Terahertz emission from diamond nitrogen-vacancy centers.

Coherent light sources emitting in the terahertz range are highly sought after for fundamental research and applications. Terahertz lasers rely on achieving population inversion. We demonstrate the generation of terahertz radiation using nitrogen-vacancy centers in a diamond single crystal. Population inversion is achieved through the Zeeman splitting of the S = 1 state in 15 tesla, resulting in a splitting of 0.42 terahertz, where the middle Sz = 0 sublevel is selectively pumped by visible light. To detect the terahertz radiation, we use a phase-sensitive terahertz setup, optimized for electron spin resonance (ESR) measurements. We determine the spin-lattice relaxation time up to 15 tesla using the light-induced ESR measurement, which shows the dominance of phonon-mediated relaxation and the high efficacy of the population inversion. The terahertz radiation is tunable by the magnetic field, thus these findings may lead to the next generation of tunable coherent terahertz sources.

Why do startups fail? A core competency deficit model.

A growing body of work aims to explore the reasons behind startup failures. However, there is a need for integrative approaches organized around conceptual frameworks to avoid fragmented and perplexing knowledge about these reasons. To our knowledge, no previous research has systematically investigated the role of competency deficits in startup failures, a crucial element of these failures. In our study, we adapted Spencer's behavioral competence model specifically for startups to identify the competencies within startup teams that, according to their Chief Executive Officers, contributed to their downfall. Three coders meticulously analyzed 50 online accounts of startup failures using a modified Critical Incident Technique. This analysis revealed two prominent competency deficits as pivotal determinants of these startups' outcomes: information-seeking and customer service orientation. Additionally, deficits in technical expertise, analytical thinking, and flexibility emerged as significant factors contributing to these failures. The competency deficits identified in this study offer focal points for evaluating and enhancing startup teams, thereby helping to prevent failure.

A concept for multi-winner tenders for medicinal products with balancing between efficient prices, long-term competition and sustainability of supply.

Achieving price efficiency via tenders, the sustainability of competition, and the prevention of shortages are hot topics in the debates about shaping the pharmaceutical markets. Single-winner tenders receive growing criticism for concentrating on achieving low prices at the expense of the long-term maintenance of a competitive pharmaceutical industry, the security of continuous supply, and disregarding the therapeutic needs of patient populations with specific conditions. This paper aims at drafting a concept to assist the design of multi-winner tenders for medicinal products with a focus on supply and sales guarantees, price efficiency, and equity in access. The concept shall be generally applicable to all kinds of medicinal products including generics, biosimilars, and on-patent products in the out- and in-patient sector. Principles for multi-winner tenders for medicinal products are set and a number of delimitations are made in order to get rid of factors that prevent clairvoyance amid the various pricing and reimbursement systems when designing a concept. The steps to plan and implement a multi-winner tendering procedure are drafted on the basis of the defined principles. The tender should consist of planning, bidding, preparation, sales, and evaluation phases. Pharmaceutical companies shall make bids with price and quantity pairs, which shall be ranked by prices and if applicable then taking into account other factors. The tenderer shall predefine market shares to the various places of the ranking. A double ceiling shall be applicable for the sales of the winners: their sales must not exceed their quantity offer and the predefined market share applicable to their place in the ranking. The implementation of the concept will require the careful adjustment of the tender conditions to the specificities of the pharmaceutical market concerned on the one hand and to the local pricing and reimbursement system on the other hand.

The composition and structure of the ubiquitous hydrocarbon contamination on van der Waals materials.

The behavior of single layer van der Waals (vdW) materials is profoundly influenced by the immediate atomic environment at their surface, a prime example being the myriad of emergent properties in artificial heterostructures. Equally significant are adsorbates deposited onto their surface from ambient. While vdW interfaces are well understood, our knowledge regarding atmospheric contamination is severely limited. Here we show that the common ambient contamination on the surface of: graphene, graphite, hBN and MoS2 is composed of a self-organized molecular layer, which forms during a few days of ambient exposure. Using low-temperature STM measurements we image the atomic structure of this adlayer and in combination with infrared spectroscopy identify the contaminant molecules as normal alkanes with lengths of 20-26 carbon atoms. Through its ability to self-organize, the alkane layer displaces the manifold other airborne contaminant species, capping the surface of vdW materials and possibly dominating their interaction with the environment.

Screening for Myocardial Injury after Mild SARS-CoV-2 Infection with Advanced Transthoracic Echocardiography Modalities.

Although the clinical manifestations of SARS-CoV-2 viral infection affect mainly the respiratory system, cardiac complications are common and are associated with increased morbidity and mortality. While echocardiographic alterations indicating myocardial involvement are widely reported in patients hospitalized for acute COVID-19 infection, much fewer data available in non-hospitalized, mildly symptomatic COVID-19 patients. In our work, we aimed to investigate subclinical cardiac alterations characterized by parameters provided by advanced echocardiographic techniques following mild SARS-CoV-2 viral infection. A total of 86 patients (30 males, age: 39.5 ± 13.0 yrs) were assessed 59 ± 33 days after mild SARS-CoV-2 viral infection (requiring no hospital or <5 days in-hospital treatment) by advanced echocardiographic examination including 2-dimensional (2D) speckle tracking echocardiography and non-invasive myocardial work analysis, and were compared to an age-and sex-matched control group. Altogether, variables from eleven echocardiographic categories representing morphological or functional echocardiographic parameters showed statistical difference between the post-COVID patient group and the control group. The magnitude of change was subtle or mild in the case of these parameters, ranging from 1−11.7% of relative change. Among the parameters, global longitudinal strain [−20.3 (−21.1−−19.0) vs. −19.1 (−20.4−−17.6) %; p = 0.0007], global myocardial work index [1975 (1789−2105) vs. 1829 (1656−2057) Hgmm%; p = 0.007] and right ventricular free wall strain values (−26.6 ± 3.80 vs. −23.8 ± 4.0%; p = 0.0003) showed the most significant differences between the two groups. Subclinical cardiac alterations are present following even mild SARS-CoV-2 viral infection. These more subtle alterations are difficult to detect by routine echocardiography. Extended protocols, involving speckle-tracking echocardiography, non-invasive measurement of cardiac hemodynamics, and possibly myocardial work are necessary for detection and adequate follow-up.

A critical assessment framework to identify, quantify and interpret the sources of uncertainty in cost-effectiveness analyses.

BACKGROUND: Using a standardized approach to describe the sources of uncertainty in cost-effectiveness analyses might bring added value to the local critical assessment procedure of reimbursement submissions in Hungary. The aim of this research is to present a procedural framework to identify, quantify and interpret sources of uncertainty, using the reimbursement dossier of darolutamide as an illustrative example. METHODS: In the procedural framework designed for the critical assessment of cost-effectiveness analyses, the quantifiability of an identified source of uncertainty is assessed through the input parameters of the originally submitted model, which is followed by the interpretation of its impact on estimates of costs and outcomes compared to the base case cost-effectiveness conclusion. RESULTS: Based on our experiences with the recent reimbursement dossier of darolutamide, the significant and quantifiable sources of uncertainty were the time horizon of the economic analysis; the restriction of the efficacy analysis population; long-term relative effectiveness of darolutamide; price discount on subsequent therapies. We identified resource use patterns for comparator and subsequent therapies as a quantifiable, yet non-significant source of uncertainty. The EQ-5D value set used to estimate utility values was identified as a non-quantifiable and potentially not significant source of uncertainty. CONCLUSIONS: The procedural framework, demonstrated with an example, was sufficiently flexible and coherent to document and structure the sources of uncertainty in cost-effectiveness analyses. The full-scale use of this framework is desirable during the decision-making process for reimbursement in Hungary. The further formalization of identifying sources of uncertainty is a possible subject of methodological development.

Direct Visualization of Ultrastrong Coupling between Luttinger-Liquid Plasmons and Phonon Polaritons.

Ultrastrong coupling of light and matter creates new opportunities to modify chemical reactions or develop novel nanoscale devices. One-dimensional Luttinger-liquid plasmons in metallic carbon nanotubes are long-lived excitations with extreme electromagnetic field confinement. They are promising candidates to realize strong or even ultrastrong coupling at infrared frequencies. We applied near-field polariton interferometry to examine the interaction between propagating Luttinger-liquid plasmons in individual carbon nanotubes and surface phonon polaritons of silica and hexagonal boron nitride. We extracted the dispersion relation of the hybrid Luttinger-liquid plasmon-phonon polaritons (LPPhPs) and explained the observed phenomena by the coupled harmonic oscillator model. The dispersion shows pronounced mode splitting, and the obtained value for the normalized coupling strength shows we reached the ultrastrong coupling regime with both native silica and hBN phonons. Our findings predict future applications to exploit the extraordinary properties of carbon nanotube plasmons, ranging from nanoscale plasmonic circuits to ultrasensitive molecular sensing.

Microstructural Evolution of a 3003 Based Aluminium Alloy during the CSET Process.

A new severe plastic deformation technique, known as the complex shearing of extruded tube (CSET), was applied to a 3003 based model aluminium alloy. This technique, consisting of a combination of extrusion and two consecutive Equal Chanel Angular Pressing (ECAP) passes accompanied with concurrent torsional straining, is capable to produce a fine-grained tubular sample directly from a bulk metallic cylinder in one forming operation. In the present paper, the microstructural development of the alloy during partial processes of CSET was studied in detail using light microscopy, electron backscatter diffraction, and transmission electron microscopy. It was found that CSET technique refines the grain size down to 0.4 µm and, consequently, increases the microhardness from the initial value of 40 HV to the final value of 120 HV. The contributions of partial processes of CSET to the total strain were estimated.

Medicine price transparency and confidential managed-entry agreements in Europe: findings from the EURIPID survey.

Pricing of pharmaceuticals is an all-time challenge for healthcare systems. Often public payers agree with companies on confidential managed-entry agreements (MEAs) that, e.g. foresee discounts under specific circumstances. The EURIPID Executive Committee surveyed 22 European countries, who all reported the use of confidential agreements between pharmaceutical companies and public payers, confirming that the actual prices paid are typically lower than the published list price. In 68% of the countries, the confidentiality of MEAs is required by non-disclosure clauses between companies and public payers. In some countries (27%) this is even backed up by a specific law. Our study identified legal constraints for the sharing of information on actual prices and confidential agreements among European countries and consequently restrictions in transparency. In conclusion, the EURIPID survey findings suggest that the current possibility to improve the medicines' price transparency across countries is limited and the issue probably requires international institutional engagement, at least to coordinate initiatives toward a greater collaboration among member states.

Solid-Phase Quasi-Intramolecular Redox Reaction of [Ag(NH3)2]MnO4: An Easy Way to Prepare Pure AgMnO2.

Two monoclinic polymorphs of [Ag(NH3)2]MnO4 containing a unique coordination mode of permanganate ions were prepared, and the high-temperature polymorph was used as a precursor to synthesize pure AgMnO2. The hydrogen bonds between the permanganate ions and the hydrogen atoms of ammonia were detected by IR spectroscopy and single-crystal X-ray diffraction. Under thermal decomposition, these hydrogen bonds induced a solid-phase quasi-intramolecular redox reaction between the [Ag(NH3)2]+ cation and MnO4- anion even before losing the ammonia ligand or permanganate oxygen atom. The polymorphs decomposed into finely dispersed elementary silver, amorphous MnOx compounds, and H2O, N2 and NO gases. Annealing the primary decomposition product at 573 K, the metallic silver reacted with the manganese oxides and resulted in the formation of amorphous silver manganese oxides, which started to crystallize only at 773 K and completely transformed into AgMnO2 at 873 K.

New design and calibration method for a tunable single-grating spatial heterodyne spectrometer.

In our paper, we present a new design for a single-grating tunable spatial heterodyne spectrometer (SHS). Our design simplifies the change of the center wavelength (Littrow wavelength) thus one can quickly tune the system to an arbitrary spectral range. Furthermore, we introduce a new calibration method that provides superior calibration accuracy over the generally used formulas involving small angle approximations. We also present considerations about the general usability of the SHS technique in broadband measurements and propose different strategies to improve the signal-to-noise ratio.

Magnesium Reinforced with Inconel 718 Particles Prepared Ex Situ-Microstructure and Properties.

Magnesium samples reinforced with 0.7, 1.4, and 2.4 vol.% of Inconel 718 particles were prepared using a disintegrated melt deposition technique followed by hot extrusion. Mechanical properties, thermal expansion, and damping were studied with the aim of revealing the particle influence on the microstructure, texture, tensile and compressive behavior, thermal expansion coefficient, and internal friction. The flow stresses are significantly influenced by the test temperature and the vol.% of particles. A substantial asymmetry in the tensile and compressive properties was observed at lower temperatures. This asymmetry is caused by different deformation mechanisms operating in tension and compression. The fiber texture of extruded composite samples, refined grain sizes, and the increased dislocation density improved the mechanical properties. On the other hand, a decrease in the thermal expansion coefficient and internal friction was observed.

Strain Hardening in an AZ31 Alloy Submitted to Rotary Swaging.

An extruded magnesium AZ31 magnesium alloy was processed by rotary swaging (RSW) and then deformed by tension and compression at room temperature. The work-hardening behaviour of 1-5 times swaged samples was analysed using Kocks-Mecking plots. Accumulation of dislocations on dislocation obstacles and twin boundaries is the deciding factor for the strain hardening. Profuse twinning in compression seems to be the reason for the higher hardening observed during compression. The main softening mechanism is apparently the cross-slip between the pyramidal planes of the second and first order. A massive twinning observed at the deformation beginning influences the Hall-Petch parameters.

Near-field infrared microscopy of nanometer-sized nickel clusters inside single-walled carbon nanotubes.

Nickel nanoclusters grown inside single-walled carbon nanotubes (SWCNT) were studied by infrared scattering-type scanning near-field optical microscopy (s-SNOM). The metal clusters give high local contrast enhancement in near-field phase maps caused by the excitation of free charge carriers. The experimental results are supported by calculations using the finite dipole model, approximating the clusters with elliptical nanoparticles. Compared to magnetic force microscopy, s-SNOM appears much more sensitive to detect metal clusters inside carbon nanotubes. We estimate that these clusters contain fewer than ≈700 Ni atoms.

Comprehensive Evaluation of the Properties of Ultrafine to Nanocrystalline Grade 2 Titanium Wires.

This paper describes the mechanical properties and microstructure of commercially pure titanium (Grade 2) processed with Conform severe plastic deformation (SPD) and rotary swaging techniques. This technology enables ultrafine-grained to nanocrystalline wires to be produced in a continuous process. A comprehensive description is given of those properties which should enable straightforward implementation of the material in medical applications. Conform SPD processing has led to a dramatic refinement of the initial microstructure, producing equiaxed grains already in the first pass. The mean grain size in the transverse direction was 320 nm. Further passes did not lead to any additional appreciable grain refinement. The subsequent rotary swaging caused fine grains to become elongated. A single Conform SPD pass and subsequent rotary swaging resulted in an ultimate strength of 1060 MPa and elongation of 12%. The achieved fatigue limit was 396 MPa. This paper describes the production possibilities of ultrafine to nanocrystalline wires made of pure titanium and points out the possibility of serial production, particularly in medical implants.

Influence of Accumulative Roll Bonding on the Texture and Tensile Properties of an AZ31 Magnesium Alloy Sheets.

Deformation behaviour of rolled AZ31 sheets that were subjected to the accumulative roll bonding was investigated. Substantially refined microstructure of samples was achieved after the first and second pass through the rolling mill. Sheets texture was investigated using an X-ray diffractometer. Samples for tensile tests were cut either parallel or perpendicular to the rolling direction. Tensile tests were performed at temperatures ranging from room temperature up to 300 °C. Tensile plastic anisotropy, different from the anisotropy observed in AZ31 sheets by other authors, was observed. This anisotropy decreases with an increasing number of rolling passes and increasing deformation temperature. Grain refinement and texture are the crucial factors influencing the deformation behaviour.

Involvement of small heat shock proteins, trehalose, and lipids in the thermal stress management in Schizosaccharomyces pombe.

Changes in the levels of three structurally and functionally different important thermoprotectant molecules, namely small heat shock proteins (sHsps), trehalose, and lipids, have been investigated upon heat shock in Schizosaccharomyces pombe. Both α-crystallin-type sHsps (Hsp15.8 and Hsp16) were induced after prolonged high-temperature treatment but with different kinetic profiles. The shsp null mutants display a weak, but significant, heat sensitivity indicating their importance in the thermal stress management. The heat induction of sHsps is different in wild type and in highly heat-sensitive trehalose-deficient (tps1Δ) cells; however, trehalose level did not show significant alteration in shsp mutants. The altered timing of trehalose accumulation and induction of sHsps suggest that the disaccharide might provide protection at the early stage of the heat stress while elevated amount of sHsps are required at the later phase. The cellular lipid compositions of two different temperature-adapted wild-type S. pombe cells are also altered according to the rule of homeoviscous adaptation, indicating their crucial role in adapting to the environmental temperature changes. Both Hsp15.8 and Hsp16 are able to bind to different lipids isolated from S. pombe, whose interaction might provide a powerful protection against heat-induced damages of the membranes. Our data suggest that all the three investigated thermoprotectant macromolecules play a pivotal role during the thermal stress management in the fission yeast.

Improved effectiveness of generic medicine markets in Hungary: analysis and recommendations

This publication summarizes the findings of a series of technical reports by many experts involved in assessing the effectiveness of pharmaceutical policy on generic essential medicines markets in the context of the Hungarian health system. Within the framework of certain agreements, WHO provided technical advice in collaboration with local experts and with involvement from international consultants. The primary objective of this report is to provide an overview of the development of incentives to use generics in the Hungarian health system up to the end of 2011, focusing in particular on the reference pricing system and assessing what impact these incentives have had in recent years.

Evaluation of factors influencing the enantioselective enzymatic esterification of lactic acid in ionic liquid.

In this paper esterification of ethanol and lactic acid catalyzed by Candida antarctica B (Novozyme 435) in ionic liquid (Cyphos 104) was studied. The influence of different variables on lipase enantioselectivity and lactic acid conversion was investigated. The variables investigated were ionic liquid mass/lipase mass ratio, water content, alcohol excess and temperature. Using the Design Expert software 2(3) factorial experimental plan (two levels, three factors) was performed to ascertain the effect of selected variables and their interactions on the ethyl lactate enantiomeric excess and lactic acid conversion. The results of the experiments and statistical processing suggest that temperature and alcohol excess have the highest effect on the ethyl lactate enantiomeric excess, while temperature and water content have the highest influence on the lactic acid conversion. The statistical mathematical model developed on the basis of the experimental data showed that the highest enantiomeric excess achieved in the investigated variable range is 34.3%, and the highest conversion is 63.8% at the initial conditions of water content at 8%; 11-fold molar excess of alcohol and temperature at 30 °C.