynamic behavior is unclear. We examined the contraction of cardiac myocytes originating from the apex, ventricle, and atrium, and found that their dynamic behavior, such as amplitude and frequency of contraction, differs depending on the heart segment of origin. Using video microscopy and high‐precision image correlation, we found that: (1) apex myocytes exhibited the highest contraction rate (∼17 beats/min); (2) ventricular myocytes exhibited the highest contraction amplitude (∼5.2 micron); and (3) as myocyte contraction synchronized, their frequency did not change significantly, but the amplitude of contraction increased in apex and ventricular myocytes. In addition, as myocyte cultures mature they formed contractile filaments, further emphasizing the difference in myocyte dynamics is persistent. These results suggest that the dynamic behavior (in addition to static properties) of myocytes is dependent on their segment of origin. Biotechnol. Bioeng. 2013; 110: 628–636. © 2012 Wiley Periodicals, Inc.
Exocyclic Bond Cleavage in Oxaphosphirane Complexes?
Authors: Espinosa Arturo , Streubel Rainer
Published: September 2012

A first computational insight into the intrinsic strength of exocyclic bonds to phosphorus in oxaphosphirane κP‐pentacarbonylmetal(0) complexes1 a–f(M=Cr, Mo) is provided using a set of PR derivatives (R=Me,tBu, CPh3). Whereas homolytic cleavage of the exocyclic PR bond was found to be always unfavored (for neutral complexes), heterolytic cleavage leading to a carbocation R+moiety and the oxaphosphiranide complex2−constitutes the lowest‐energy process, especially if R is bulky and can stabilize the positive charge, that is, triphenylmethyl (trityl), efficiently. The energies required for PM bond cleavage are about 30 kcal mol−1, and decrease with the increasing bulk of the R substituent (from Me to trityl) and ongoing from Cr to Mo. The reactivities of complexes1 a–ftowards oxidative and reductive single electron transfer (SET) reactions were analyzed using the facile variation of bond‐strength‐related descriptors (VBSD) methodology, thus enabling the design of synthetically useful strategies addressing decomplexation and P‐functionalization. Reductive SET reactions with sodium naphthalenides enable selective PM bond cleavage (i.e., decomplexation) for the case of P‐Me and P‐tBu substitution, whereas reductive PR bond cleavage is favored in the case of the P‐trityl complexes1 c,f, and results in the formation of the (anionic) oxaphosphiranide complex2−, which may be regarded as a potential key intermediate for further P‐functionalization.
Efficiency of Resources for Production of Density Reduced Steels by Direct Strip Casting
Authors: Klöpfer Eugenie , Bach Friedrich‐Wilhelm , Evertz Thomas , Otto Manuel , Redenius Alexander
Published: September 2012

Das Bandgießen bietet beachtliche Chancen zur energieeffizienten und ressourcenschonenden Erzeugung von Warmband bei gleichzeitig erheblichen Anforderungen an die Anlagen‐ und Prozessentwicklung des endabmessungsnahen Gießverfahrens. Das Verfahren ermöglicht insbesondere die Herstellung von hochmanganhaltigen Stählen, wie dem HSD®‐Stahl oder weiter dichtereduzierten Stahlsorten. Im ersten Schritt wurde der Al‐Gehalt bis zu 8 Gew.‐% variiert, die mechanisch‐technologischen und physikalischen Eigenschaften sind hier dargestellt.
Health‐related quality of life among survivors of aggressive non‐Hodgkin lymphoma
Authors: Jensen Roxanne E. , Arora Neeraj K. , Bellizzi Keith M. , Rowland Julia H. , Hamilton Ann S. , Aziz Noreen M. , Potosky Arnold L.
Published: September 2012

BACKGROUND:

Non‐Hodgkin lymphoma (NHL) is the fifth most common cancer among men and women. Patients with aggressive NHL receive intense medical treatments that can significantly compromise health‐related quality of life (HRQOL). However, knowledge of HRQOL and its correlates among survivors of aggressive NHL is limited.

METHODS:

Self‐reported data on HRQOL (physical and mental function, anxiety, depression, and fatigue) were analyzed for 319 survivors of aggressive NHL. Survivors 2 to 5 years postdiagnosis were selected from the Los Angeles County Cancer Registry. Bivariate and multivariable methods were used to assess the influence of sociodemographic, clinical, and cognitive health‐appraisal factors on survivors' HRQOL.

RESULTS:

After accounting for other covariates, marital status was associated with all HRQOL outcomes (P < .05). Younger survivors reported worse mental function and higher levels of depression, anxiety, and fatigue (P < .01). Survivors who had more comorbid conditions or lacked private health insurance reported worse physical and mental function and higher levels of depression and fatigue (P < .05). Survivors who experienced a recurrence reported worse physical function and higher levels of depression and fatigue (P < .05). With the exception of a nonsignificant association between perceived control and physical function, greater perceptions of personal control and health competence were associated significantly with more positive HRQOL outcomes (P < .01).

CONCLUSIONS:

The current results indicated that survivors of aggressive NHL who are younger, are unmarried, lack private insurance, or experience greater illness burden may be at risk for poorer HRQOL. Cognitive health‐appraisal factors were strongly related to HRQOL, suggesting potential benefits of interventions focused on these mutable factors for this population. Cancer 2013. © 2012 American Cancer Society.
Small molecule inhibitors of RORγt: Targeting Th17 cells and other applications
Authors: Huh Jun R. , Littman Dan R.
Published: September 2012

Nuclear hormone receptors (NHRs) form a family of transcription factors that are composed of modular protein structures with DNA‐ and ligand‐binding domains (DBDs and LBDs). The DBDs confer gene target site specificity, whereas LBDs serve as control switches for NHR function. For many NHRs, both endogenous and synthetic small molecule ligands bind to small pockets within the LBDs, resulting in conformational changes that regulate transcriptional activity. This property of NHRs has been exploited by the pharmaceutical industry for therapeutic targeting of a wide variety of diseases, ranging from inflammatory diseases and cancer to endocrine and metabolic diseases. Th17 cells are CD4+ T helper effector cells that express several pro‐inflammatory cytokines, including IL‐17A, and the actions of these cells have been linked to multiple human autoimmune diseases. Our laboratory previously identified the NHR RORγt, an immune cell‐specific isoform of RORγ (retinoic acid receptor‐related orphan nuclear receptor gamma), as a key transcription factor for the development of Th17 cells both in human and mouse. Although endogenous ligands for RORγt have not yet been reported, it is thought that RORγt activity and Th17‐cell development can be modulated with highly specific small molecules that bind to the RORγt LBD and displace its endogenous ligands. Recent studies from multiple groups have reported the activities of such inhibitors. In this mini review, we describe how RORγt inhibitors were identified and how they may contribute to our understanding about RORγt and its biology.
T‐cell exhaustion due to persistent antigen: Quantity not quality?
Authors: Zuniga Elina I. , Harker James A.
Published: September 2012

T‐cell exhaustion is characterized by failure to respond to a persistent antigen and is a hallmark of chronic infections and cancer. Here, we discuss several recent reports on T‐cell exhaustion, including one in this issue of the European Journal of Immunology where Richter et al. [Eur. J. Immunol. 42:2290–2304] examine the importance of the amount of persistent antigen versus the cell type presenting it to induce CD8+ T‐cell exhaustion, and the consequences for host survival during chronic viral infection.
Diastereomeric Atropisomers from a Chiral Diyne by Cobalt(I)‐Catalyzed Cyclotrimerization
Authors: Fischer Fabian , Jungk Phillip , Weding Nico , Spannenberg Anke , Ott Holger , Hapke Marko
Published: September 2012

The reaction of new, chiral, proline‐based naphthyl diynes with different nitriles through a key [2+2+2] cycloaddition reaction step catalyzed by CoI–olefin complexes under thermal and photochemical conditions gave diastereomeric atropisomers in good yield and nearly 1:1 ratios. Facile chromatographic separation of the naphthyl tetrahydroisoquinolines gave access to both pure and stable diastereomeric atropisomers. The deprotection and direct functionalization of the methyl‐ or methoxymethyl‐protected 2‐naphthyl position of the atropisomers were investigated. The configuration of the formed atropisomers was assigned from results of X‐ray studies and circular dichroism spectroscopy.
4‐Phosphatephenyl Covalently Modified Glassy Carbon Electrode for Real‐Time Electrochemical Monitoring of Paracetamol Release from Electrospun Nanofibers
Authors: Yang Guocheng , Wang Lu , Yang Yingshu , Chen Xuesong , Zhou Defeng , Jia Jianbo , Li Dongfeng
Published: September 2012

A glassy carbon electrode (GCE) was covalently modified by 4‐phosphatephenyl (4‐PP). Sensing paracetamol (PCT) via linear sweep voltammetry in sulfuric buffer solution of pH 1.02 at 36.8 °C, the 4‐PP‐modified GCE showed high electrochemical sensitivity and long reusability. PCT‐loaded poly(vinyl alcohol) (PVA) nanofibers were prepared by electrospinning. Based on the calibration curve of PCT on the 4‐PP‐modified GCE, the PCT release process from the nanofibers was electrochemically monitored in real time via two routes. The results showed that the covalently modified GCE can be repeatedly used as real‐time electrochemical monitoring platform for drug release from drug‐loaded nanofibers in the long term.
Modeling Corrosion of Archaeological Silver‐Copper Coins Using the Voltammetry of Immobilized Particles
Authors: Doménech Antonio , Doménech‐Carbó María Teresa , Pasies Trinidad , del Carmen Bouzas María
Published: September 2012

Two complementary models to describe the long‐term corrosion of silver‐copper coins, based on potential rate laws for smooth corrosion and those combined with diffusive law, for gross corrosion, are proposed. Theoretical kinetics can be tested using signatures of copper and silver corrosion products using the voltammetry of immobilized particles technique. The method is applied to silver coins minted during the 13th–14th centuries from the Libertad street hoard in Valencia (Spain) using non‐invasive one‐touch graphite pencil sampling. Voltammetric features yield functional dependences in agreement with the proposed model potentially useful for distinguishing between different mints.
Reduced one‐dimensional modelling and numerical simulation for mass transport in fluids
Authors: Köppl T. , Wohlmuth B. , Helmig R.
Published: September 2012

On the basis of the Navier–Stokes equations in three space dimensions and a convection–diffusion equation, we use a nonlinear system of three hyperbolic PDEs in one space dimension to simulate mass transport. We focus on the modelling of mass transport at a bifurcation of a vessel. For the numerical treatment of the hyperbolic PDE system, we use stabilised discontinuous Galerkin (DG) approximations with a Taylor basis. DG approximations together with a suitable time integration method enable us to simulate wave propagations for many periods avoiding excessive dispersion and dissipation effects. However, standard DG approximations tend to create non‐physical oscillations at sharp fronts, and thus stabilisation techniques are required. Finally, we present some numerical results illustrating the robustness of our model and the numerical discretisation.Copyright © 2012 John Wiley & Sons, Ltd.
Intraventricular injection of FGF‐2 promotes generation of oligodendrocyte‐lineage cells in the postnatal and adult forebrain
Authors: Azim Kasum , Raineteau Olivier , Butt Arthur M.
Published: September 2012

FGF2 is considered a key factor in the generation of oligodendrocytes (OLs) derived from neural stem cells (NSCs) located within the subventricular zone (SVZ). Here, we have examined FGF2 signaling in the forebrain of postnatal and adult mice. Using qPCR of microdissected microdomains of the dorsal SVZ (dSVZ) and lateral SVZ (lSVZ), and prominin1‐sorted NSCs purified from these microdomains, we show that transcripts for FGF receptor 1 (FGFR1) and FGFR2 are enriched in the dSVZ, from which OLs are largely derived, whereas FGFR3 are significantly enriched within prominen1‐sorted NSC of the lSVZ, which mainly generate olfactory interneurons. We show that direct administration of FGF2 into the lateral ventricle increased the generation of oligodendrocyte progenitors (OPCs) throughout the SVZ, both within the dSVZ and ectopically in the lSVZ and ependymal wall of the SVZ. Furthermore, FGF2 stimulated proliferation of neural progenitors (NPs) and their differentiation into OPCs. The results indicate that FGF2 increased specification of OPCs, inducing NPs to follow an oligodendrocyte developmental pathway. Notably, FGF2 did not block OPC differentiation and increased the number of oligodendrocytes in the periventricular white matter (PVWM) and cortex. However, FGF2 markedly disrupted myelination in the PVWM. A key finding was that FGF2 had equivalent actions on the generation of OPCs and myelin disruption in postnatal and adult mice. This study demonstrates a central role for FGF2 in promoting oligodendrocyte generation in the developing and adult brain. © Wiley Periodicals, Inc.
Loss of PBRM1 expression is associated with renal cell carcinoma progression
Authors: Pawłowski Rafal , Mühl Sarah M. , Sulser Tullio , Krek Wilhelm , Moch Holger , Schraml Peter
Published: September 2012

Although von Hippel‐Lindau (VHL) tumor suppressor gene alterations dominate the genetic landscape of clear cell renal cell carcinoma (ccRCC), recent studies have identified new ccRCC genes, including SETD2, KDM6A, KDM5C, BAP1 and PBRM1. Strikingly, all these genes fall into a category of histone/chromatin regulators. Polybromo‐1 (PBRM1) is the second most frequently mutated gene after VHL; however, the clinical relevance of its loss in ccRCC has not yet been reported. Here, we analyzed the expression of PBRM1, the product encoded by PBRM1, in ccRCC cell lines and in more than 300 RCC tumor samples. The data were correlated with clinicopathological parameters and VHL mutation status. We found that a significant number of ccRCC cancer cell lines lack detectable PBRM1 expression. Loss of PBRM1 was predominant in the clear cell subtype of RCC (∼ 70%) and correlated with advanced tumor stage (p < 0.0001), low differentiation grade (p = 0.0002) and worse patient outcome (p = 0.025), but not with the VHL mutation status. Our results indicate a critical role for PBRM1 in the suppression of ccRCC progression. Moreover, the results suggest that functional inactivation of PBRM1 in the context of pVHL loss‐of‐function may represent a key event in facilitating the development of key aspects of an aggressive tumor behavior. Given the role of PBRM1 in chromatin modification, the gene expression pathways disrupted by the inactivation of this protein may lead to new treatment strategies for ccRCC.
Antifactor Xa Levels versus Activated Partial Thromboplastin Time for Monitoring Unfractionated Heparin
Authors: Vandiver Jeremy W. , Vondracek Thomas G.
Published: September 2012

Intravenous unfractionated heparin (UFH) remains an important therapeutic agent, particularly in the inpatient setting, for anticoagulation. Historically, the activated partial thromboplastin time (aPTT) has been the primary laboratory test used to monitor and adjust UFH. The aPTT test has evolved since the 1950s, and the historical goal range of 1.5–2.5 times the control aPTT, which first gained favor in the 1970s, has fallen out of favor due to a high degree of variability in aPTT readings from one laboratory to another, and even from one reagent to another. As a result, it is now recommended that the aPTT goal range be based on a corresponding heparin concentration of 0.2–0.4 unit/ml by protamine titration or 0.3–0.7 unit/ml by antifactor Xa assay. Given that several biologic factors can influence the aPTT independent of the effects of UFH, many institutions have transitioned to monitoring heparin with antifactor Xa levels, rather than the aPTT. Clinical data from the last 10–20 years have begun to show that a conversion from aPTT to antifactor Xa monitoring may offer a smoother dose‐response curve, such that levels remain more stable, requiring fewer blood samples and dosage adjustments. Given the minimal increased acquisition cost of the antifactor Xa reagents, it can be argued that the antifactor Xa is a cost‐effective method for monitoring UFH. In this review, we discuss the relative advantages and disadvantages of the aPTT, antifactor Xa, and protamine titration tests, and provide a clinical framework to guide practitioners who are seeking to optimize UFH monitoring within their own institutions.
Hypoglycemia in Hospitalized Patients Treated with Sulfonylureas
Authors: Deusenberry Christina M. , Coley Kim C. , Korytkowski Mary T. , Donihi Amy C.
Published: September 2012

Study Objective

To identify the incidence of and risk factors associated with hypoglycemia in hospitalized patients taking sulfonylureas.

Design

Nested case‐control study.

Setting

Tertiary care academic medical center.

Patients

Adults who received a sulfonylurea during hospitalization between November 1, 2008, and October 31, 2009. Case patients were those who experienced at least one episode of hypoglycemia, defined as a blood glucose level less than 70 mg/dl; potential control patients were those who did not experience hypoglycemia. One hundred seventeen cases were matched in a 1:1 ratio with controls based on sex and the number of days treated with a sulfonylurea in the hospital. For case patients, the index date was defined as the date of first blood glucose level less than 70 mg/dl. The number of days that the patient was taking the sulfonylurea before the index date was determined, and this same number was used to define the index date for the matched controls.

Measurements and Main Results

Overall, 19% of patients who received a sulfonylurea experienced at least one episode of hypoglycemia: 22% receiving glyburide, 19% receiving glimepiride, and 16% receiving glipizide. Variables included in the multivariate regression were age 65 years or older, glomerular filtration rate (GFR)≤30 ml/min/1.73 m2, and treatment with glipizide, glyburide, or concurrent intermediate‐ or long‐acting insulin. Age 65 years or older (odds ratio [OR] 3.07, p < 0.001), intermediate‐ or long‐acting insulin (OR 3.01, p=0.002), and GFR of 30 ml/minute/1.73 m2 or lower (OR 3.64, p=0.006) were predictors of hypoglycemia. Cases were less likely than controls to receive glipizide (OR 0.44, p=0.005).

Conclusion

Hospitalized patients at increased risk for sulfonylurea‐related hypoglycemia were those aged 65 years or older, those with a GFR of 30 ml/minute/1.73 m2 or lower, and those who received concurrent intermediate‐ or long‐acting insulin during inpatient sulfonylurea therapy. Sulfonylureas should be avoided or used with caution in these patients.
Denosumab for the Prevention of Skeletal‐Related Events in Patients with Bone Metastasis from Solid Tumor
Authors: Iranikhah Maryam , Wilborn Teresa W. , Wensel Terri M. , Ferrell Jodi B.
Published: September 2012

Most patients with advanced malignancy develop bone metastases during the course of their disease. For the remainder of the patient's life, these bone metastases lead to skeletal‐related events such as pathologic fractures and spinal cord compression, as well as bone pain or lesions requiring palliative radiation therapy or surgery to prevent or treat fractures. Skeletal‐related events result in increased morbidity, mortality and health care costs. For the past decade, intravenous bisphosphonates (zoledronic acid, pamidronate) have been recognized as the primary pharmacologic options in the prevention or treatment of skeletal‐related events in patients with bone metastasis. Recently, the United States Food and Drug Administration approved denosumab, a fully human monoclonal antibody, for the prevention of skeletal‐related events in patients with bone metastases from solid tumors. Three prominent clinical trials were conducted to establish the efficacy of denosumab. In two of three trials, denosumab was found to delay the time to first skeletal‐related event significantly more than zoledronic acid in patients with breast or castration‐resistant prostate cancer with bone metastasis. The third trial found denosumab to be noninferior to zoledronic acid in patients with metastases from solid tumors, excluding breast and prostate solid tumors. Overall survival and progression‐free survival were similar between zoledronic acid and denosumab. Thus, evidence is insufficient to prove a greater efficacy of one agent over the other. According to the American Society of Clinical Oncology and the National Comprehensive Cancer Network, patients with bone metastasis should have zoledronic acid, pamidronate, or denosumab (with calcium and vitamin D supplementation) added to their chemotherapy regimen if they have an expected survival of 3 months or longer and have adequate renal function.
The CHADS2 versus the New CHA2DS2‐VASc Scoring Systems for Guiding Antithrombotic Treatment of Patients with Atrial Fibrillation: Review of the Literature and Recommendations for Use
Authors: Odum Lauren E. , Cochran Kelly A. , Aistrope Daniel S. , Snella Kathleen A.
Published: September 2012

The association of atrial fibrillation and resultant thromboembolic stroke is readily recognized in the published literature. However, the identification and weight of other risk factors that increase stroke risk are varied. To predict which patients are at greatest risk for thromboembolic stroke, numerous risk stratification schemas have been developed to guide thromboprophylactic treatment decisions. The well‐known CHADS2 scoring system incorporates risk factors such as congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and previous stroke or transient ischemic attack. Recently, a novel risk stratification model, CHA2DS2‐VASc, has entered the literature and international guidelines, prompting further review of newly added risk factors—age 65–74 years, presence of vascular disease, and female sex—and the increased allotment of 2 points (vs 1 point in CHADS2) for age 75 years or older. The rationale for CHA2DS2‐VASc, as put forth by its authors, is that other risk assessment models omit important risk factors, have low predictive ability, and categorize too many patients as intermediate risk, leaving the choice of anticoagulant or antiplatelet therapy to the discretion of the clinician. Although CHA2DS2‐VASc readily identifies those patients truly at low risk, it classifies more patients as high risk who would then receive anticoagulation therapy. Therefore, implementation of this risk schema warrants further evaluation, especially when weighing the risk for bleeding and the risk for stroke. This critical review provides practitioners with an understanding of the literature that prompted the inclusion of these new risk factors and increased point allocations, compares and contrasts the risk schemas, and reviews national and international guidelines, thereby equipping the health care provider with the knowledge to aid clinical decision‐making.
Hemopericardium in a Patient Treated with Dabigatran Etexilate
Authors: Barton Cassie A. , McMillian Wesley D. , Sadi Raza S. , Keller Ray E.
Published: September 2012

Dabigatran etexilate is a new oral anticoagulant used for the prevention of systemic thromboembolism in patients with atrial fibrillation. Acute bleeding episodes are known to occur with dabigatran etexilate therapy; however, only a few case reports in the literature describe such events. We describe a 70‐year‐old man treated with dabigatran etexilate for newly diagnosed, nonvalvular atrial fibrillation who developed a large hemopericardium that appeared to be temporally related to dabigatran etexilate administration. One month after starting the drug, an incidental finding of a small pericardial effusion was found on echocardiography. One month later, the patient came to his pulmonologist's office complaining of shortness of breath; a large pericardial effusion was found on a noncontrast computed tomographic scan, and the patient was admitted to the hospital. Laboratory monitoring of his coagulation status was limited due to the lack of assays available to directly monitor the therapeutic effects of dabigatran. The internal laboratory was able to perform a dilute thrombin time (DTT) test as part of a quality improvement project aiming to validate an assay for monitoring patients receiving dabigatran therapy. A DTT was therefore performed in conjunction with routine coagulation assays to evaluate the patient's coagulation status. After pericardiocentesis, the patient recovered without incident and was discharged without anticoagulant therapy. Although the Naranjo adverse reaction probability scale only indicated a possible relationship (score of 1) between the patient's development of hemopericardium and dabigatran etexilate therapy, investigation into the patient's clinical course, comorbidities, and laboratory results led us to conclude that dabigatran etexilate was responsible for the hemopericardium. To our knowledge, this report is the first to describe a case of potentially life‐threatening pericardial bleeding that was temporally related to starting dabigatran etexilate therapy. Although we found that the DTT was a viable method of monitoring coagulation status in a patient receiving dabigatran etexilate therapy, the assay lacks approval by the United States Food and Drug Administration, which limits its clinical utility and widespread use at this time. Clinicians should be aware of the potential for life‐threatening bleeding with use of this agent and the difficulty associated with monitoring and reversing this therapy in the setting of acute bleeding.
Measuring and Reporting of the Treatment Effect of Hormonal Emergency Contraceptives
Authors: Leung Vivian W. Y. , Soon Judith A. , Levine Marc
Published: September 2012

Study Objectives

To derive summary estimates of observed pregnancy rates in women who used the Yuzpe or levonorgestrel emergency contraceptive regimen and identify the various ways in which data related to regimen effectiveness were reported, to discuss the limitations of the effectiveness estimates as they are currently reported, and to propose alternative reporting methods that are less susceptible to misinterpretation.

Design

Analysis of pooled data from 34 experimental or observational studies that had an explicit method of follow‐up to systematically evaluate pregnancy outcome after a single course of emergency contraception treatment within a given menstrual cycle.

Patients

Women who took either the Yuzpe or levonorgestrel emergency contraceptive regimen to prevent pregnancy.

Measurements and Main Results

We searched the MEDLINE and EMBASE databases for clinical studies that systematically evaluated pregnancy outcomes of women who used the Yuzpe or levonorgestrel regimen for emergency contraception. The effectiveness of these regimens is typically reported in relative terms as the reduction of pregnancy risk from a theoretical baseline risk. We reported the effectiveness using absolute risk reductions and numbers needed to treat. We pooled relevant data by using the β‐binomial method to derive observed pregnancy rates. The pooled observed pregnancy rates for studies of the Yuzpe and levonorgestrel regimens were 2.0% (95% confidence interval [CI] 1.5–2.5%) and 1.7% (95% CI 1.2–2.2%), respectively. Against expected pregnancy rates of 4–8%, relative emergency contraceptive effectiveness ranges were 50.0–75.0% and 57.5–78.8% for the Yuzpe and levonorgestrel regimens, respectively. Absolute risk reductions were 2.0–6.0% and 2.3–6.3%, respectively. This means that 17–50 women would need to have received the Yuzpe regimen and 16–43 women the levonorgestrel regimen to prevent one pregnancy.

Conclusion

Emergency contraception effectiveness data are susceptible to misinterpretation when data are reported in relative terms without the expected pregnancy rate (i.e., the baseline risk). We recommend that the effect of emergency contraceptives be expressed in absolute terms and accompanied by the expected pregnancy rate used in its estimation.
Cost‐Effectiveness of Cytochrome P450 2C19 Genotype Screening for Selection of Antiplatelet Therapy with Clopidogrel or Prasugrel
Authors: Reese Emily S. , Daniel Mullins C. , Beitelshees Amber L. , Onukwugha Eberechukwu
Published: September 2012

Study Objective

To estimate the cost‐effectiveness of genotype‐guided selection of antiplatelet therapy compared with selecting clopidogrel or prasugrel irrespective of genotype.

Design

Decision model based on event occurrence in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON‐TIMI) 38.

Patients

Simulated cohort of patients with acute coronary syndrome scheduled to undergo percutaneous coronary intervention (PCI), consisting of three arms: those receiving genotype‐guided antiplatelet therapy with clopidogrel or prasugrel, those receiving clopidogrel regardless of genotype, and those receiving prasugrel regardless of genotype.

Measurements and Main Results

All three arms of the model incorporated the probability that patients would experience a cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), a bleeding event (major or minor bleeding), or no event while receiving antiplatelet therapy during the 15 months after the scheduled PCI. The cytochrome P450 (CYP) 2C19 genotype determined antiplatelet drug selection in the genotyping group. Cost‐effectiveness was expressed as the incremental cost‐effectiveness ratio (ICER) for each event avoided in the genotype‐guided therapy arm versus the other two arms. Genotype‐guided antiplatelet therapy was dominant, or more effective and less costly, when compared with the selection of clopidogrel (ICER −$6760 [95% confidence interval (CI) −$6720 to −$6790]) or prasugrel (ICER −$11,710 [95% CI −$11,480 to −$11,950]) for all patients without regard to genotype. Genotype‐guided therapy that included generic clopidogrel was dominant to prasugrel for all patients (ICER −$27,160 [95% CI −$27,890 to −$26,420]). Cost savings were not evident when genotype‐guided therapy that included generic clopidogrel was compared with generic clopidogrel for all patients (ICER $2300 [95% CI $2290 to $2320]). [Correction added after online publication 12‐Mar‐2012: In the
previous sentence −$2300 has been corrected as $2300.].

Conclusion

Genotype‐guided antiplatelet therapy selection may be more cost‐effective and may provide more clinical value due to fewer adverse outcomes.
Effect of a Pharmacist‐Managed Hypertension Program on Health System Costs: An Evaluation of the Study of Cardiovascular Risk Intervention by Pharmacists—Hypertension (SCRIP‐HTN)
Authors: Houle Sherilyn K. D. , Chuck Anderson W. , McAlister Finlay A. , Tsuyuki Ross T.
Published: September 2012

Study Objective

To quantify the potential cost savings of a community pharmacy–based hypertension management program based on the results of the Study of Cardiovascular Risk Intervention by Pharmacists—Hypertension (SCRIP‐HTN) study in terms of avoided cardiovascular events—myocardial infarction, stroke, and heart failure hospitalization, and to compare these cost savings with the cost of the pharmacist intervention program.

Design

An economic model was developed to estimate the potential cost avoidance in direct health care resources from reduced cardiovascular events over a 1‐year period.

Measurements and Main Results

The SCRIP‐HTN study found that patients with diabetes mellitus and hypertension who were receiving the pharmacist intervention had a greater mean reduction in systolic blood pressure of 5.6 mm Hg than patients receiving usual care. For our model, published meta‐analysis data were used to compute cardiovascular event absolute risk reductions associated with a 5.6‐mm Hg reduction in systolic blood pressure over 6 months. Costs/event were obtained from administrative data, and probabilistic sensitivity analyses were performed to assess the robustness of the results. Two program scenarios were evaluated—one with monthly follow‐up for a total of 1 year with sustained blood pressure reduction, and the other in which pharmacist care ended after the 6‐month program but the effects on systolic blood pressure diminished over time. The cost saving results from the economic model were then compared with the costs of the program. Annual estimated cost savings (in 2011 Canadian dollars) from avoided cardiovascular events were $265/patient (95% confidence interval [CI] $63–467) if the program lasted 1 year or $221/patient (95%CI $72–371) if pharmacist care ceased after 6 months with an assumed loss of effect afterward. Estimated pharmacist costs were $90/patient for 6 months or $150/patient for 1 year, suggesting that pharmacist‐managed programs are cost saving, with the annual net total cost savings/patient estimated to be $131 for a program lasting 6 months or $115 for a program lasting 1 year.

Conclusion

Our model found that community pharmacist interventions capable of reducing systolic blood pressure by 5.6 mm Hg within 6 months are cost saving and result in improved patient outcomes. Wider adoption of pharmacist‐managed hypertension care for patients with diabetes and hypertension is encouraged.
Impact of Various Body Weights and Serum Creatinine Concentrations on the Bias and Accuracy of the Cockcroft‐Gault Equation
Authors: Winter Mary A. , Guhr Kelly N. , Berg Gina M.
Published: September 2012

Study Objective

To evaluate the impact of various body weights and serum creatinine (Scr) concentrations on the bias and accuracy of the Cockcroft‐Gault creatinine clearance (C‐G Clcr) equation compared with measured 24‐hour Clcr.

Design

Retrospective analysis.

Setting

Tertiary care hospital.

Patients

A total of 3678 patients with stable renal function and who underwent a 24‐hour urine collection between July 1, 1996, and June 30, 2010.

Measurements and Main Results

For each patient, C‐G Clcr was calculated and compared with a measured 24‐hour Clcr. Body weight adjustments to the calculation were performed based on the following weight classifications: underweight, normal weight, overweight, obese, and morbidly obese. In addition, C‐G Clcr was calculated by using rounded Scr values based on two Scr thresholds—0.8  mg/dl and 1 mg/dl—for patients with measured Scr values below those thresholds. Those patients were then evaluated after stratification into two age groups: all ages and a subgroup of patients aged 65 years or older. The Scr‐rounded C‐G Clcr values were compared with the C‐G Clcr values using actual Scr values. Mean differences were calculated, and accuracy was evaluated. Use of actual body weight in the calculations for underweight patients resulted in an unbiased Clcr of −0.22 ml/minute (p=0.898). Use of ideal body weight in the calculations of patients of normal weight returned an unbiased Clcr of −1.3 ml/minute (p=0.544). An unbiased C‐G Clcr could not be calculated for other weight categories. In those patients, adjusted body weight using a factor of 0.4 (ABW0.4) was the least biased and most accurate. In patients aged 65 years or older with an Scr less than 0.8 mg/dl and less than 1 mg/dl, actual Scr was unbiased (−3 ml/min [p=1] and −9 ml/min [p=0.279], respectively) and more accurate than rounded Scr. In patients of all ages with an Scr less than 0.8  mg/dl and less than 1 mg/dl, actual Scr proved less biased (−4.5 ml/min [p=0.038] and −5.5 ml/min [p<0.001], respectively) and more accurate than rounded Scr.

Conclusion

An unbiased C‐G Clcr can be calculated using actual body weight in underweight patients and ideal body weight in patients of normal weight. Using ABW0.4 for overweight, obese, and morbidly obese patients appears to be the least biased and most accurate method for calculating their C‐G Clcr. Rounding Scr in patients with low Scr did not improve accuracy or bias of the Clcr calculations.
Antimicrobial Stewardship: A Matter of Process or Outcome?
Authors: Khadem Tina M. , Dodds Ashley Elizabeth , Wrobel Mark J. , Brown Jack
Published: September 2012

The risk of antimicrobial resistance and superinfection is increasing alongside rates of hospital‐acquired infection. Imprudent antibiotic use combined with few novel antimicrobials can speed resistance. Antimicrobial stewardship programs (ASPs) advocate for judicious use of available antimicrobials to preserve their usefulness. Decreased antibiotic expenditures was the backbone of early justification for ASPs, but the function of these programs has evolved into measuring the quality and appropriateness of antimicrobial use. Proper evaluation of an ASP helps to inform which methods work best for a particular institution and can help to define best practices at a more global level. Study design and duration limitations, however, can make it difficult to measure the impact of these programs. Process measures have been validated and can evaluate quality of care; however, they do not adequately describe the clinical impact of these programs at the patient level. Outcome measures also have limitations; they are not a direct measure of quality of care. Therefore, both process and outcome measures need to be defined and assessed when evaluating an ASP to confirm that goals of the intervention are attained and clinical objectives are met. Most available well‐designed studies judging the effectiveness of ASPs use process measures alone. Adding improvements in clinical outcomes to process measures would theoretically attract the attention of a broader audience and provide additional support to expand current ASPs and develop novel ASPs.
111In‐ and 203Pb‐labeled cyclic arginine‐glycine‐aspartic acid peptide conjugate as an αvβ3 integrin‐binding radiotracer
Authors: Nwe Kido , Kim Young‐Seung , Milenic Diane E. , Baidoo Kwamena E. , Brechbiel Martin W.
Published: September 2012

Methodology for site‐specific modification and chelate conjugation of a cyclic arginine‐glycine‐aspartic acid (cRGD) peptide for the preparation of a radiotracer molecular imaging agent suitable for detecting αvβ3 integrin is described. The method involves functionalizing the peptide with an aldehyde moiety and conjugation to a 1,4,7,10‐tetraazacyclododecane‐N,N′,N″,N‴‐tetraacetic acid derivative that possesses an aldehyde reactive aminooxy group. The binding assay of the 111In‐labeled peptide conjugate with αvβ3 integrin showed 60% bound when four equivalents of the integrin was added, a reasonable binding affinity for a monovalent modified RGD peptide.