Technology adoption by primary care physicians.

We study primary care physicians' prevention and monitoring technology adoption. Physicians' adoption decisions are based on benefits and costs, which depend on payment incentives, educational assistance, and market characteristics. The empirical study uses national Norwegian register and physician claims data between 2009 and 2014. In 2006, a new annual comprehensive checkup for Type 2 diabetic patients was introduced. A physician collects a fee for each checkup. In 2013, an education assistance program was introduced in two Norwegian counties. We estimate adoption decisions by fixed-effect regressions, and two-part and hazard models. We use a difference-in-difference model to estimate the education program impact. Fixed-effect estimations and separate analyses of physicians who have moved between municipalities support a peer effect. The education program has a strongly positive effect, which is positively associated with a physician's number of diabetic patients, and the fraction of physician-adopters in the same market.

Carbon nanotube-fullerene hybrid nanostructures by C60 bombardment: formation and mechanical behavior.

This study reports the investigation on C60 bombardment on the carbon nanotube (CNT) by molecular dynamic (MD) simulations. We found that carbon nanotube nanobuds or nanotube-fullerene hybrid nanostructures can be formed by C60 bombardment. Different from the nanobuds in earlier studies, more structural patterns are found in the bombardment formed nanobuds and nanotube-fullerene hybrid nanostructures. In addition, the attaching strengths of the carbon nanobuds are explored, and results indicate that the junction between C60 and CNTs in the nanobuds is very stable. Moreover, we also found that the bombardment formed nanobuds and nanotube-fullerene hybrid nanostructures generally decrease the maximum tensile strength and Young's modulus of carbon nanotubes.

Microstructures and Corrosion Properties of Wire Arc Additive Manufactured Copper-Nickel Alloys.

The 70/30 copper-nickel alloy is used mainly in critical parts with more demanding conditions in marine settings. There is a need for innovative methods that offer fast production and cost-effectiveness in order to supplement current copper-nickel alloy manufacturing processes. In this study, we employ wire arc additive manufacturing (WAAM) to fabricate the 70/30 copper-nickel alloy. The as-built microstructure is characterized by columnar grains with prominent dendrites and chemical segregation in the inter-dendritic area. The aspect ratio of the columnar grain increases with increasing travel speed (TS) at the same wire feed speed (WFS). This is in contrast with the equiaxed grain structure, with a more random orientation, of the conventional sample. The sample built with a WFS of 8 m/min, TS of 1000 mm/min, and a track distance of 3.85 mm exhibits superior corrosion properties in the 3.5 wt% NaCl solution when compared with the conventional sample, as evidenced by a higher film resistance and breakdown potential, along with a lower passive current density of the WAAM sample. The corrosion morphology reveals the critical roles played by the nickel element that is unevenly distributed between the dendrite core and inter-dendritic area.

Characterization of Two Highly Specific Monoclonal Antibodies Targeting the Glycan Loop of the Zika Virus Envelope Protein.

Zika virus (ZIKV) is an emerging flavivirus associated with several neurological diseases such as Guillain-Barré syndrome in adults and microcephaly in newborn children. Its distribution and mode of transmission (via Aedes aegypti and Aedes albopictus mosquitoes) collectively cause ZIKV to be a serious concern for global health. High genetic homology of flaviviruses and shared ecology is a hurdle for accurate detection. Distinguishing infections caused by different viruses based on serological recognition can be misleading as many anti-flavivirus monoclonal antibodies (mAbs) discovered to date are highly cross-reactive, especially those against the envelope (E) protein. To provide more specific research tools, we produced ZIKV E directed hybridoma cell lines and characterized two highly ZIKV-specific mAb clones (mAbs A11 and A42) against several members of the Flavivirus genus. Epitope mapping of mAb A11 revealed glycan loop specificity in Domain I of the ZIKV E protein. The development of two highly specific mAbs targeting the surface fusion protein of ZIKV presents a significant advancement in research capabilities as these can be employed as essential tools to enhance our understanding of ZIKV identification on infected cells ex vivo or in culture.

Thermostable bivalent filovirus vaccine protects against severe and lethal Sudan ebolavirus and marburgvirus infection.

Although two vaccines for Zaire ebolavirus (EBOV) have been licensed and deployed successfully to combat recurring outbreaks of Ebolavirus Disease in West Africa, there are no vaccines for two other highly pathogenic members of the Filoviridae, Sudan ebolavirus (SUDV) and Marburg marburgvirus (MARV). The results described herein document the immunogenicity and protective efficacy in cynomolgus macaques of a single-vial, thermostabilized (lyophilized) monovalent (SUDV) and bivalent (SUDV & MARV) protein vaccines consisting of recombinant glycoproteins (GP) formulated with a clinical-grade oil-in-water nanoemulsion adjuvant (CoVaccine HT™). Lyophilized formulations of the vaccines were reconstituted with Water for Injection and used to immunize groups of cynomolgus macaques before challenge with a lethal dose of a human SUDV or MARV isolate. Sera collected after each of the three immunizations showed near maximal GP-binding IgG concentrations starting as early as the second dose. Most importantly, the vaccine candidates (monovalent or bivalent) provided 100% protection against severe and lethal filovirus disease after either SUDV or MARV infection. Although mild, subclinical infection was observed in a few macaques, all vaccinated animals remained healthy and survived the filovirus challenge. These results demonstrate the value that thermostabilized protein vaccines could provide for addressing an important gap in preparedness for future filovirus outbreaks.

Unusually high room and elevated-temperature tensile properties observed in direct aged wire-arc directed energy deposited Inconel 718.

Wire-arc directed energy deposition (DED) processed Inconel (IN) 718 is known to have coarse columnar grains, strong texture, and significant chemical and microstructural inhomogeneity in the as-fabricated condition. Homogenization treatment is commonly used prior to aging to eliminate the inhomogeneity and detrimental precipitation for better mechanical properties. In this study, however, direct aging (DA) at 700 °C without homogenization has resulted in room-temperature yield strength, ultimate tensile strength (UTS), and elongation that are comparable to wrought condition and among the highest reported properties for wire-arc DED IN718. The DA samples at between 650 and 750 °C aging also demonstrates remarkable ductility when deformed at elevated temperatures. In addition, when aged below 750 °C the DA IN718 possesses significantly higher UTS compared to those with homogenization treatment. These superior mechanical properties are highly likely due to the non-uniform and hierarchical precipitation consisting of disk-shaped γ″ in diameter from a few to tens of nm in the dendritic core area and micron-sized Laves phase and carbides in the inter-dendritic region.

Changing preferences: An experiment and estimation of market-incentive effects on altruism.

This paper studies how altruistic preferences are changed by markets and incentives. We conduct a laboratory experiment with a within-subject design. Subjects are asked to choose health care qualities for hypothetical patients in monopoly, duopoly, and quadropoly. Prices, costs, and patient benefits are experimental incentive parameters. In monopoly, subjects choose quality by trading off between profits and altruistic patient benefits. In duopoly and quadropoly, subjects play a simultaneous-move game. Uncertain about an opponent's altruism, each subject competes for patients by choosing qualities. Bayes-Nash equilibria describe subjects' quality decisions as functions of altruism. Using a nonparametric method, we estimate the population altruism distributions from Bayes-Nash equilibrium qualities in different markets and incentive configurations. Competition tends to reduce altruism, but duopoly and quadropoly equilibrium qualities are much higher than monopoly. Although markets crowd out altruism, the disciplinary powers of market competition are stronger. Counterfactuals confirm markets change preferences.

Toward Real-Time Blood Pressure Monitoring via High-Fidelity Iontronic Tonometric Sensors with High Sensitivity and Large Dynamic Ranges.

Continuous, noninvasive blood pressure (CNIBP) monitoring provides valuable hemodynamic information that renders detection of the early onset of cardiovascular diseases. Wearable mechano-electric pressure sensors that mount on the skin are promising candidates for monitoring continuous blood pressure (BP) pulse waveforms due to their excellent conformability, simple sensing mechanisms, and convenient signal acquisition. However, it is challenging to acquire high-fidelity BP pulse waveforms since it requires highly sensitive sensors (sensitivity larger than 4 × 10-5 kPa-1 ) that respond linearly with pressure change over a large dynamic range, covering the typical BP range (5-25 kPa). Herein, this work introduces a high-fidelity, iontronic-based tonometric sensor (ITS) with high sensitivity (4.82 kPa-1 ), good linearity (R2 > 0.995), and a large dynamic range (up to 180% output change) over a broad working range (0 to 38 kPa). Additionally, the ITS demonstrates a low limit of detection at 40 Pa, a fast load response time (35 ms) and release time (35 ms), as well as a stable response over 5000 load per release cycles, paving ways for potential applications in human-interface interaction, electronic skins, and robotic haptics. This work further explores the application of the ITS in monitoring real-time, beat-to-beat BP by measuring the brachial and radial pulse waveforms. This work provides a rational design of a wearable pressure sensor with high sensitivity, good linearity, and a large dynamic range for real-time CNIBP monitoring.

Adjuvants Differentially Modulate the Immunogenicity of Lassa Virus Glycoprotein Subunits in Mice.

Lassa Fever (LF) is an acute viral hemorrhagic fever caused by Lassa virus (LASV) that is primarily transmitted through contact with wild rodents in West Africa. Although several advanced vaccine candidates are progressing through clinical trials, some effective vaccines are virally vectored and thus require a stringent cold-chain, making distribution to rural and resource-poor areas difficult. Recombinant subunit vaccines are advantageous in this aspect as they can be thermostabilized and deployed with minimal storage and transportation requirements. However, antigen dose and adjuvant formulation must be carefully selected to ensure both the appropriate humoral and cell-mediated immune responses are elicited. In this study, we examine the immunogenicity of a two-step immunoaffinity-purified recombinant LASV glycoprotein (GP) with five clinical- and preclinical-grade adjuvants. Swiss Webster mice immunized intramuscularly with 2 or 3 doses of each vaccine formulation showed complete seroconversion and maximal GP-specific antibody response after two immunizations. Formulations with GPI-0100, LiteVax, Montanide™ ISA 51, and Montanide™ ISA 720 induced both IgG1 and IgG2 antibodies suggesting a balanced Th1/Th2 response, whereas formulation of LASV GP with Alhydrogel elicited a IgG1-dominant response. Splenocytes secreting both Th1 and Th2 cytokines i.e., IFN-γ, TNF-α, IL-2, IL-4 and IL-5, were observed from mice receiving both antigen doses formulated with ISA 720, LiteVax and GPI-0100. However, robust, multifunctional T-cells were only detected in mice receiving a higher dose of LASV GP formulated with GPI-0100. Our results emphasize the importance of careful adjuvant selection and lay the immunological basis for a recombinant subunit protein LF vaccine formulation.

Lyophilized Filovirus Glycoprotein Vaccines: Peroxides in a Vaccine Formulation with Polysorbate 80-Containing Adjuvant are Associated with Reduced Neutralizing Antibody Titers in Both Mice and Non-Human Primates.

Zaire ebolavirus, Sudan ebolavirus, and Marburg marburgvirus are the filoviruses most commonly associated with human disease. Previously, we administered a three-dose regimen of trivalent vaccines comprising glycoprotein antigens from each virus in mice and non-human primates (NHPs). The vaccines, which contained a polysorbate 80-stabilized squalane-in-water emulsion adjuvant and were lyophilized from a solution containing trehalose, produced high antibody levels against all three filovirus antigens. Subsequently, single-vial formulations containing a higher concentration of adjuvant were generated for testing in NHPs, but these vaccines elicited lower neutralizing antibody titers in NHPs than previously tested formulations. In order to explain these results, in the current work we measured the size of adjuvant emulsion droplets and the peroxide levels present in the vaccines after lyophilization and reconstitution and tested the effects of these variables on the immune response in mice. Increases in squalane droplet sizes were observed when the ratio of adjuvant to trehalose was increased beyond a critical value, but antibody and neutralizing antibody titers in mice were independent of the droplet size. Higher levels of peroxides in the vaccines correlated with higher concentrations of adjuvant in the formulations, and higher peroxide levels were associated with increased levels of oxidative damage to glycoprotein antigens. Neutralizing titers in mice were inversely correlated with peroxide levels in the vaccines, but peroxide levels could be reduced by adding free methionine, resulting in retention of high neutralizing antibody titers. Overall, the results suggest that oxidation of glycoprotein antigens by peroxides in the polysorbate 80-stabilized squalane-in-water emulsion adjuvant, but not lyophilization-induced increases in adjuvant emulsion droplet size may have been responsible for the decreased neutralizing titers seen in formulations containing higher amounts of adjuvant.

A Recombinant Subunit Vaccine Induces a Potent, Broadly Neutralizing, and Durable Antibody Response in Macaques against the SARS-CoV-2 P.1 (Gamma) Variant.

FDA-approved and emergency use-authorized vaccines using new mRNA and viral-vector technology are highly effective in preventing moderate to severe disease; however, information on their long-term efficacy and protective breadth against severe acute respiratory syndrome coronavirus 2 variants of concern (VOCs) is currently scarce. Here, we describe the durability and broad-spectrum VOC immunity of a prefusion-stabilized spike (S) protein adjuvanted with liquid or lyophilized CoVaccine HT in cynomolgus macaques. This recombinant subunit vaccine is highly immunogenic and induces robust spike-specific and broadly neutralizing antibody responses effective against circulating VOCs (B.1.351 [Beta], P.1 [Gamma], and B.1.617 [Delta]) for at least three months after the final boost. Protective efficacy and postexposure immunity were evaluated using a heterologous P.1 challenge nearly three months after the last immunization. Our results indicate that while immunization with both high and low S doses shorten and reduce viral loads in the upper and lower respiratory tract, a higher antigen dose is required to provide durable protection against disease as vaccine immunity wanes. Histologically, P.1 infection causes similar COVID-19-like lung pathology as seen with early pandemic isolates. Postchallenge IgG concentrations were restored to peak immunity levels, and vaccine-matched and cross-variant neutralizing antibodies were significantly elevated in immunized macaques indicating an efficient anamnestic response. Only low levels of P.1-specific neutralizing antibodies with limited breadth were observed in control (nonvaccinated but challenged) macaques, suggesting that natural infection may not prevent reinfection by other VOCs. Overall, these results demonstrate that a properly dosed and adjuvanted recombinant subunit vaccine can provide protective immunity against circulating VOCs for at least three months.

Surface structure and properties of functionalized nanodiamonds: a first-principles study.

The goal of this work is to gain fundamental understanding of the surface and internal structure of functionalized detonation nanodiamonds (NDs) using quantum mechanics based density functional theory (DFT) calculations. The unique structure of ND assists in the binding of different functional groups to its surface which in turn facilitates binding with drug molecules. The ability to comprehensively model the surface properties, as well as drug-ND interactions during functionalization, is a challenge and is the problem of our interest. First, the structure of NDs of technologically relevant size (∼5 nm) was optimized using classical mechanics based molecular mechanics simulations. Quantum mechanics based density functional theory (DFT) was then employed to analyse the properties of smaller relevant parts of the optimized cluster further to address the effect of functionalization on the stability of the cluster and reactivity at its surface. It is found that functionalization is preferred over reconstruction at the (100) surface and promotes graphitization in the (111) surface for NDs functionalized with the carbonyl oxygen (C = O) group. It is also seen that the edges of ND are the preferred sites for functionalization with the carboxyl group (-COOH) vis-à-vis the corners of ND.

Market conditions and general practitioners' referrals.

We study how market conditions influence referrals of patients by general practitioners (GPs). We set up a model of GP referral for the Norwegian health care system, where a GP receives capitation payment based on the number of patients in his practice, as well as fee-for-service reimbursements. A GP may accept new patients or close the practice to new patients. We model GPs as partially altruistic, and compete for patients. We show that a GP operating in a more competitive market has a higher referral rate. To compete for patients and to retain them, a GP satisfies patients' requests for referrals. Furthermore, a GP who faces a patient shortage will refer more often than a GP who does not. Tests with Norwegian GP radiology referral data support our theory.

Integrating Geometric Data into Topology Optimization via Neural Style Transfer.

This research proposes a novel topology optimization method using neural style transfer to simultaneously optimize both structural performance for a given loading condition and geometric similarity for a reference design. For the neural style transfer, the convolutional layers of a pre-trained neural network extract and quantify characteristic features from the reference and input designs for optimization. The optimization analysis is evaluated as a single weighted objective function with the ability for the user to control the influence of the neural style transfer with the structural performance. As seen in architecture and consumer-facing products, the visual appeal of a design contributes to its overall value along with mechanical performance metrics. Using this method, a designer allows the tool to find the ideal compromise of these metrics. Three case studies are included to demonstrate the capabilities of this method with various loading conditions and reference designs. The structural performances of the novel designs are within 10% of the baseline without geometric reference, and the designs incorporate features in the given reference such as member size or meshed features. The performance of the proposed optimizer is compared against other optimizers without the geometric similarity constraint.

Recombinant protein subunit SARS-CoV-2 vaccines formulated with CoVaccine HT adjuvant induce broad, Th1 biased, humoral and cellular immune responses in mice.

The speed at which several COVID-19 vaccines went from conception to receiving FDA and EMA approval for emergency use is an achievement unrivaled in the history of vaccine development. Mass vaccination efforts using the highly effective vaccines are currently underway to generate sufficient herd immunity and reduce transmission of the SARS-CoV-2 virus. Despite the most advanced vaccine technology, global recipient coverage, especially in resource-poor areas remains a challenge as genetic drift in naïve population pockets threatens overall vaccine efficacy. In this study, we described the production of insect-cell expressed SARS-CoV-2 spike protein ectodomain constructs and examined their immunogenicity in mice. We demonstrated that, when formulated with CoVaccine HTTM adjuvant, an oil-in-water nanoemulsion compatible with lyophilization, our vaccine candidates elicit a broad-spectrum IgG response, high neutralizing antibody (NtAb) titers against SARS-CoV-2 prototype and variants of concern, specifically B.1.351 (Beta) and P.1. (Gamma), and an antigen-specific IFN-γ secreting response in outbred mice. Of note, different ectodomain constructs yielded variations in NtAb titers against the prototype strain and some VOC. Dose response experiments indicated that NtAb titers increased with antigen dose, but not adjuvant dose, and may be higher with a lower adjuvant dose. Our findings lay the immunological foundation for the development of a dry-thermostabilized vaccine that is deployable without refrigeration.

Recombinant protein subunit SARS-CoV-2 vaccines formulated with CoVaccine HT adjuvant induce broad, Th1 biased, humoral and cellular immune responses in mice.

The speed at which several COVID-19 vaccines went from conception to receiving FDA and EMA approval for emergency use is an achievement unrivaled in the history of vaccine development. Mass vaccination efforts using the highly effective vaccines are currently underway to generate sufficient herd immunity and reduce transmission of the SARS-CoV-2 virus. Despite the most advanced vaccine technology, global recipient coverage, especially in resource-poor areas remains a challenge as genetic drift in naïve population pockets threatens overall vaccine efficacy. In this study, we described the production of insect-cell expressed SARS-CoV-2 spike protein ectodomain and examined its immunogenicity in mice. We demonstrated that, when formulated with CoVaccine HT™adjuvant, an oil-in-water nanoemulsion compatible with lyophilization, our vaccine candidates elicit a broad-spectrum IgG response, high neutralizing antibody titers, and a robust, antigen-specific IFN-γ secreting response from immune splenocytes in outbred mice. Our findings lay the foundation for the development of a dry-thermostabilized vaccine that is deployable without refrigeration.

Single-vial filovirus glycoprotein vaccines: Biophysical characteristics and immunogenicity after co-lyophilization with adjuvant.

Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV), and Marburg marburgvirus (MARV) are the most prevalent and pathogenic species of filovirus. Previously, we showed that glycoprotein antigens from each virus could be lyophilized to create thermostable monovalent subunit vaccines. However, cross-protection is not expected from the monovalent vaccines and therefore developing a trivalent filovirus vaccine would be desirable. Subunit protein vaccines often require the addition of an adjuvant to sufficiently boost the immunogenicity. Typically, liquid suspensions or emulsions of adjuvants and lyophilized antigens are stored in separate vials to avoid destabilizing interactions and are only mixed immediately before administration. Herein, we describe the development and characterization of monovalent and trivalent filovirus vaccines that are co-lyophilized with a squalane-in-water emulsion adjuvant. We found that the single-vial presentation retained adjuvant particle diameter and zeta potential after lyophilization and reconstitution. Furthermore, the trivalent vaccines elicited high antibody levels against all three antigens in mice and non-human primates. These results advance the prospect of developing a single-vial trivalent filovirus vaccine, which would enable easier distribution and administration of the vaccine to resource-poor areas.

Anomalous heat conduction behavior in thin finite-size silicon nanowires.

Anomalous heat conduction behavior is observed for the first time using non-equilibrium molecular dynamics (NEMD) simulations to obtain the thermal conductivity of thin finite-size silicon nanowires (NWs) in the 001 lattice direction. In the series of simulations, the length dependence of thermal conductivity of thin silicon nanowires (NWs) ranging from 6 to 434 nm is analyzed. It is found that a transition occurs in the thermal conductivity versus length curve after the initial convergence trend appears near the mean free path of bulk silicon. Because no experimental measurements of thermal conductivity are available for sub-10 nm diameter silicon NWs, different NEMD methods are used to test and analyze this anomalous thermal behavior of thin Si NWs with different boundary conditions. The underlying mechanism of the observed behavior is inferred from MD simulations with different boundary conditions so that the anomalous behavior is mainly caused by border restriction and boundary scattering of the thin silicon NWs.

Preservation of Quaternary Structure in Thermostable, Lyophilized Filovirus Glycoprotein Vaccines: A Search for Stability-Indicating Assays.

The filoviruses Zaire ebolavirus (EBOV), Marburg marburgvirus (MARV), and Sudan ebolavirus (SUDV) are some of the most lethal infectious agents known. To date, the Zaire ebolavirus vaccine (ERVEBO®) is the only United States Food and Drug Administration (FDA) approved vaccine available for any species of filovirus. However, the ERVEBO® vaccine requires cold-chain storage not to exceed -60 °C. Such cold-chain requirements are difficult to maintain in low- and middle-income countries where filovirus outbreaks originate. To improve the thermostability of filovirus vaccines in order to potentially relax or eliminate these cold-chain requirements, monovalent subunit vaccines consisting of glycoproteins from EBOV, MARV, and SUDV were stabilized within amorphous disaccharide glasses through lyophilization. Lyophilized formulations and liquid controls were incubated for up to 12 weeks at 50 °C to accelerate degradation. To identify a stability-indicating assay appropriate for monitoring protein degradation and immunogenicity loss during these accelerated stability studies, filovirus glycoprotein secondary, tertiary, and quaternary structures and vaccine immunogenicity were measured. Size-exclusion chromatography was the most sensitive indicator of glycoprotein stability in the various formulations for all three filovirus immunogens. Degradation of the test vaccines during accelerated stability studies was reflected in changes in quaternary structure, which were discernible with size-exclusion chromatography. Filovirus glycoproteins in glassy lyophilized formulations retained secondary, tertiary, and quaternary protein structure over the incubation period, whereas the proteins within liquid controls both aggregated to form higher molecular weight species and dissociated from their native quaternary structure to form a variety of structurally-perturbed lower molecular weight species.

Service motives and profit incentives among physicians.

We model physicians as health care professionals who care about their services and monetary rewards. These preferences are heterogeneous. Different physicians trade off the monetary and service motives differently, and therefore respond differently to incentive schemes. Our model is set up for the Norwegian health care system. First, each private practice physician has a patient list, which may have more or less patients than he desires. The physician is paid a fee-for-service reimbursement and a capitation per listed patient. Second, a municipality may obligate the physician to perform 7.5 h/week of community services. Our data are on an unbalanced panel of 435 physicians, with 412 physicians for the year 2002, and 400 for 2004. A physician's amount of gross wealth and gross debt in previous periods are used as proxy for preferences for community service. First, for the current period, accumulated wealth and debt are predetermined. Second, wealth and debt capture lifestyle preferences because they correlate with the planned future income and spending. The main results show that both gross debt and gross wealth have negative effects on physicians' supply of community health services. Gross debt and wealth have no effect on fee-for-service income per listed person in the physician's practice, and positive effects on the total income from fee-for-service. The higher income from fee-for-service is due to a longer patient list. Patient shortage has no significant effect on physicians' supply of community services, a positive effect on the fee-for-service income per listed person, and a negative effect on the total income from fee for service. These results support physician preference heterogeneity.