Cerium Nanophases from Cerium Ammonium Nitrate.

Ceria nanomaterials with facile CeIII/IV redox behavior are used in sensing, catalytic, and therapeutic applications, where inclusion of CeIII has been correlated with reactivity. Understanding assembly pathways of CeO2 nanoparticles (NC-CeO2) in water has been challenged by "blind" synthesis, including rapid assembly/precipitation promoted by heat or strong base. Here, we identify a layered phase denoted Ce-I with a proposed formula CeIV(OH)3(NO3)·xH2O (x ≈ 2.5), obtained by adding electrolytes to aqueous cerium ammonium nitrate (CAN) to force precipitation. Ce-I represents intermediate hydrolysis species between dissolved CAN and NC-CeO2, where CAN is a commonly used CeIV compound that exhibits unusual aqueous and organic solubility. Ce-I features Ce-(OH)2-Ce units, representing the first step of hydrolysis toward NC-CeO2 formation, challenging prior assertions about CeIV hydrolysis. Structure/composition of poorly crystalline Ce-I was corroborated by a pair distribution function, Ce-L3 XAS (X-ray absorption spectroscopy), compositional analysis, and 17O nuclear magnetic resonance spectroscopy. Formation of Ce-I and its transformation to NC-CeO2 is documented in solution by small-angle X-ray scattering (SAXS) and in the solid-state by transmission electron microscopy (TEM) and powder X-ray diffraction. Morphologies identified by TEM support form factor models for SAXS analysis, evidencing the incipient assembly of Ce-I. Finally, two morphologies of NC-CeO2 are identified. Sequentially, spherical NC-CeO2 particles coexist with Ce-I, and asymmetric NC-CeO2 with up to 35% CeIII forms at the expense of Ce-I, suggesting direct replacement.

Ligand-Dependent Coalescence Behaviors of Gold Nanoparticles Studied by Multichamber Graphene Liquid Cell Transmission Electron Microscopy.

The formation mechanism of colloidal nanoparticles is complex because significant nonclassical pathways coexist with the conventional nucleation and growth processes. Particularly, the coalescence of the growing clusters determines the final morphology and crystallinity of the synthesized nanoparticles. However, the experimental investigation of the coalescence mechanism is a challenge because the process is highly kinetic and correlates with surface ligands that dynamically modify the surface energy and the interparticle interactions of nanoparticles. Here, we employ quantitative in situ TEM with multichamber graphene liquid cell to observe the coalescence processes occurring in the synthesis of gold nanoparticles in different ligand systems, thus affording us an insight into their ligand-dependent coalescence kinetics. The analyses of numerous liquid-phase TEM trajectories of the coalescence and MD simulations of the ligand shells demonstrate that enhanced ligand mobility, employing a heterogeneous ligand mixture, results in the rapid nanoparticle pairing approach and a fast post-merging structural relaxation.

Cost-effectiveness analysis of trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2): positive advanced breast cancer.

PURPOSE: The EMILIA trial demonstrated that trastuzumab emtansine (T-DM1) significantly increased the median profession-free and overall survival relative to combination therapy with lapatinib plus capecitabine (LC) in patients with HER2-positive advanced breast cancer (ABC) previously treated with trastuzumab and a taxane. We performed an economic analysis of T-DM1 as a second-line therapy compared to LC and monotherapy with capecitabine (C) from both perspectives of the US payer and society. METHODS: We developed four possible Markov models for ABC to compare the projected life-time costs and outcomes of T-DM1, LC, and C. Model transition probabilities were estimated from the EMILIA and EGF100151 clinical trials. Direct costs of the therapies, major adverse events, laboratory tests, and disease progression, indirect costs (productivity losses due to morbidity and mortality), and health utilities were obtained from published sources. The models used 3 % discount rate and reported in 2015 US dollars. Probabilistic sensitivity analysis and model averaging were used to account for model parametric and structural uncertainty. RESULTS: When incorporating both model parametric and structural uncertainty, the resulting incremental cost-effectiveness ratios (ICER) comparing T-DM1 to LC and T-DM1 to C were $183,828 per quality-adjusted life year (QALY) and $126,001/QALY from the societal perspective, respectively. From the payer's perspective, the ICERs were $220,385/QALY (T-DM1 vs. LC) and $168,355/QALY (T-DM1 vs. C). CONCLUSIONS: From both perspectives of the US payer and society, T-DM1 is not cost-effective when comparing to the LC combination therapy at a willingness-to-pay threshold of $150,000/QALY. T-DM1 might have a better chance to be cost-effective compared to capecitabine monotherapy from the US societal perspective.

A Systematic Review of Health Economic Evaluation Studies Using the Patient's Perspective.

BACKGROUND: Patient-centered care has become increasingly important and relevant for informed health care decision making. OBJECTIVE: Our study aimed to perform a systematic review of health economic evaluation studies from the patient's perspective. METHODS: PubMed, EMBASE, and Cochrane Central databases were searched through May 2014 for cost-effectiveness, cost-utility, and cost-benefit studies using the patient's perspective in their analysis. The reporting quality of the studies was evaluated on the basis of Consolidated Health Economic Evaluation Reporting Standards. RESULTS: We identified 30 health economic evaluations using the patient's perspective, of which 7 were conducted in the United States, 9 in Europe, and 14 in Asian or other countries. Seventeen of 23 health conditions evaluated were chronic in nature. Among 12 studies that justified the use of the patient's perspective, patient's financial burden associated with medical treatment was the most commonly cited rationale. A total of 29, 17, and 15 studies examined direct medical, direct nonmedical, and indirect costs, respectively. Seventeen studies also included societal, governmental or payer's, and/or provider's perspective(s) in their analyses. Based on Consolidated Health Economic Evaluation Reporting Standards, more than 20% of the reporting items in these studies were either partially satisfied or not satisfied. CONCLUSIONS: There is a paucity of health economic evaluations conducted from the patient's perspective in the literature. For those studies using the patient's perspective, the true patient costs were not fully explored and study reporting quality was not optimal. With the increasing focus on patient-centered outcomes in health policy research, more frequent use of the patient's perspective in economic studies should be advocated.

Putting words into action: A simple focused education improves prescription label comprehension and functional health literacy.

OBJECTIVES: To assess the effectiveness of an educational intervention on prescription (Rx) label comprehension and functional health literacy (FHL) in older adults. Outcomes were compared between current and redesigned Rx labels. Additional objectives were to examine the correlation between 2 outcome measures and to determine the characterizing variables that are predictors for the outcome measures. SETTING: Southern California, January 2013 to March 2015. PRACTICE DESCRIPTION: Older adults (>55 y) taking 2 or more Rx medications daily were recruited at senior and community centers by a trained data collection team. PRACTICE INNOVATION: The validated Modified LaRue Tool (MLT) tested Rx label comprehension before and after a short, focused educational intervention and correlated it with FHL. INTERVENTIONS: A simple one-on-one education provided by student pharmacists that was focused on critical elements of an Rx label. EVALUATION: Short Test of Functional Health Literacy in Adults (STOFHLA) and MLT scores of all current and redesigned label participants at baseline and follow-up. RESULTS: Participants using redesigned Rx labels (n = 90) showed significantly higher MLT scores than with current Rx labels (n = 28) both before (23.0 ± 2.3 vs. 21.0 ± 2.4; P <0.001) and after educational intervention (23.8 ± 1.7 vs. 22.1 ± 3.1; P <0.001). With the use of analysis of covariance, intervention participants using redesigned label (n = 48) showed significant improvement in both MLT (23.1 ± 2.0 to 24.3 ± 1.0; P <0.001) and STOFHLA (29.8 ± 7.5 to 31.5 ± 5.7; P = 0.011) scores, whereas intervention participants using current Rx label (n = 16) did not show significant improvement in either MLT (P = 0.530) or STOFHLA (P = 0.215) scores. Effect size of intervention (redesigned label) was 0.77, indicating practical significance. MLT and STOFHLA scores were significantly correlated with each other, and age and education level were common significant predictors for both outcomes. CONCLUSION: Older adults using redesigned Rx labels showed improved Rx label comprehension and FHL after educational intervention, as well as higher comprehension compared with those using current Rx labels. Use of a redesigned Rx label and a simple educational intervention should be encouraged to improve Rx label comprehension and FHL.

Moisture-Induced Degradation of Quantum-Sized Semiconductor Nanocrystals through Amorphous Intermediates.

Elucidating the water-induced degradation mechanism of quantum-sized semiconductor nanocrystals is an important prerequisite for their practical application because they are vulnerable to moisture compared to their bulk counterparts. In-situ liquid-phase transmission electron microscopy is a desired method for studying nanocrystal degradation, and it has recently gained technical advancement. Herein, the moisture-induced degradation of semiconductor nanocrystals is investigated using graphene double-liquid-layer cells that can control the initiation of reactions. Crystalline and noncrystalline domains of quantum-sized CdS nanorods are clearly distinguished during their decomposition with atomic-scale imaging capability of the developed liquid cells. The results reveal that the decomposition process is mediated by the involvement of the amorphous-phase formation, which is different from conventional nanocrystal etching. The reaction can proceed without the electron beam, suggesting that the amorphous-phase-mediated decomposition is induced by water. Our study discloses unexplored aspects of moisture-induced deformation pathways of semiconductor nanocrystals, involving amorphous intermediates.

Liquid-Phase Transmission Electron Microscopy for Reliable In Situ Imaging of Nanomaterials.

Liquid-phase transmission electron microscopy (LPTEM) is a powerful in situ visualization technique for directly characterizing nanomaterials in the liquid state. Despite its successful application in many fields, several challenges remain in achieving more accurate and reliable observations. We present LPTEM in chemical and biological applications, including studies for the morphological transformation and dynamics of nanoparticles, battery systems, catalysis, biomolecules, and organic systems. We describe the possible interactions and effects of the electron beam on specimens during observation and present sample-specific approaches to mitigate and control these electron-beam effects. We provide recent advances in achieving atomic-level resolution for liquid-phase investigation of structures anddynamics. Moreover, we discuss the development of liquid cell platforms and the introduction of machine-learning data processing for quantitative and objective LPTEM analysis.

Conformation Dynamics of Single Polymer Strands in Solution.

Conformational changes in macromolecules significantly affect their functions and assembly into high-level structures. Despite advances in theoretical and experimental studies, investigations into the intrinsic conformational variations and dynamic motions of single macromolecules remain challenging. Here, liquid-phase transmission electron microscopy enables the real-time tracking of single-chain polymers. Imaging linear polymers, synthetically dendronized with conjugated aromatic groups, in organic solvent confined within graphene liquid cells, directly exhibits chain-resolved conformational dynamics of individual semiflexible polymers. These experimental and theoretical analyses reveal that the dynamic conformational transitions of the single-chain polymer originate from the degree of intrachain interactions. In situ observations also show that such dynamics of the single-chain polymer are significantly affected by environmental factors, including surfaces and interfaces.

Real-space imaging of nanoparticle transport and interaction dynamics by graphene liquid cell TEM.

Thermal motion of colloidal nanoparticles and their cohesive interactions are of fundamental importance in nanoscience but are difficult to access quantitatively, primarily due to the lack of the appropriate analytical tools to investigate the dynamics of individual particles at nanoscales. Here, we directly monitor the stochastic thermal motion and coalescence dynamics of gold nanoparticles smaller than 5 nm, using graphene liquid cell (GLC) transmission electron microscopy (TEM). We also present a novel model of nanoparticle dynamics, providing a unified, quantitative explanation of our experimental observations. The nanoparticles in a GLC exhibit non-Gaussian, diffusive motion, signifying dynamic fluctuation of the diffusion coefficient due to the dynamically heterogeneous environment surrounding nanoparticles, including organic ligands on the nanoparticle surface. Our study shows that the dynamics of nanoparticle coalescence is controlled by two elementary processes: diffusion-limited encounter complex formation and the subsequent coalescence of the encounter complex through rotational motion, where surface-passivating ligands play a critical role.

A Large-Scale Array of Ordered Graphene-Sandwiched Chambers for Quantitative Liquid-Phase Transmission Electron Microscopy.

Liquid-phase transmission electron microscopy (TEM) offers a real-time microscopic observation of the nanometer scale for understanding the underlying mechanisms of the growth, etching, and interactions of colloidal nanoparticles. Despite such unique capability and potential application in diverse fields of analytical chemistry, liquid-phase TEM studies rely on information obtained from the limited number of observed events. In this work, a novel liquid cell with a large-scale array of highly ordered nanochambers is constructed by sandwiching an anodic aluminum oxide membrane between graphene sheets. TEM analysis of colloidal gold nanoparticles dispersed in the liquid is conducted, employing the fabricated nanochamber array, to demonstrate the potential of the nanochamber array in quantitative liquid-phase TEM. The independent TEM observations in the multiple nanochambers confirm that the monomer attachment and coalescence processes universally govern the overall growth of nanoparticles, although individual nanoparticles follow different growth trajectories.

Validating the Modified Drug Adherence Work-Up (M-DRAW) Tool to Identify and Address Barriers to Medication Adherence.

Barriers to medication adherence stem from multiple factors. An effective and convenient tool is needed to identify these barriers so that clinicians can provide a tailored, patient-centered consultation with patients. The Modified Drug Adherence Work-up Tool (M-DRAW) was developed as a 13-item checklist questionnaire to identify barriers to medication adherence. The response scale was a 4-point Likert scale of frequency of occurrence (1 = never to 4 = often). The checklist was accompanied by a GUIDE that provided corresponding motivational interview-based intervention strategies for each identified barrier. The current pilot study examined the psychometric properties of the M-DRAW checklist (reliability, responsiveness and discriminant validity) in patients taking one or more prescription medication(s) for chronic conditions. A cross-sectional sample of 26 patients was recruited between December 2015 and March 2016 at an academic medical center pharmacy in Southern California. A priming question that assessed self-reported adherence was used to separate participants into the control group of 17 "adherers" (65.4%), and into the intervention group of nine "unintentional and intentional non-adherers" (34.6%). Comparable baseline characteristics were observed between the two groups. The M-DRAW checklist showed acceptable reliability (13 item; alpha = 0.74) for identifying factors and barriers leading to medication non-adherence. Discriminant validity of the tool and the priming question was established by the four-fold number of barriers to adherence identified within the self-selected intervention group compared to the control group (4.4 versus 1.2 barriers, p < 0.05). The current study did not investigate construct validity due to small sample size and challenges on follow-up with patients. Future testing of the tool will include construct validation.

Do value thresholds for oncology drugs differ from nononcology drugs?

BACKGROUND: In the past decade, many oncologic drugs have been approved that extend life and/or improve patients' quality of life. However, new cancer drugs are often associated with high price and increased medical spending. For example, in 2010, the average annual cost of care for breast cancer in the final stage of disease was reported to be $94,284, and the total estimated cost in the United States was $16.50 billion. OBJECTIVE: To determine whether value threshold, as defined by the incremental cost-effectiveness ratio (ICER), differed between oncology and other therapeutic areas.  METHODS: The PubMed database was searched for articles published between January 2003 and December 2013 with calculated ICER for therapeutic drug entities in a specific therapeutic area. The search term used was "ICER" and "United States." From 275 results, only those articles that reported ICERs using quality-adjusted life-years (QALY) were included. In addition, only those articles that used a U.S. payer perspective were retained. Among those, nondrug therapy articles and review articles were excluded. The mean ICER and value threshold for oncologic drugs and nononcologic drugs were evaluated for the analysis.  RESULTS: From 54 articles selected for analysis, 13 pertained to drugs in oncology therapeutics, and the remaining 41 articles addressed ICER for drugs in other therapeutic areas. The mean and median of ICERs calculated for cancer-specific drug intervention was $138,582/QALY and $55,500/QALY, respectively, compared with $49,913/QALY and $31,000/QALY, respectively, for noncancer drugs. Among the cancer drugs, 45.0% had ICERs below $50,000/QALY and 70.0% below $100,000/QALY. In comparison, 72.0% of noncancer drugs showed ICERs below $50,000/QALY, and 90.0% had ICERs below $100,000/QALY. When a specific threshold was mentioned, it was in the range of $100,000-$150,000 in cancer drugs, whereas drugs in other therapeutic areas used traditional threshold value within the range of $50,000-$100,000. CONCLUSIONS: The average ICER reported for cancer drugs was more than 2-fold greater than the average ICER for noncancer drugs. In general, articles that addressed the relative value of oncologic pharmaceuticals used higher value thresholds and reported higher ICERs than articles evaluating noncancer drugs.