bluuebunny/crossref_metadata_2025 huggingface dataset:
Le patrimoine saharien tunisien au défi d’un tourisme durable : le cas de Tozeur et Nefta
Authors: Dhaher Najem
Published: November 2017

En las ciudades saharianas del suroeste de Túnez, afamadas por su cultura, sus tradiciones y por un patrimonio arquitectónico muy particular, el turismo ha provocado estos últimos años un esfuerzo de reflexión en torno a la noción de patrimonio orientada a sistematizar la oferta turística y a promover un desarrollo local. El turismo y el patrimonio en estos espacios desérticos frágiles y vulnerables son hoy dos realidades que marcan profundamente los paisajes, las actividades económicas y culturales y los movimientos de población. Estos procesos, que se han convertido en una de las preocupaciones tanto de los actores públicos como de los privados, han contribuido, a través de nuevas creaciones en términos de representación y de uso de los lugares, a una reinvención de la ciudad tradicional sahariana y de su oasis, conocidos como bienes comunes territoriales por excelencia que alimentan la adhesión de los individuos a los lugares donde viven. Frente a un turismo que no siempre se adhiere a estrategias y a prácticas de desarrollo sostenible especialmente en estos espacios concretos, nos preguntamos precisamente cómo este último puede reducir los perjuicios para el patrimonio que el turismo puede ocasionar en una perspectiva de sostenibilidad territorial.

[fr] Dans les villes sahariennes du sud-ouest Tunisien réputées pour leur culture, leurs traditions et leur patrimoine architectural très particulier, le tourisme a provoqué ces dernières années un effort réflexif autour de la notion de patrimoine destinée à systématiser l’offre touristique et à promouvoir un développement local. Aujourd’hui, le tourisme et le patrimoine dans ces espaces désertiques fragiles et vulnérables sont deux réalités qui marquent profondément les paysages, les activités économiques et culturelles et les mouvements de population. Ces processus, devenus une des préoccupations des acteurs aussi bien publics que privés, ont contribué par les créations nouvelles qu’ils engendrent en termes de représentation et d’utilisation des lieux, à une réinvention de la ville traditionnelle saharienne et de son oasis connus comme biens communs territoriaux par excellence qui nourrissent l’attachement des individus à leurs lieux de vie. En effet, face à un tourisme qui n’est pas toujours inscrit dans des stratégies et des pratiques de développement durable notamment dans ces espaces spécifiques, l’on se demande comment ce dernier peut réduire les nuisances que le tourisme peut occasionner pour le patrimoine dans une perspective de durabilité territoriale?.
A Hard(y) Look at B-1 Cell Development and Function
Authors: Baumgarth Nicole
Published: November 2017

A small population of B cells exists in lymphoid tissues and body cavities of mice that is distinct in development, phenotype, and function from the majority (B-2) B cell population. This population, originally termed “Ly-1” and now “B-1,” has received renewed interest as an innate-like B cell population of fetal-derived hematopoiesis, responsible for natural Ab production and rapid immune responses. Molecular analyses have begun to define fetal and adult hematopoiesis, while cell-fate mapping studies have revealed complex developmental origins of B-1 cells. Together the studies provide a more detailed understanding of B-1 cell regulation and function. This review outlines studies that defined B-1 cells as natural Ab- and cytokine-producing B cells of fetal origin, with a focus on work conducted by R.R. Hardy, an early pioneer and codiscoverer of B-1 cells, whose seminal contributions enhanced our understanding of this enigmatic B cell population.
Fan-Out Wafer-Level Packaging (FOWLP) of Large Chip with Multiple Redistribution-Layers (RDLs)
Authors: Lau John , Li Ming , Fan Nelson , Kuah Eric , Li Zhang , Tan Kim Hwee , Chen Tony , Xu Iris , Li Margie , Cheung Y. M. , Kai Wu , Hao Ji , Beica Rozalia , Taylor Tom , Ko CT , Yang Henry , Chen YH , Lim Sze Pei , Lee NC , Ran Jiang , Wee Koh Sau , Yong Qingxiang , Xi Cao , Tao Mian , Lo Jeffery , Lee Ricky
Published: November 2017

This study is for fan-out wafer-level packaging (FOWLP) with chip-first (die face-up) formation. The chips with Cu contact-pads on the front-side and a die attach film (DAF) on the backside are picked and placed face-up on a temporary glass wafer carrier with a thin layer of light-to-heat conversion (LTHC) material. It is followed by compression molding with epoxy molding compound (EMC) and post mold cure (PMC) on the reconstituted wafer carrier, and then backgrinding the molded EMC to expose the Cu contact-pads of the chips. The next step is to build up the redistribution layers (RDLs) from the Cu contact-pads and then mount the solder balls. Next comes the de-bonding of the carrier with a laser, and then the dicing of the whole reconstituted wafer into individual packages. A 300mm reconstituted wafer with a package/die ratio = 1.8 and a die-top EMC cap = 100μm has also been fabricated (a total of 325 test packages on the reconstituted wafer.) This test package has three RDLs; the line width/spacing of the first RDL is 5μm/5μm, of the second RDL is 10μm/10μm, and of the third RDL is 15μm/15μm. The dielectric layer of the RDLs is fabricated with a photosensitive polyimide (PI) and the conductor layer of the RDLs is fabricated by electrochemical Cu deposition (ECD).
Investigation & Resolution of Current Leakage Failure caused by Carbon Black Aggregation in Mold Compound
Authors: Singh Akhilesh Kumar , Lau Teck Beng , Lakhera Nishant , James Hoffmann , Low Boon Yew
Published: November 2017

Encapsulation materials (e.g. mold compounds) are inherently designed to have very high resistivity (volume resistivity of > 1013 Ohm.cm) to avoid any current leakage or shorting of pins. However, multiple ingredients in mold compound, if processed inappropriately, have enough conductivity to cause significant leakage resulting poor yield and/or inferior quality of products. For a Molded Array Process Ball Grid Array (MAPBGA) package, high current leakage (> 1 μA) failure was observed. For standard electronic packages, the allowable leakage is in the range of two to three order of magnitude lower than the leakage observed. Significant current leakage was observed at a specific pin using a standard organic substrate. The problem persisted across multiple substrate suppliers. Electrical and failure analysis did not suggest interlayer dielectric cracking or wire bond related anomalies. Secondary factors such as mold flow direction, mold cap thickness and substrate design aggravated the current leakage issue. Curve trace was able to isolate the problem away from die, and toward package assembly. Further, strategically designed experiments successfully led to the root cause. Current leakage was caused by formation of conductive path between two pins due agglomeration of carbon black in mold compound. Thermogravimetric analysis (TGA) technique was used to characterize the moisture uptake of carbon black and to differentiate between agglomerated and finely disperse carbon black. With the material improvement (change in the carbon black pH to avoid agglomeration), the leakage mechanism was fully understood and the problem was resolved. Surface of carbon black particle was modified by further oxidation process resulting in lower pH, finely dispersed carbon black.
Prototyping and Production of High-temperature Power Electronic Substrates through Additive Manufacturing Processes
Authors: Stoll Thomas , Syed-Khaja Aarief , Franke Joerg
Published: November 2017

This paper reveals a study on Selective Laser Melting (SLM) as an alternative technology for producing power electronic substrates, and shows the possibility of producing a stable interface between alumina and copper through SLM technique. Additive Manufacturing (AM) has not yet been established in the manufacturing of electronic devices. The prevalent benefits of the generative manufacturing sector such as material efficiency, product customization/–flexibility, elimination of the usage of tools, constructional freedom and less process steps in contrast to the conventional fabrication methods of ceramic substrates for power electronic applications like DBC or AMB, are pointed out. Moreover, AM reduces energy costs due to the elimination of the necessary firing, etching and washing processes. The realized study focuses on the examination of adhesion strengths of copper structures, melted on different Al2O3 ceramics with and without pre-copper and -glass paste coating. The melting process was categorized for different laser parameters (1–3) based on the same energy input. Maximum shear values of the substrate probes reached were at about 30 N/mm2 for copper coated ceramic, and at 20 N/mm2 for conventional and glass paste coated substrates. All results were determined in a full factorial design of experiment (DoE) with 54 combinations and a sample size of six samples per parameter combination. Furthermore, several cross sections of the probes produced were illustrated to better understand the melting and joining behavior of the copper powder applied on the ceramic substrates. For improved mechanical adhesion, the ceramic substrates were roughened by laser radiation, with roughness values measured, and the cracking behavior of the exposed ceramics explained.
A Generic Strategy to Assess and Mitigate Chip Package Interaction Risk Factors for Semiconductor Devices with Ultra-low k Dielectric Materials in Back End of Line
Authors: Kuechenmeister Frank , Breuer Dirk , Geisler Holm , Klewer Christian , Boehme Bjoern , Machani Kashi Vishwanath , Hecker Michael , Goetze Christian , Cho Jae Kyu , Kamineni Himani , Paul Jens , Thiele Michael
Published: November 2017

This paper describes a systematic approach to the identification of primary contributing factors to the Chip Package Interaction (CPI) risk and reveals the mitigation strategy successfully applied by GLOBALFOUNDRIES. The strategy includes modeling at bump and package level, gathering experimental data on blanket dielectric back end of line (BEoL) films, collecting data on wafer material with a complete BEoL stack, and finally using readouts on the package level.

Advanced measurement methods generate data on the wafer level to achieve fast turn-around times. These methods include: (i) Dual-Cantilever Beam (DCB) test, (ii) Modified Edge Lift-off Test (MELT), (iii) Single Pillar Shear Test (SPST) and (iv) Bump Assisted BEoL Stability Indentation (BABSI) tests. The paper describes the methodology to gather data on the wafer level with a complete BEoL metallization stack that assesses the BEoL integrity.

Furthermore, the package level thermomechanical modeling approach is discussed. The model has been used to determine the critical factors on BEoL stress/strain during the flip-chip assembly reflow processes.

Silicon design-related factors in the BEoL that contribute to the risk for CPI related failures were investigated and options to reduce the CPI risk are discussed. Finally the paper reveals package level qualification data flip-chip CSP and wafer level packaging Fan-In for advanced technology nodes.
Investigation of Wafer Level Packaging schemes for 3D RF interposer multi-chip module
Authors: Vereecke Bart , Soussan Philippe , Zhu Jian
Published: November 2017

Very small RF modules can be realized through heterogenous integration of GaAs MMIC (monolithic microwave integrated circuit) onto a low loss Si sub-mount, with high density routing lines realized by advanced patterning. In this paper we investigate how to integrate MMIC active devices on GaAs with the RF passives produced on an interposer, using Si wafer process technology. High resistive Silicon substrates are required to minimize RF losses. The interposer is thinned below 100 μm to reveal Cu TSVs from the back of the interposer, while the front side is covered entirely with a silicon capping wafer for shielding the device. We compare different wafer level packaging approaches for producing the low RF-loss interposers, and populating them using die-to-die (D2D) or die-to-wafer (D2W) bonding of the MMIC components, followed by wafer level encapsulation. Two D2W approaches are compared, in the first approach the D2W mounting and the encapsulation happens before the Si interposer is thinned for TSV reveal. To avoid damage during thinning of the wafer, thicker substrates with deeper TSV of 150 μm or more are required. In a second approach, the thinning of the interposer is done prior to the mounting. Initial electrical data showed that the approach yielded proper RF performance, but further yield optimization is required.
Characterization of Silicone Gel for High Temperature Encapsulation in High Voltage WBG Power Modules
Authors: Morgan Adam , Zhao Xin , Rouse Jason , Hopkins Douglas
Published: November 2017

One of the most important advantages of wide-bandgap (WBG) devices is high operating temperature (>200°C). Power modules have been recognized as an enabling technology for many industries, such as automotive, deep-well drilling, and on-engine aircraft controls. These applications are all required to operate under some form of extreme environmental conditions. Silicone gels are the most popular solution for the encapsulation of power modules due to mechanical stress relief enabled by a low Young's modulus, electrical isolation achieved due to high dielectric strength, and a dense material structure that protects encapsulated devices against moisture, chemicals, contaminants, etc. Currently, investigations are focused on development of silicone gels with long-term high-temperature operational capability. The target is to elevate the temperature beyond 200°C to bolster adoption of power modules in the aforementioned applications. WACKER has developed silicone gels with ultra-high purity levels of < 2ppm of total residual ions combined with > 200°C thermal stability. In this work, leakage currents through a group of WACKER Chemie encapsulant silicone gels (A, B, C) are measured and compared for an array of test modules after exposure to a 12kV voltage sweep at room temperature up to 275°C, and thermal aging at 150°C for up to more than 700 hours. High temperature encapsulants capable of producing leakage currents less than 1μA, are deemed acceptable at the given applied blocking voltage and thermal aging soak temperature.

To fully characterize the high temperature encapsulants, silicone gel A, B, and C, an entire high temperature module is used as a common test vehicle. The power module test vehicle includes: 12mil/40mil/12mil Direct Bonded Copper (DBC) substrates, gel under test (GUT), power and Kelvin connected measurement terminals, thermistor thermal sensor to sense real-time temperature, and 12mil Al bonding wires to manage localized high E-Fields around wires. It was ultimately observed that silicone gels B and C were capable of maintaining low leakage current capabilities under 12kV and 275°C conditions, and thus present themselves as strong candidates for high-temperature WBG device power modules and packaging.
Direct copper metallization on TGV (Thru-Glass-Via) for high performance glass substrate
Authors: ONITAKE Shigeo , INOUE Kotoku , TAKAYAMA Masatoshi
Published: November 2017

IoT (Internet of things) society will be coming in the near future, and everything will be connected by the Internet. Consequently, data traffic will be increased, and so will the demand to improve the performance of communication devices. Currently, plastics and ceramics are commonly used as insulating materials for communication components, but they are getting close to the limit in terms of material properties, because the next generation high performance communication devices require signal frequency of 20GHz and beyond. Therefore, further improvements in the properties of the insulating materials as well as in the performance of electronic devices are being demanded.

Copper conformal metallization on glass provides many opportunities for high frequency electronic devices. The most obvious advantage is given by the material properties. The glass substrate was chosen for low conductivity and low dielectric loss for high frequency application, and for its scalability to the larger area panels with low cost. While applications require strong interfacial adhesion between copper film and glass substrate, glass is often inferior as compared to metal-to metal adhesion. Direct copper metallization on glass is conventionally a difficult task, and it usually does not provide enough peeling strength either. Therefore, forming Ni and Ti seed layers by sputtering and precursors deposited by sol-gel method are being studied. However, these processes have been limitedly used or not been used in mass production, because creation of vias and simultaneous formation of seed layers on both sides by sputtering is difficult to undertake. The Sol-gel method does not provide stable peel strength and it takes a long process. This additional process requirement to add a layer to promote the adhesion of Cu to glass burdens the factories in a couple of ways: 1) enlarging the glass substrate is difficult due to the limitation in equipment size, 2) forming the film inside the through holes is also difficult due to high-aspect ratio via requirements, and 3) high cost due to slow processing speed.

In an earlier reports, we presented evidence that we have successfully demonstrated direct copper plating on glass, showing the adhesion strength of 0.42kN/m between glass and copper seed layer. In the present work, we are reporting wet plating process which enables easy and uniform film formation on large glass substrates and inside through holes. This low cost wet plating process enables forming copper film directly on glass without adhesion layer and enhancing the adhesion strength without degrading glass properties and copper conductivity.
Postcolonial leadership between the sovereign and the beast
Authors: Meylahn Johann A.
Published: November 2017

There is a crisis in leadership throughout the world, but the focus of this article will be on the crisis in postcolonial Africa. How is this crisis constructed within the politics of the global village? The leadership crisis in Africa is often portrayed by Western-influenced media as leaders being beasts if they do not comply with the wishes and dictates of Western capital, or characterised as puppets of Western capital, a puppet of the Western sovereign. Is there a way beyond these characterisations, or is it a political necessity to divide the world into friends and enemies, as Carl Schmitt would like us to believe? Taking Derrida into consideration, a way will be sought beyond this characterisation. Derrida’s ideas concerning the sovereign will pose the question: can leadership move beyond being either a puppet of a Western sovereign or being the beast of darkest Africa? The article will argue that the political gathering into a collective will not be destroyed if this distinction disappears, although the distinction will be ruined. Yet, these ruins will be the place for the possibility of something other, an impossible possibility – the madness of the impossible possible, or the madness of holy folly and the hope and dream of leadership still to come.Intradisciplinary and/orinterdisciplinary implications: The article addresses the postcolonial context, specifically of Africa, but not limited to Africa. It challenges traditional theories on leadership and proposes a hermeneutical approach to interpreting and understanding leadership.
Possible Impact of Salivary Influence on Cytokine Analysis in Exhaled Breath Condensate
Authors: Ichikawa T. , Matsunaga K. , Minakata Y. , Yanagisawa S. , Ueshima K. , Akamatsu K. , Hirano T. , Nakanishi M. , Sugiura H. , Yamagata T. , Ichinose M.
Published: November 2017

Background

Exhaled breath condensate (EBC) is thought to contain substances of the lower airway epithelial lining fluid (ELF) aerosolized by turbulent flow. However, contamination by saliva may affect the EBC when collected orally.

Objective

The purpose of this study was to compare the cytokine expression levels in EBC with those in saliva, and to clarify the influence of saliva on cytokine measurements of EBC.

Methods

EBC and saliva samples were obtained from 10 adult subjects with stable asthma. To estimate differences in the contents of substances between EBC and saliva, the total protein concentration of each sample was measured. Further, we also measured the total protein concentration of ELF obtained from another patient group with suspected lung cancer using a micro sampling probe during bronchoscopic examination and roughly estimated the dilution of EBC by comparing the total protein concentration of EBC and ELF from those two patient groups. The cytokine expression levels of EBC and saliva from asthmatic group were assessed by a cytokine protein array.

Results

The mean total protein concentrations in EBC, saliva and ELF were 4.6 μg/ml, 2,398 μg/ml and 14,111 μg/ml, respectively. The dilution of EBC could be estimated as 1:3000. Forty cytokines were analyzed by a cytokine protein array and each cytokine expression level of EBC was found to be different from that of saliva. Corrected by the total protein concentration, all cytokine expression levels of EBC were significantly higher than those of saliva.

Conclusion

These results suggest that the salivary influence on the cytokine assessment in EBC may be negligible.
Canine Plasminogen: Spectral Responses to Changes in 6-Aminohexanoate and Temperature
Authors: Kornblatt Jack A. , Barretto Tanya A. , Chigogidze Ketevan , Chirwa Bahati
Published: November 2017

We studied the near UV absorption spectrum of canine plasminogen. There are 19 tryptophans, 19 phenylalanines and 34 tyrosines in the protein. 4th derivative spectra optimized for either tryptophan or tyrosine give a measure of the polarity of the environments of these two aromatic amino acids. Plasminogen at temperatures between 0°C and 37°C exists as a mixture of four conformations: closed-relaxed, open-relaxed, closed-compact, and open-compact. The closed to open transition is driven by addition of ligand to a site on the protein. The relaxed to compact transition is driven by increasing temperature from 0°C to above 15-20°C.

When the conformation of plasminogen is mainly closed-relaxed, the 4th derivative spectra suggest that the average tryptophan environment is similar to a solution of 20% methanol at the same temperature. Under the same conditions, 4th derivative spectra suggest that the average tyrosine environment is similar to water. These apparent polarities change as the plasminogen is forced to assume the other conformations. We try to rationalize the information based on the known portions of the plasminogen structure.
Biomedical and Forensic Applications of Combined Catalytic Hydrogenation-Stable Isotope Ratio Analysis
Authors: Sephton Mark A. , Meredith Will , Sun Cheng-Gong , Snape Colin E.
Published: November 2017

Studies of biological molecules such as fatty acids and the steroid hormones have the potential to benefit enormously from stable carbon isotope ratio measurements of individual molecules. In their natural form, however, the body's molecules interact too readily with laboratory equipment designed to separate them for accurate measurements to be made. Some methods overcome this problem by adding carbon to the target molecule, but this can irreversibly overprint the carbon source ‘signal’. Hydropyrolysis is a newly-applied catalytic technique that delicately strips molecules of their functional groups but retains their carbon skeletons and stereochemistries intact, allowing precise determination of the carbon source. By solving analytical problems, the new technique is increasing the ability of scientists to pinpoint molecular indicators of disease, elucidate metabolic pathways and recognise administered substances in forensic investigations.
Solid Phase Extraction for Monitoring of Occupational Exposure to Cr (III)
Authors: Shahtaheri S.J. , Khadem M. , Golbabaei F. , Rahimi-Froushani A.
Published: November 2017

Chromium is an important constituent widely used in different industrial processes for production of various synthetic materials. For evaluation of workers' exposure to trace toxic metal of Cr (III), environmental and biological monitoring are essential processes, in which, preparation of samples is one of the most time-consuming and error-prone aspects prior to analysis. The use of solid-phase extraction (SPE) has grown and is a fertile technique of sample preparation as it provides better results than those produced by liquid-liquid extraction (LLE). SPE using mini columns filled with XAD-4 resin was optimized regarding to sample pH, ligand concentration, loading flow rate, elution solvent, sample volume, elution volume, amount of resins, and sample matrix interferences. Chromium was retained on solid sorbent and was eluted with 2 M HNO3 followed by simple determination of analytes by using flame atomic absorption spectrometery. Obtained recoveries of metal ion were more than 92%. The optimized procedure was also validated with three different pools of spiked urine samples and showed a good reproducibility over six consecutive days as well as six within-day experiments. Through this study, suitable results were obtained for relative standard deviation, therefore, it is concluded that, this optimized method can be considered to be successful in simplifying sample preparation for trace residue analysis of Cr in different matrices for evaluation of occupational and environmental exposures. To evaluate occupational exposure to chromium, 16 urine samples were taken, prepared, and analyzed based on optimized procedure.
Hazard Identification on a Single Cell Level Using a Laser Beam
Authors: Wu Xing-Zheng , Kato Tomohisa , Tsuji Yumiko , Terada Satoshi
Published: November 2017

This research shows a novel method for hazard identification of a chemical and UV light on a single cell level with a laser probe beam. The laser probe beam was passed through interface of cell membrane/culture medium of a cultured human hepatoblastoma cell line HepG2. Deflection of the laser probe beam, which was induced by changes in concentration gradients due to the active materials movement across the cell membrane, was monitored. When a toxic hazard existed, a living cell was expected to be killed or injured, or cellular behaviors to be changed greatly. Then, the changing deflection signal from the living cell would become unchanged or altered in a different way. This was successfully demonstrated with cytotoxity of UV light and H2O2. Most of the cultured HepG2 cells showed changing deflection signals after 10 min illumination of UV-visible light longer than 370 nm, while almost all HepG2 cells showed unchanged deflection signal after 10 min illumination of UV-visible light with wavelength longer than 330 nm. The results suggested that UV light between 330-370 nm could kill the cells. Additions of H2O2 solution with different concentrations to the cell cultures caused the changing deflection signal from a living cell either unchanged or changed in different trend, suggesting toxicity of H2O2 to the cells. The results from the beam deflection detection agreed well with those obtained by the conventional trypane blue method.
Palm-Based Standard Reference Materials for Iodine Value and Slip Melting Point
Authors: Tarmizi Azmil Haizam Ahmad , Lin Siew Wai , Kuntom Ainie
Published: November 2017

This work described study protocols on the production of Palm-Based Standard Reference Materials for iodine value and slip melting point. Thirty-three laboratories collaborated in the inter-laboratory proficiency tests for characterization of iodine value, while thirty-two laboratories for characterization of slip melting point. The iodine value and slip melting point of palm oil, palm olein and palm stearin were determined in accordance to MPOB Test Methods p3.2:2004 and p4.2:2004, respectively. The consensus values and their uncertainties were based on the acceptability of statistical agreement of results obtained from collaborating laboratories. The consensus values and uncertainties for iodine values were 52.63 ± 0.14 Wijs in palm oil, 56.77 ± 0.12 Wijs in palm olein and 33.76 ± 0.18 Wijs in palm stearin. For the slip melting points, the consensus values and uncertainties were 35.6 ± 0.3 °C in palm oil, 22.7 ± 0.4 °C in palm olein and 53.4 ± 0.2 °C in palm stearin. Repeatability and reproducibility relative standard deviations were found to be good and acceptable, with values much lower than that of 10%. Stability of Palm-Based Standard Reference Materials remained stable at temperatures of -20 °C, 0 °C, 6 °C and 24 °C upon storage for one year.
Pharmacotherapy Options in Atrial Fibrillation: Focus on Vernakalant
Authors: Cheng Judy W.M. , Rybak Iwona
Published: November 2017

This article reviews the role of vernakalant in the management of atrial fibrillation (AF). Published data in English language were identified from MEDLINE and Current Content database (both 1966 to January 30, 2009). Vernakalant is an antiarrhythmic agent with sodium and ultra-rapid potassium channel blockage property and atrial selective effect. In clinical studies evaluating intravenous vernakalant in cardioversion of patients with recent onset AF, vernakalant improve the chance of acute restoration to normal sinus rhythm (NSR). In post-operative AF, the chance of conversion to NSR was also improved. Phase II studies demonstrated that oral vernakalant 300 mg or 600 mg twice daily successfully maintained normal sinus rhythm compared to placebo. Common side effects include dysgeusia, sneezing, and paresthesia. Future studies are needed to explore the efficacy and safety of using vernakalant with patient populations who are prone to AF, as well as its comparative efficacy and safety to other antiarrhythmic agents.
Pharmacotherapy of Epilepsy: Focus on Levetiracetam
Authors: Adams Molly E. , Chung Allison M. , Eiland Lea S.
Published: November 2017

Levetiracetam is a second-generation antiepileptic drug which first came to the United States market in 1999. It has a mechanism of action that is not well elucidated. However, it is a very favorable antiepileptic drug due to its reliable pharmacokinetics, minimal drug interactions, seizure efficacy and good tolerability. It is an agent that has established efficacy as an adjunct therapy agent for partial and refractory seizures. As a monotherapy agent, levetiracetam also appears to be an attractive agent with observed efficacy and tolerability. Since levetiracetam has recently become available intravenously, it is also being reviewed as an agent for acute status epilepticus. In pediatrics, levetiracetam is widely used with efficacy seen in small clinical trials for a variety of seizure types. Levetiracetam is well tolerated: the most common adverse effect being somnolence and behavioral effects. Overall, levetiracetam is a notable antiepileptic drug that has added significantly to the current antiepileptic armamentarium.
Prophylaxis of Invasive Fungal Infections: A Review of the Use of Posaconazole
Authors: Collins Curtis D. , Smith Jeannina A. , Kaul Daniel R.
Published: November 2017

Invasive fungal infections (IFIs) cause significant morbidity, mortality, and increased cost of care in patients with hematological malignancies, prolonged (i.e. >7-10 days) treatment induced neutropenia, and other disease states causing underlying immunosuppression. One strategy often used to combat the development of invasive infections is the use of antifungal agents as prophylaxis in at risk patients. Posaconazole is an oral triazole with a useful spectrum of activity against many fungal pathogens of concern in patients at risk for the development of IFIs. Posaconazole is only available in oral formulation and therapeutic drug monitoring may provide value due to variable absorption and serum concentrations. Clinical efficacy and pharmacoeconomic data have demonstrated the utility of posaconazole in the treatment of oropharyngeal candidiasis and for prophylaxis in patients at risk for development of IFIs. Several organizations or expert groups involved in developing guidelines for the management of IFIs recommend posaconazole anti-fungal prophylaxis in patients with AML or MDS and chemotherapy induced neutropenia or significant GVHD. In addition, nonrandomized studies (largely of salvage therapy) and case series suggest that posaconazole may be effective as treatment for invasive aspergillosis, zygomycosis, and coccidiomycosis. Further, small case series or individual case reports suggest activity against other less commonly encountered filamentous fungi and Histoplasma.
Benefits of ACE Inhibitors in Diabetes
Authors: Ramos-Nino Maria E. , Blumen Steven R.
Published: November 2017

Angiotensin-converting enzyme (ACE) inhibitors have been FDA-approved for treating refractory hypertension since 1981. Since then, clinical investigations support the benefits of ACE inhibition (ACE-I) in pathologies like congestive heart failure, myocardial infarction, diabetes mellitus, chronic renal insufficiency, and atherosclerotic cardiovascular disease. Both, clinical trials and animal models of type I and type II diabetes have shown that hyperactivity of the angiotensin II signaling pathway contributes to the development of diabetes and its complications, and that blockade of the renin-angiotensin system prevents new onset diabetes and reduces the risk of diabetic complications. Furthermore, ACE inhibitors are generally well tolerated and have few contraindications. This article describes ACE as a target molecule and gives an overview on the clinical evidence that supports the use of ACE inhibitors in diabetes.
Safety and Efficacy Review of Doxycycline
Authors: Holmes Natasha E. , Charles Patrick G.P.
Published: November 2017

Doxycycline is a member of the tetracycline class of antibiotics and has been used clinically for more than 40 years. It is a well-tolerated drug that is bacteriostatic and acts via the inhibition of bacterial ribosomes. It is generally given at a dose of 100-mg daily or twice daily. It is well absorbed and has generally good tissue penetration. The serum half-life is 18-22 hours and dosage does not need to be adjusted in the presence of renal or hepatic impairment. Major side effects are gastro-intestinal and dermatological and it is generally contra-indicated in pregnancy or childhood because of concerns about discolouration of developing teeth and potential effects on growing bones. Drug interactions are not common although can occur with the concomitant use of methotrexate and the oral contraceptive pill, and its absorption can be reduced by the co-administration with some antacids and iron preparations. It has activity against many organisms, including Gram-positives, Gram-negatives and atypical bacteria. In addition, it appears to have some potentially clinically useful anti-inflammatory properties.
A Review of the Prevention of Invasive Breast Cancer with Raloxifene in Postmenopausal Women
Authors: Arango Belisario A. , Castrellon Aurelio B. , Santos Edgardo S. , Gluck Stefan
Published: November 2017

Breast cancer remains the second leading cause of malignancy-related death in women in the United States, regardless of advances in novel therapeutic agents. High priority should be emphasized in research aimed at the study of pharmacological and natural compounds that may potentially prevent the development of breast cancer in susceptible patients. Among the known selective estrogen receptor modulators with proven chemopreventive effects, raloxifene has been studied in a number of clinical trials evaluating this drug for the prevention of osteoporosis and coronary heart disease. The MORE and CORE trials had as a primary end point the efficacy of raloxifene in the treatment of women with osteoporosis. These studies showed that raloxifene reduced the risk of invasive breast cancer in postmenopausal women. However, the STAR trial showed no significant difference between raloxifene and tamoxifen recipients in the incidence of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer. This review focuses on the chemopreventive properties of raloxifene and the clinical trials that have proven its efficacy as a chemopreventive agent in invasive breast cancer.
Pharmacotherapy Options in Cancer Treatment-induced Bone Loss: Focus on Bisphosphonates
Authors: Ito Kouta
Published: November 2017

Bone loss and its associated risk of fracture is a serious long-term health issue for breast cancer and prostate cancer survivors. Hormone ablation therapy, in particular aromatase inhibitors (AIs) for breast cancer and androgen deprivation therapy (ADT) for prostate cancer, causes marked reduction in circulating estrogen or testosterone levels, resulting in increased bone resorption, decreased bone mineral density (BMD), and an increased risk of fragility fracture. In several clinical trials with small sample sizes and short follow-up periods, oral and intravenous bisphosphonates have been shown to improve BMD, but not actual fracture rates, in cancer patients on hormone ablation therapy. A number of professional organizations and expert panels recommend the use of bisphosphonates for selected patients at risk. Although bisphosphonates are generally well tolerated, physicians should be aware of safety concerns, including the risk of osteonecrosis of the jaw. With the growing number of older breast and prostate cancer survivors, additional research is needed to characterize patients who would benefit from pharmacotherapy and optimize strategies to prevent cancer treatment-induced bone loss.
The Prevention of Respiratory Syncytial Virus Infection in Children: Focus on Palivizumab
Authors: Speer Michael E. , Good Amy B.
Published: November 2017

Recurrent upper respiratory infections caused by respiratory syncytial virus (RSV) and other respiratory viruses occur throughout life. During the first 2 years of life, RSV infected children have up to a 40% risk of a lower respiratory tract infection (LRTI). In turn LRTI, including bronchiolitis, due to RSV is the most common cause of hospitalization among infants less than one year of age. While mortality from RSV infection has fallen over the last 2 decades, approximately 400-500 deaths occur annually in the United States again primarily in infants less than 1 year of age. Palivizumab, a humanized monoclonal antibody, has been shown to reduce the risk of hospitalization in high risk infants if given monthly during RSV season. Post marketing safety surveillance originating from a variety of sources, mostly active surveillance, has confirmed the prelicensure safety profile of palivizumab. Other than very rare anaphylactic reactions (<1/100000), no significant adverse reactions have been noted.
Infliximab: A Review of its Use in the Treatment of Crohn's Disease
Authors: Molloy Jeffrey W. , Stengel Joel Z. , Arnold Hays L.
Published: November 2017

Infliximab is a chimeric monoclonal antibody to human tumor necrosis factor alpha. While its use was developed in the treatment of rheumatologic diseases its effects on Crohn's disease have revolutionized the management of this chronic illness. Infliximab has effects on both immune and epithelial cells leading to a reduction in gut inflammation and collagen deposition which promotes wound healing. Large randomized trials have proven efficacy of the drug in luminal and fistulizing Crohn's disease. Over time our understanding of antibody formation and long-term tolerability of the drug have refined our use of infliximab, eliminating episodic dosing and utilizing concomitant immunomodulator therapy to improve efficacy. Questions remain regarding top-down strategies, length of therapy, cost, reduction in surgical procedures, and the determination of which patients will respond best to any strategy chosen.
A Review on the Use of Eltrombopag in Patients with Advanced Liver Disease
Authors: Giannini Edoardo G. , Greco Alfredo , Savarino Vincenzo
Published: November 2017

Thrombocytopenia is the most common hematological abnormality in patients with chronic, advanced liver disease. In these patients, the presence of severe thrombocytopenia is an obstacle to the performance of invasive diagnostic and therapeutic procedures, and the current standard treatment for these patients is platelet transfusions, a remedy whose characteristics are far from being ideal. Furthermore, thrombocytopenia in patients with chronic hepatitis C virus infection may render the patients ineligible to antiviral treatment or may limit its efficacy because of premature discontinuation. Although the cause of thrombocytopenia in patients with chronic liver disease is likely multi-factorial, decreased thrombopoietin production by the liver undoubtedly plays a significant role. In this regard, eltrombopag, a non-peptide, orally bioavailable thrombopoietin receptor agonist has been shown to safely increase platelet count in a dose-dependent fashion in both healthy subjects and thrombocytopenic patients with chronic hepatitis C. Furthermore, in this latter group of patients, it has been shown to be superior to placebo in counteracting the myelosuppressive effect of short-term pegylated interferon treatment.
Current Approaches to the Treatment of Gastrointestinal Infections: Focus on Nitazoxanide
Authors: Halsey Jennifer L.
Published: November 2017

Nitazoxanide is a broad-spectrum agent active against several protozoa, helminths, and bacteria, including C. difficile and H. pylori. It is available as an oral tablet and suspension, both with adequate bioavailability. Nitazoxanide is associated with minimal side effects, has an acceptable safety profile, and has been classified as a pregnancy category B agent. It is 99% protein bound, which could result in drug interactions. It is the preferred agent for the treatment of Cryptospordiosis and Giardiasis in immunocompetent patients and has shown promise for the treatment of rotavirus, mild to moderate initial C. difficile infection, refractory C. difficile infection, Amoebiasis, Blastocystosis, and Taenia saginata.
A review of the use of telbivudine in the treatment of chronic hepatitis B
Authors: Charuworn Prista , Keeffe Emmet B.
Published: November 2017

Chronic hepatitis B is a major global health problem. Fortunately there are currently a number of agents licensed in most countries to treat chronic hepatitis B, including the oral nucleos(t)ide agents lamivudine, adefovir, entecavir, telbivudine, and tenofovir, and the immune modulators interferon alfa-2b and peginterferon alfa-2a. Large clinical trials have shown potent suppression of viral replication with telbivudine and a good safety profile, and superiority of telbivudine over lamivudine and adefovir in head-to-head trials. The potential of resistance with use of telbivudine mandates careful monitoring and on-treatment strategies to avoid or reduce the development of resistance. This review article provides an overview of the pharmacokinetics, clinical efficacy, safety, and resistance profile of telbivudine.
Sitaxentan for the Oral Treatment of Pulmonary Arterial Hypertension: Benefits from Endothelin Receptor Subtype Selectivity?
Authors: Mucke Hermann A.M.
Published: November 2017

Pulmonary arterial hypertension (PAH) is a deadly and underdiagnosed disease which causes right heart failure secondary to pressure overload resulting from the thickening of the pulmonary artery endothelium, associated with elevated levels of circulating endothelin-1. Sitaxentan was the first endothelin antagonist with high selectivity for receptor subtype A (over subtype ET-B) to gain regulatory approval for the treatment of PAH in major pharmaceutical markets. This review traces the development history of sitaxentan, summarizes the designs and results from its clinical studies, and relates the drug's profile to that of the two other broadly available endothelin receptor antagonists, bosentan and ambrisentan. All three drugs have comparable therapeutic efficacy in the 6-minute walk test–-a frequently employed standard–-during the first 3-4 months of therapy. Their performance might differ slightly in other clinically relevant outcome measures, especially in longer-term treatment where fully comparable data have not yet been reported. In clinical trials of up to one year duration the propensity of sitaxentan to induce elevation of liver transaminases and hepatic failure was significantly lower than that of bosentan. As a once-daily oral drug with good tolerability sitaxentan has become a crucial element in the treatment of PAH.
Ibandronate in the Management of Postmenopausal Osteoporosis
Authors: Reginster Jean-Yves , Hiligsmann Mickaël , Rabenda Véronique , Zegels Brigitte , Neuprez Audrey , Bruyere Olivier
Published: November 2017

Oral daily and weekly bisphosphonates were considered, for several years, as the mainstay for the treatment of postmenopausal osteoporosis. However, the inconvenience of frequent dosing is known to negatively affect adherence to therapy in the long-term, hence outcomes. This has prompted the development of convenient oral bisphosphonate regimens that feature simple, less frequent dosing schedules. Ibandronate is a potent, nitrogen-containing bisphosphonate which, uniquely, can be administered either orally, monthly, or as an intravenous injection, every 3 months. A positive impact for adherence has been observed with a reduction in the bisphosphonate dosing frequency. Anti-fracture efficacy of the various currently available regimens of ibandronate is documented in randomized controlled clinical trials, non-inferiority studies, meta-analyses and real-life settings studies. The present paper summarizes the pharmacology, efficacy and tolerability of oral and intravenous ibandronate, when administered with extended dosing intervals, in postmenopausal osteoporosis.
Safety and efficacy update: Alvimopan in postoperative ileus
Authors: Beattie David T.
Published: November 2017

Postoperative ileus (POI) in patients undergoing abdominal surgery is associated with significant morbidity. In 2008, alvimopan (Entereg®) was approved by the Food and Drug Administration (FDA), and is the only available POI therapy in the United States for patients undergoing bowel resection. Data from preclinical studies demonstrate that alvimopan and its primary metabolite, ADL 08-0011, behave as potent μ. opioid receptor antagonists. In animals, alvimopan and ADL 08-0011 attenuate opioid agonist-induced reductions in gastrointestinal (GI) transit. Higher doses of alvimopan are required to inhibit opioid-induced analgesia as a result of its inability to penetrate the central nervous system (CNS). ADL 08-0011 is also peripherally selective, although to a lesser degree than alvimopan. In multiple species, including humans, alvimopan has low oral bioavailability, while ADL 08-0011, following its generation by human gut microflora, is more readily absorbed and achieves higher exposures. Three Phase 2 and five Phase 3 clinical trials have been conducted to investigate the efficacy and tolerability of alvimopan in patients undergoing bowel resection. An additional Phase 3 study was conducted in hysterectomy patients. In the majority of the studies, statistically significant, and clinically meaningful, acceleration of GI recovery has been demonstrated. Consistent with animal data, alvimopan has no effect on opioid agonist-induced analgesia in healthy human subjects and POI patients. Clinical experience to date in POI patients indicates that alvimopan is well tolerated when used according to its approved dosing regimen (12 mg b.i.d. for up to 7 days). In this article, the preclinical and clinical properties of alvimopan are reviewed.