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Di-tert-butyldiphosphatetrahedrane (tBuCP)2 (1) is a mixed carbon- and phosphorus-based tetrahedral molecule, isolobal to white phosphorus (P4). However, despite the fundamental significance and well-explored reactivity of the latter molecule, the precise structure of the free (tBuCP)2 molecule (1) and a detailed analysis of its electronic properties have remained elusive. Here, single-crystal X-ray structure determination of 1 at low temperature confirms the tetrahedral structure. Furthermore, quantum chemical calculations confirm that 1 is isolobal to P4 and shows a strong largely isotropic diamagnetic response in the magnetic field and thus pronounced spherical aromaticity. A spectroscopic and computational study on the photochemical reactivity reveals that diphosphatetrahedrane 1 readily dimerises to the ladderane-type phosphaalkyne tetramer (tBuCP)4 (2) under irradiation with UV light. With sufficient thermal activation energy, the dimerisation proceeds also in the dark. In both cases, an isomerisation to a 1,2-diphosphacyclobutadiene 1' is the first step. This intermediate subsequently undergoes a [2 + 2] cycloaddition with a second 1,2-diphosphacyclobutadiene molecule to form 2. The 1,2-diphosphacyclobutadiene intermediate 1' can be trapped chemically by N-methylmaleimide as an alternative [2 + 2] cycloaddition partner.
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Two porphyrinoid nanorings have been studied computationally. They were built by linking 40 Zn-porphyrin units with butadiyne bridges. The molecular structures belonging to the D40h point group were fully optimized with the Turbomole program at the density functional theory (DFT) level using the B3LYP functional and the def2-SVP basis sets. The aromatic character was studied at the DFT level by calculating the magnetically induced current-density (MICD) susceptibility using the GIMIC program. The neutral molecules are globally non-aromatic with aromatic Zn-porphyrin units. Charged nanorings could not be studied because almost degenerate frontier orbitals led to vanishing optical gaps for the cations. Since DFT calculations of the MICD are computationally expensive, we also calculated the MICD using three pseudo-π models. Appropriate pseudo-π models were constructed by removing the outer hydrogen atoms and replacing all carbon and nitrogen atoms with hydrogen atoms. The central Zn atom was either replaced with a beryllium atom or with two inner hydrogen atoms. Calculations with the computationally inexpensive pseudo-π models yielded qualitatively the same magnetic response as obtained in the all-electron calculations.
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Introduction: Meaningful patient involvement in health technology assessment (HTA) is essential in ensuring that the interests of the affected patient population, their families, and the general public are accurately reflected in coverage and reimbursement decisions. Central and Eastern European (CEE) countries are generally at less advanced stages of implementing HTA, which is particularly true for patient involvement activities. As part of the Horizon2020 HTx project, this research aimed to form recommendations for critical barriers to patient involvement in HTA in CEE countries. Methods: Built on previous research findings on potential barriers, a prioritisation survey was conducted online with CEE stakeholders. Recommendations for prioritised barriers were formed through a face-to-face workshop by CEE stakeholders and HTx experts. Results: A total of 105 stakeholders from 13 CEE countries completed the prioritisation survey and identified 12 of the 22 potential barriers as highly important. The workshop had 36 participants representing 9 CEE countries, and 5 Western European countries coming together to discuss solutions in order to form recommendations based on best practices, real-life experience, and transferability aspects. Stakeholder groups involved in both phases included HTA organisation representatives, payers, patients, caregivers, patient organisation representatives, patient experts, health care providers, academic and non-academic researchers, health care consultants and health technology manufacturers/providers. As a result, 12 recommendations were formed specified to the CEE region's context, but potentially useful for a broader geographic audience. Conclusion: In this paper, we present 12 recommendations for meaningful, systematic, and sustainable patient involvement in HTA in CEE countries. Our hope is that engaging more than a hundred CEE stakeholders in the study helped to spread awareness of the importance and potential of patient involvement and that the resulting recommendations provide tangible steps for the way forward. Future studies shall focus on country-specific case studies of the implemented recommendations.
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Participación del Paciente , Evaluación de la Tecnología Biomédica , Humanos , Evaluación de la Tecnología Biomédica/métodos , Europa (Continente)RESUMEN
We have calculated the current density induced by an external magnetic field in a set of figure-eight-shaped expanded porphyrinoids. The studied octaphyrins can be divided into three classes (N2, N4, and N6) based on the number of the inner hydrogen atoms of the pyrrole rings. Using the Runge-Kutta method, the current density is split into diatropic and paratropic contributions that are analyzed separately. The calculations show that one common ring current consists of two rather independent pathways. Each of them follows the outer side of the molecular frame of one half of the molecule and passes to the inner side of the frame on the other half. The ring-current pathways are similar to the ones for [12]infinitene. However, the current density of the octaphyrins is more complex having many branching points and pathways. Vertical through-space current-density pathways pass in the middle of the molecules through a plane that is parallel to the figure-eight-shaped view of the molecules when the magnetic field is perpendicular to the plane. The isolectronic N2 and the N4 dication sustain a weak paratropic ring current inside the molecule, which is also observed in the 1H NMR magnetic shielding constant of the inner hydrogen atoms. The diatropic current-density contribution dominates in the studied molecules. For the N4 and N6 molecules, the global current-density pathways are only diatropic and N6 sustains the strongest global diatropic current-density flux of 13.2 nA T-1.
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Introduction: Breast cancer is the most common type of cancer affecting women in Europe. Advanced breast cancer (ABC) poses a significant therapeutic challenge, and therefore, timely access to treatment is crucial. The aim of the present study was to evaluate the treatment patterns and patients' access to new therapies for ABC in Bulgaria. Methods: We conducted a retrospective study in the period 2008-2021. Based on the European Medicines Agency (EMA) database, we analyzed a number of medicinal products with marketing authorization for ABC in the last 13 years. Time to market access was evaluated as the degree of availability, which is measured by the number of medicines that are available to patients (availability index, AI), and the average time elapsed between obtaining a marketing authorization and time to inclusion in the Positive Drug List. Data were analyzed through descriptive statistics via Microsoft Excel version 10. Results: The average time to access was 564 days for targeted therapy. The availability and compliance index for chemotherapy and hormonal therapy in advanced breast cancer was 1, while the average AI for targeted therapy was 0.67. Patient access to targeted oncology therapy of ABC is above average for Europe and takes 1-2 years. Conclusion: Faster access is more evident for biosimilars. National regulatory requirements for pricing and reimbursement have a major impact on market access.
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Biosimilares Farmacéuticos , Neoplasias de la Mama , Humanos , Femenino , Bulgaria , Neoplasias de la Mama/tratamiento farmacológico , Estudios Retrospectivos , Europa (Continente)RESUMEN
Aim: Real-world data and real-world evidence (RWE) are becoming more important for healthcare decision making and health technology assessment. We aimed to propose solutions to overcome barriers preventing Central and Eastern European (CEE) countries from using RWE generated in Western Europe. Materials & methods: To achieve this, following a scoping review and a webinar, the most important barriers were selected through a survey. A workshop was held with CEE experts to discuss proposed solutions. Results: Based on survey results, we selected the nine most important barriers. Multiple solutions were proposed, for example, the need for a European consensus, and building trust in using RWE. Conclusion: Through collaboration with regional stakeholders, we proposed a list of solutions to overcome barriers on transferring RWE from Western Europe to CEE countries.
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Política de Salud , Evaluación de la Tecnología Biomédica , Humanos , Europa (Continente) , Confianza , Toma de DecisionesRESUMEN
Central and Eastern European countries (CEEC) have among the highest rates of increase in healthcare expenditure. External reference pricing, generics and biologics price capping, regressive scale for price setting, health technology assessment (HTA), and positive drug lists for reimbursed medicines are among the variety of implemented cost-containment measures aimed at reducing and controlling the rising cost for pharmaceuticals. The aim of our study was to analyze the influence of a recently introduced measure in Bulgaria-budget capping in terms of overall budget expenditure. A secondary goal was to analyze current and extrapolate future trends in the healthcare and pharmaceutical budget based on data from 2016 to 2021. The study is a retrospective, observational and prognostic, macroeconomic analysis of the National Health Insurance Fund's (NHIF) budget before (2016-2018) and after (2019-2021) the introduction of the new budget cap model. Subgroups analysis for each of the three new budget groups of medicines (group A: medicines for outpatient treatment, prescribed after approval by a committee of 3 specialists; group B: all other medicines out of group A; and group C: oncology and life-saving medicines out of group A) was also performed, and the data were extrapolated for the next 3 years. The Kruskal-Wallis test was applied to establish statistically significant differences between the groups. During 2016-2021, healthcare services and pharmaceutical spending increased permanently, observing a growth of 82 and 80%, respectively. The overall healthcare budget increased from European 1.8 billion to 3.3 billion. The subgroup analysis showed a similar trend for all three groups, with similar growth between them. The highest spending was observed in group C, which outpaced the others mainly due to the particular antineoplastic (chemotherapy) medicines included in it. The rising overall healthcare cost in Bulgaria (from European 1.8 billion to 3.3 billion) reveals that implementation of a mechanism for budget predictability and sustainability is needed. The introduced budget cap is a relatively effective measure, but the high level of overspending and pay-back amount (from European 34 billion to 59 billion during 2019-2021) reveals that the market environmental risk factors are not well foreseen and practically implemented.
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Costos de los Medicamentos , Bulgaria , Estudios Retrospectivos , Control de Costos , Preparaciones FarmacéuticasRESUMEN
Phosphorus analogues of the ubiquitous cyclopentadienyl (Cp) are a rich and diverse family of compounds, which have found widespread use as ligands in organometallic complexes. By contrast, phospholes incorporating heavier group 14 elements (Si, Ge, Sn, and Pb) are hardly known. Here, we demonstrate the isolation of the first metal complexes featuring heavy cyclopentadienyl anions SnP42- and PbP42-. The complexes [(η4-tBu2C2P2)2Co2(µ,η5:η5-P4Tt)] [Tt = Sn (6), Pb (7)] are formed by reaction of white phosphorus (P4) with cyclooctadiene cobalt complexes [Ar'TtCo(η4-P2C2tBu2)(η4-COD)] [Tt = Sn (2), Pb (3), Ar' = C6H3-2,6{C6H3-2,6-iPr2}2, COD = cycloocta-1,5-diene] and Tt{Co(η4-P2C2tBu2)(COD)}2 [Tt = Sn (4), Pb (5)]. While the SnP42- complex 6 was isolated as a pure and stable compound, compound 7 eliminated Pb(0) below room temperature to afford [(η4-tBu2C2P2)2Co2(µ,η4:η4-P4) (8), which is a rare example of a tripledecker complex with a P42- middle deck. The electronic structures of 6-8 are analyzed using theoretical methods including an analysis of intrinsic bond orbitals and magnetic response theory. Thereby, the aromatic nature of P5- and SnP42- was confirmed, while for P42-, a specific type of symmetry-induced weak paramagnetism was found that is distinct from conventional antiaromatic species.
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Magnetically induced current densities (MICDs) of Zn-porphyrinoid nanostructures have been studied at the density functional theory level using the B3LYP functional and the def2-SVP basis set. Six of the studied Zn-porphyrinoid nanostructures consist of two crossing porphyrinoid belts, and one is a porphyrinoid nanoball belonging to the octahedral (O) point group. The Zn-porphyrin units are connected to each other via butadiyne linkers as in a recently synthesized porphyrinoid structure resembling two crossed belts. The MICDs are calculated using the gauge-including magnetically induced current method. Current-density pathways and their strengths were determined by numerically integrating the MICD passing through selected planes that cross chemical bonds or molecular rings. The current-density calculations show that the studied neutral molecules are globally nonaromatic but locally aromatic sustaining ring currents only in the individual porphyrin rings or around two neighboring porphyrins. The ring-current strengths of the individual porphyrin rings are 20% weaker than in Zn-porphyrin, whereas oxidation leads to globally aromatic cations sustaining ring currents that are somewhat stronger than for Zn-porphyrin.
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A new natural scheme is introduced to analyze quantitatively the magnetically induced molecular current density vector field, J. The set of zero points of J, which is called its stagnation graph (SG), has been previously used to study the topological features of the current density of various molecules. Here, the line integrals of the induced magnetic field along edges of the connected subset of the SG are calculated. The edges are oriented such that all weights, i.e., flux values become non-negative, thereby, an oriented flux-weighted (current density) stagnation graph (OFW-SG) is obtained. Since in the exact theoretical limit, J is divergence-free and due to the topological characteristics of such vector fields, the flux of all separate vortices (current density domains) and neighbouring connected vortices can be determined exactly by adding the weights of cyclic subsets of edges (i.e., closed loops) of the OFW-SG. The procedure is exemplified by the minimal example of LiH for a weak homogeneous external magnetic field, B, perpendicular to the chemical bond. The OFW-SG exhibits one closed loop (formally decomposed into two edges), and an open line extending to infinity on both of its ends. The method provides the means of accurately determining the strength of the current density even in molecules with a complicated set of distinct vortices.
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Patients' perspectives are important to identify preferences, estimate values and appreciate unmet medical needs in the process of research and development and subsequent assessment of new health technologies. Patient and public involvement in health technology assessment (HTA) is essential in understanding and assessing wider implications of coverage and reimbursement decisions for patients, their relatives, caregivers, and the general population. There are two approaches to incorporating the patients' voice in HTA, preferably used in a mix. In the first one, patients, caregivers and/or their representatives directly participate at discussions in different stages of the HTA process, often at the same table with other stakeholders. Secondly, patient involvement activities can be supported by evidence on patient value and experience collected directly from patients, caregivers and/or their representatives often by patient groups Patient involvement practices, however, are limited in Central and Eastern European (CEE) countries without clear methodology or regulatory mechanisms to guide patient involvement in the HTA process. This poses the question of transferability of practices used in other countries, and might call for the development of new CEE-specific guidelines and methods. In this study we aim to map potential barriers of patient involvement in HTA in countries of the CEE region.
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Participación del Paciente , Evaluación de la Tecnología Biomédica , Europa (Continente) , Humanos , Evaluación de la Tecnología Biomédica/métodosRESUMEN
The aim of this paper is to identify the barriers that are specifically relevant to the use of Artificial Intelligence (AI)-based evidence in Central and Eastern European (CEE) Health Technology Assessment (HTA) systems. The study relied on two main parallel sources to identify barriers to use AI methodologies in HTA in CEE, including a scoping literature review and iterative focus group meetings with HTx team members. Most of the other selected articles discussed AI from a clinical perspective (n = 25), and the rest are from regulatory perspective (n = 13), and transfer of knowledge point of view (n = 3). Clinical areas studied are quite diverse-from pediatric, diabetes, diagnostic radiology, gynecology, oncology, surgery, psychiatry, cardiology, infection diseases, and oncology. Out of all 38 articles, 25 (66%) describe the AI method and the rest are more focused on the utilization barriers of different health care services and programs. The potential barriers could be classified as data related, methodological, technological, regulatory and policy related, and human factor related. Some of the barriers are quite similar, especially concerning the technologies. Studies focusing on the AI usage for HTA decision making are scarce. AI and augmented decision making tools are a novel science, and we are in the process of adapting it to existing needs. HTA as a process requires multiple steps, multiple evaluations which rely on heterogenous data. Therefore, the observed range of barriers come as a no surprise, and experts in the field need to give their opinion on the most important barriers in order to develop recommendations to overcome them and to disseminate the practical application of these tools.
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Inteligencia Artificial , Evaluación de la Tecnología Biomédica , Niño , Humanos , Evaluación de la Tecnología Biomédica/métodosRESUMEN
The aim of presenting this case was to show the difficulties in making the differential diagnosis of viral meningitis during the COVID pandemic situation.
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COVID-19 , Herpes Simple , Herpesvirus Humano 1 , Meningitis Aséptica , Diagnóstico Diferencial , Herpes Simple/diagnóstico , Humanos , Meningitis Aséptica/diagnósticoRESUMEN
INTRODUCTION: Cognitive impairment has been found in all stages and subtypes of multiple sclerosis (MS). It has a broad negative impact on the lives of people with MS independent of physical symptoms. Perhaps the most severe and far-reaching effect is unemployment, which results in extensive personal, social, and financial costs. Cognition has been linked to unemployment in many countries and shown to mediate the effects of disability on employment status.
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Disfunción Cognitiva , Esclerosis Múltiple , Cognición , Disfunción Cognitiva/etiología , Empleo/psicología , Humanos , Esclerosis Múltiple/psicología , Pruebas Neuropsicológicas , Interacción SocialRESUMEN
The macrocyclic structures with local conjugation readily undergo a redox-triggered change in the diatropic character, leading to a global current-density pathway of the doubly charged systems. The figure-eight geometry of the neutral dimer does not significantly change upon oxidation according to the spectroscopic and computational data. The oxidation leads to 3D cross-conjugation at the intersection of the two ethylene bridges resulting in a global ring current.
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The silanide [Si4 {N(SiMe3 )Dipp}3 ]- (1) transforms into the anionic siliconoid cluster [Si7 {N(SiMe3 )Dipp}3 ]- (2) with four unsubstituted silicon atoms as a contact ion pair with [K([18]crown-6)] in C6 D6 at room temperature within five weeks. Anion 2 was investigated by natural population analysis and visualization of intrinsic atomic orbitals. Magnetically induced current-density calculations of 2 revealed two distinct strong diatropic vortices that sum up in one direction and create a strongly shielded apical silicon atom in 2.
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As part of the HTx (Next Generation Health Technology Assessment) project, this study was aimed at identifying the main barriers for application of real-world evidence (RWE) for the purposes of health technology assessment in the Central and Eastern European countries. A mixed methods approach was employed to identify the main barriers: a scoping review of the literature and a series of discussions with stakeholders. Based on the applied approaches, we attempted to summarize the main barriers and challenges related to transferability of RWE in five main groups: technical, regulatory, clinical, scientific and perceptional barriers. Further research should pursue the development of detailed, consensus-based guidelines to improve the harmonization and standardization of RWE.
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Atención a la Salud , Evaluación de la Tecnología Biomédica , Europa (Continente) , Europa Oriental , HumanosRESUMEN
The molecular structures of porphyrinoid cages were obtained by constructing small polyhedral graphs whose vertices have degree-4. The initial structures were then fully optimized at the density functional theory (DFT) level using the generalized gradient approximation. Some of polyhedral vertices were replaced with Zn-porphyrin units and their edges were replaced with ethyne or butadiyne bridges or connected by fusing two neighboring Zn-porphyrin units. Molecule 1 is an ethyne-bridge porphyrinoid nanotube, whose ends are sealed with a Zn-porphyrin. Molecule 2 is the corresponding open porphyrinoid nanotube. Molecule 3 is a clam-like porphyrinoid cage, whose shells consist of fused Zn-porphyrins, and the two halves are connected via butadiyne bridges. Molecule 4 is a cross-belt of fused Zn-porphyrins, and molecule 5 is a cross-belt of Zn-porphyrins connected with butadiyne bridges. The magnetically induced current density of the optimized porphyrinoid cages was calculated for determining the aromatic character, the degree of aromaticity and the current-density pathways. The current-density calculations were performed at the DFT level with the gaugeâincluding magnetically induced currents (GIMIC) method using the B3LYP hybrid functional and def2-SVP basis sets. Calculations of the current densities show that molecule 2 sustains a paratropic ring current around the nanotube, whereas sealing the ends as in molecule 1 leads to an almost nonaromatic nanotube. Fusing porphyrinoids as in molecules 3 and 4 results in complicated current-density pathways that differ from the ones usually appearing in porphyrinoids. The aromatic character of molecules 4 and 5 changes upon oxidation. The neutral molecule 4 is antiaromatic, whereas the dication is nonaromatic. Molecule 5 is nonaromatic, and its dication is aromatic.