REMS pharmacy tasks: The adoption of an innovative electronic support system.

OBJECTIVES: The objective of this study was to evaluate the pharmacy adoption rates of an online Risk Evaluation and Mitigation Strategy (REMS) Pharmacy Portal designed as an alternative for REMS-certified pharmacies to perform mandatory pharmacy dispense confirmations and to assess whether Pharmacy Portal uptake was affected by the pharmacy daily dispense volume. SETTING: REMS-certified pharmacies dispensing lenalidomide (Revlimid), pomalidomide (Pomalyst), or thalidomide (Thalomid). PRACTICE DESCRIPTION: Primarily specialty and hospital pharmacies in the limited distribution network that used the REMS Pharmacy Portal. PRACTICE INNOVATION: A self-service pharmacy portal was developed to allow REMS-certified pharmacies to obtain confirmation numbers instead of calling a Celgene Customer Care Representative (CCR) or using the Interactive Voice Response System (IVR) system. EVALUATION: The numbers of pharmacy dispense confirmations obtained were identified, and the mean percentages by quarter (Q) were calculated from January 2013 through August 2016 for the Pharmacy Portal, Celgene CCR, and IVR. RESULTS: In Q1 2013, the CCR and IVR options were used for 57% and 43% of dispense confirmations, respectively. After the training period, the Pharmacy Portal rapidly became the most used option (67% of confirmations from Q2 2014). By August 2016, data displayed the continued preference for the pharmacy portal (98% of all confirmations) regardless of the daily dispense volume of the pharmacy. As of March 30, 2018, the pharmacy portal continued to be the preferred option for all pharmacies (maintained at 98.5% use). CONCLUSION: There is an overwhelming REMS pharmacy preference to use the pharmacy portal over the IVR and CCR options, irrespective of the pharmacy daily dispense volume. The rapid uptake of the pharmacy portal is most likely attributed to robust and comprehensive 1-on-1 training and support provided by the REMS sponsor to the REMS-certified pharmacies, but also because it might be easier to use than the other options, resulting in reduced REMS burden for the pharmacy.

Friction between van der Waals Solids during Lattice Directed Sliding.

Nanometer-scale crystals of the two-dimensional oxide molybdenum trioxide (MoO3) were formed atop the transition metal dichalcogenides MoS2 and MoSe2. The MoO3 nanocrystals are partially commensurate with the dichalcogenide substrates, being aligned only along one of the substrate's crystallographic axes. These nanocrystals can be slid only along the aligned direction and maintain their alignment with the substrate during motion. Using an AFM probe to oscillate the nanocrystals, it was found that the lateral force required to move them increased linearly with nanocrystal area. The slope of this curve, the interfacial shear strength, was significantly lower than for macroscale systems. It also depended strongly on the duration and the velocity of sliding of the crystal, suggesting a thermal activation model for the system. Finally, it was found that lower commensuration between the nanocrystal and the substrate increased the interfacial shear, a trend opposite that predicted theoretically.

Protection from Below: Stabilizing Hydrogenated Graphene Using Graphene Underlayers.

We show that dehydrogenation of hydrogenated graphene proceeds much more slowly for bilayer systems than for single layer systems. We observe that an underlayer of either pristine or hydrogenated graphene will protect an overlayer of hydrogenated graphene against a number of chemical oxidants, thermal dehydrogenation, and degradation in an ambient environment over extended periods of time. Chemical protection depends on the ease of oxidant intercalation, with good intercalants such as Br2 demonstrating much higher reactivity than poor intercalants such as 1,2-dichloro-4,5-dicyanonbenzoquinone (DDQ). Additionally, the rate of dehydrogenation of hydrogenated graphene at 300 °C in H2/Ar was reduced by a factor of roughly 10 in the presence of a protective underlayer of graphene or hydrogenated graphene. Finally, the slow dehydrogenation of hydrogenated graphene in air at room temperature, which is normally apparent after a week, could be completely eliminated in samples with protective underlayers over the course of 39 days. Such protection will be critical for ensuring the long-term stability of devices made from functionalized graphene.

Transfer of Chemically Modified Graphene with Retention of Functionality for Surface Engineering.

Single-layer graphene chemically reduced by the Birch process delaminates from a Si/SiOx substrate when exposed to an ethanol/water mixture, enabling transfer of chemically functionalized graphene to arbitrary substrates such as metals, dielectrics, and polymers. Unlike in previous reports, the graphene retains hydrogen, methyl, and aryl functional groups during the transfer process. This enables one to functionalize the receiving substrate with the properties of the chemically modified graphene (CMG). For instance, magnetic force microscopy shows that the previously reported magnetic properties of partially hydrogenated graphene remain after transfer. We also transfer hydrogenated graphene from its copper growth substrate to a Si/SiOx wafer and thermally dehydrogenate it to demonstrate a polymer- and etchant-free graphene transfer for potential use in transmission electron microscopy. Finally, we show that the Birch reduction facilitates delamination of CMG by weakening van der Waals forces between graphene and its substrate.

Fluorination of graphene enhances friction due to increased corrugation.

The addition of a single sheet of carbon atoms in the form of graphene can drastically alter friction between a nanoscale probe tip and a surface. Here, for the first time we show that friction can be altered over a wide range by fluorination. Specifically, the friction force between silicon atomic force microscopy tips and monolayer fluorinated graphene can range from 5-9 times higher than for graphene. While consistent with previous reports, the combined interpretation from our experiments and molecular dynamics simulations allows us to propose a novel mechanism: that the dramatic friction enhancement results from increased corrugation of the interfacial potential due to the strong local charge concentrated at fluorine sites, consistent with the Prandtl-Tomlinson model. The monotonic increase of friction with fluorination in experiments also demonstrates that friction force measurements provide a sensitive local probe of the degree of fluorination. Additionally, we found a transition from ordered to disordered atomic stick-slip upon fluorination, suggesting that fluorination proceeds in a spatially random manner.

Chemical stability of graphene fluoride produced by exposure to XeF2.

Fluorination can alter the electronic properties of graphene and activate sites for subsequent chemistry. Here, we show that graphene fluorination depends on several variables, including XeF2 exposure and the choice of substrate. After fluorination, fluorine content declines by 50-80% over several days before stabilizing. While highly fluorinated samples remain insulating, mildly fluorinated samples regain some conductivity over this period. Finally, this loss does not reduce reactivity with alkylamines, suggesting that only nonvolatile fluorine participates in these reactions.

High-quality uniform dry transfer of graphene to polymers.

In this paper we demonstrate high-quality, uniform dry transfer of graphene grown by chemical vapor deposition on copper foil to polystyrene. The dry transfer exploits an azide linker molecule to establish a covalent bond to graphene and to generate greater graphene-polymer adhesion compared to that of the graphene-metal foil. Thus, this transfer approach provides a novel alternative route for graphene transfer, which allows for the metal foils to be reused.

Engineering graphene mechanical systems.

We report a method to introduce direct bonding between graphene platelets that enables the transformation of a multilayer chemically modified graphene (CMG) film from a "paper mache-like" structure into a stiff, high strength material. On the basis of chemical/defect manipulation and recrystallization, this technique allows wide-range engineering of mechanical properties (stiffness, strength, density, and built-in stress) in ultrathin CMG films. A dramatic increase in the Young's modulus (up to 800 GPa) and enhanced strength (sustainable stress ≥1 GPa) due to cross-linking, in combination with high tensile stress, produced high-performance (quality factor of 31,000 at room temperature) radio frequency nanomechanical resonators. The ability to fine-tune intraplatelet mechanical properties through chemical modification and to locally activate direct carbon-carbon bonding within carbon-based nanomaterials will transform these systems into true "materials-by-design" for nanomechanics.

High-density amine-terminated monolayers formed on fluorinated CVD-grown graphene.

There has been considerable interest in chemically functionalizing graphene films to control their electronic properties, to enhance their binding to other molecules for sensing, and to strengthen their interfaces with matrices in a composite material. Most reports to date have largely focused on noncovalent methods or the use of graphene oxide. Here, we present a method to activate CVD-grown graphene sheets using fluorination followed by reaction with ethylenediamine (EDA) to form covalent bonds. Reacted graphene was characterized via X-ray photoelectron spectroscopy (XPS), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and Raman spectroscopy as well as measurements of electrical properties. The functionalization results in stable, densely packed layers, and the unbound amine of EDA was shown to be active toward subsequent chemical reactions.

Chemically isolated graphene nanoribbons reversibly formed in fluorographene using polymer nanowire masks.

We demonstrated the fabrication of graphene nanoribbons (GNRs) as narrow as 35 nm created using scanning probe lithography to deposit a polymer mask(1-3) and then fluorinating the sample to isolate the masked graphene from the surrounding wide band gap fluorographene. The polymer protected the GNR from atmospheric adsorbates while the adjacent fluorographene stably p-doped the GNRs which had electron mobilities of ∼2700 cm2/(V·s). Chemical isolation of the GNR enabled resetting the device to nearly pristine graphene.

Maskless nanoscale writing of nanoparticle-polymer composites and nanoparticle assemblies using thermal nanoprobes.

Nanoparticle polymer composites containing metal, semiconductor, magnetic, and optically active nanoparticles were deposited onto multiple substrates from a heatable atomic force microscope tip. The nanoparticle nanostructures were functional as deposited or could be etched with an oxygen plasma, revealing single nanoparticle lithographic resolution. Many types of nanoparticles can be patterned with the same technique, without the need to tailor the substrate chemistry and without solution processing.

Properties of fluorinated graphene films.

Graphene films grown on Cu foils have been fluorinated with xenon difluoride (XeF(2)) gas on one or both sides. When exposed on one side the F coverage saturates at 25% (C(4)F), which is optically transparent, over 6 orders of magnitude more resistive than graphene, and readily patterned. Density functional calculations for varying coverages indicate that a C(4)F configuration is lowest in energy and that the calculated band gap increases with increasing coverage, becoming 2.93 eV for one C(4)F configuration. During defluorination, we find hydrazine treatment effectively removes fluorine while retaining graphene's carbon skeleton. The same films may be fluorinated on both sides by transferring graphene to a silicon-on-insulator substrate enabling XeF(2) gas to etch the Si underlayer and fluorinate the backside of the graphene film to form perfluorographane (CF) for which calculated the band gap is 3.07 eV. Our results indicate single-side fluorination provides the necessary electronic and optical changes to be practical for graphene device applications.

Conductance anisotropy in epitaxial graphene sheets generated by substrate interactions.

We present the first microscopic transport study of epitaxial graphene on SiC using an ultrahigh vacuum four-probe scanning tunneling microscope. Anisotropic conductivity is observed that is caused by the interaction between the graphene and the underlying substrate. These results can be explained by a model where charge buildup at the step edges leads to local scattering of charge carriers. This highlights the importance of considering substrate effects in proposed devices that utilize nanoscale patterning of graphene on electrically isolated substrates.

Evaluating REMS Burden: A Comparative Time Analysis of 3 Channels for REMS Stakeholders to Perform Mandatory REMS Tasks.

BACKGROUND: To determine the time taken to perform 5 Risk Evaluation and Mitigation Strategy (REMS) tasks across 3 channels for the Celgene REMS programs, with an aim to better understand which channels may minimize REMS administrative burden. METHODS: Five mandatory REMS tasks (new prescriber and patient enrollments, prescriber and patient surveys, and pharmacy dispenses) were performed across applicable REMS channels (online portals, telephone interactions with customer care representatives [CCRs], or an interactive voice response [IVR] system). Five REMS representatives, who had ≥1 year of experience as a CCR, simulated the completion of the same set of testing activities across REMS channels. The execution time for each task by channel was measured and averaged across the participating CCRs. RESULTS: Using the online portal, less time was taken to enroll a new prescriber (1.3 minutes) and adult male (6.7 minutes), compared to when the CCR channel was used (21.9 and 25.9 minutes, respectively). Similarly, completion of 3 AFRP prescriber surveys, the adult male patient survey, and 5 pharmacy dispenses was faster using the online portals (3.1, 1.3, and 1.7 minutes, respectively) compared to when the CCR (4.9, 1.8, and 3.4 minutes, respectively) and IVR (10.7, 4.0, and 11.3 minutes, respectively) channels were used. CONCLUSION: The use of online channels may alleviate some of the REMS burden by reducing the administrative time it takes for prescribers, patients, and pharmacy stakeholders to complete mandatory REMS tasks. More education and awareness of the available efficient channels should be provided to REMS stakeholders.

Chemistries for Making Additive Nanolithography in OrmoComp Permissive for Cell Adhesion and Growth.

Two-photon lithography allows writing of arbitrary nanoarchitectures in photopolymers. This design flexibility opens almost limitless possibilities for biological studies, but the acrylate-based polymers frequently used do not allow for adhesion and growth of some types of cells. Indeed, we found that lithographically defined structures made from OrmoComp do not support E18 murine cortical neurons. We reacted OrmoComp structures with several diamines, thereby rendering the surfaces directly permissive for neuron attachment and growth by presenting a surface coating similar to the traditional cell biology coating achieved with poly-d-lysine (PDL) and laminin. However, in contrast to PDL-laminin coatings that cover the entire surface, the amine-terminated OrmoComp structures are orthogonally modified in deference to the surrounding glass or plastic substrate, adding yet another design element for advanced biological studies.

Fluoroquinolone resistance during 2000-2005: an observational study.

BACKGROUND: Moxifloxacin is a respiratory fluoroquinolone with a community acquired pneumonia indication. Unlike other fluoroquinolones used in our healthcare system, moxifloxacin's urinary excretion is low and thus we hypothesized that increased use of moxifloxacin is associated with an increase in fluoroquinolone resistance amongst gram negative uropathogens. METHODS: All antibiograms for Gram negative bacteria were obtained for 2000 to 2005. The defined daily dose (DDD) for each fluoroquinolone was computed according to World Health Organization criteria. To account for fluctuation in patient volume, DDD/1000 bed days was computed for each year of study. Association between DDD/1000 bed days for each fluoroquinolone and the susceptibility of Gram negative bacteria to ciprofloxacin was assessed using Pearson's Correlation Coefficient, r. RESULTS: During the study period, there were 48,261 antibiograms, 347,931 DDD of fluoroquinolones, and 1,943,338 bed days. Use of fluoroquinolones among inpatients decreased from 237.2 DDD/1000 bed days in 2000 to 115.2 DDD/1000 bed days in 2005. With the exception of Enterobacter aerogenes, moxifloxacin use was negatively correlated with sensitivity among all 13 Gram negative species evaluated (r = -0.07 to -0.97). When the sensitivities of all Gram negative organisms were aggregated, all fluoroquinolones except moxifloxacin were associated with increased sensitivity (r = 0.486 to 1.000) while moxifloxacin was associated with decreased sensitivity (r = -0.464). CONCLUSION: Moxifloxacin, while indicated for empiric treatment of community acquired pneumonia, may have important negative influence on local antibiotic sensitivities amongst Gram negative organisms. This effect was not shared by other commonly used members of the fluoroquinolone class.

Scanning probe lithography of polymers: tailoring morphology and functionality at the nanometer scale.

This article reviews the patterning of the polymer via scanning probe lithography (SPL). Several different lithographies are characterized by the source of the patterned material, whether a mechanical, electrical, or thermal field is used, and whether the lithography modifies morphology, functionality, or both. The merits of the different strategies are discussed with respect to the fabrication goals.

Effectiveness of Risk Evaluation and Mitigation Strategies (REMS) for Lenalidomide and Thalidomide: Patient Comprehension and Knowledge Retention.

INTRODUCTION: The effectiveness of patient education activities conducted within the lenalidomide and thalidomide risk evaluation and mitigation strategies (REMS) programs was evaluated by measuring understanding of serious risk and safe-use messages. METHODS: Results from mandatory knowledge, attitude, and behavior surveys and voluntary patient surveys completed between June 2012 and June 2013 were analyzed, and responses to questions relating to compliance with birth control measures and understanding of safe-use messages are presented by patient risk category. RESULTS: In total, 73,645 patients were enrolled into the REMS programs for lenalidomide and thalidomide and completed mandatory surveys prior to medication dispense. Of these, 2790 (3.8%) completed an additional voluntary survey. Among voluntary survey participants, for all patient pregnancy risk categories, reported compliance with birth control requirements was above 90% when starting therapy and at follow-up. At the beginning of therapy, complete compliance was 96.3%; 3 months later it was 96.4%. Patient understanding of safe-use messages was very high in all pregnancy risk groups, notably for messages repeated at each physician visit. Overall, 98.2% of patients knew that lenalidomide and thalidomide could cause birth defects, which is part of the repeated educational messaging. In contrast, 87.1% recalled that unused product should be returned to their healthcare professional, which is not included in repeated messaging. CONCLUSION: The lenalidomide and thalidomide REMS programs enhance patient understanding of safe-use messages, resulting in high levels of compliance with the birth control precautions essential to prevent fetal exposure to these known and potential human teratogens. Overall compliance was maintained after 3 months of follow-up and throughout therapy.