bluuebunny/crossref_metadata_2025 huggingface dataset:
The therapeutic dilemma of immunosuppressive drugs for refractory cardiac sarcoidosis in COVID‐19 infection
Authors: Goto Kohsaku , Uehara Masae , Okamoto Koh , Takeda Norifumi , Morita Hiroyuki , Hatano Masaru , Komuro Issei
Published: October 2021

Patients with refractory cardiac sarcoidosis (CS) take a high dose of corticosteroid and immunosuppressive agents. During the pandemic outbreak of severe acute respiratory syndrome coronavirus 2, appropriate treatment of corticosteroids or immunosuppressive agents in CS patients with coronavirus disease 2019 (COVID‐19) is unknown. Here, the woman with refractory CS receiving maintenance therapy with 15 mg of prednisolone daily and 10 mg of methotrexate weekly was emergently admitted to our hospital because of COVID‐19. This case was successfully treated by the intravenous administration of dexamethasone 6 mg/day instead of prednisolone and interruption of methotrexate without resulting in recurrent life‐threatening ventricular lethal arrhythmias or obvious sarcoidosis flare‐ups. She started taking prednisolone and methotrexate at the maintenance dose immediately and at 2 weeks after discharge, respectively. Although the optimal regimen of immunosuppressive agents during COVID‐19 is under intense debate, this report might provide an effective treatment strategy for CS patients with COVID‐19.
Analytical solution to dielectric droplet diffusiophoresis under Debye–Hückel approximation
Authors: Tsai Meng‐Yu , Wu Yvonne , Fan Leia , Jian Elaine , Lin Jason , Tseng Jessica , Tseng Andy , Wan Renee , Lee Eric
Published: October 2021

A simple analytical formula is obtained for the diffusiophoresis of a dielectric fluid droplet in symmetric binary electrolyte solutions under Debye–Hückel approximation valid for weakly charged droplets. The chemiphoresis is found to yield negative mobilities most of the time for droplets of constant surface charge density, which implies that the droplets tend to move away from the source releasing ionic chemicals. This is undesirable in some practical applications like drug delivery with liposomes in terms of conveying the drug‐carrying liposomes to the desired area in the human body releasing specific ionic chemicals utilizing the self‐guiding nature of diffusiophoresis. The further involvement of the electrophoresis component, however, may change the scenario via the oriented electric field generated by the induced diffusion potential. The lesson here is that while the impact of the chemiphoresis component is determined by nature and uncontrollable, the electrophoresis component serves as an artificially adjustable factor via choosing droplets with the surface charge of appropriate sign in practical applications. The results here have potential use in practical applications such as drug delivery. The portable simple analytical formula is a powerful asset to experimental researchers and design engineers in colloid science and technology to facilitate their works.
US‐China cooperation on low carbon development planning and analysis in China's provinces and cities
Authors: Peterson Thomas D. , Roe Stephen M. , Ugliano Arianna , Yu Qingchan , Liao Cuiping
Published: October 2021

From 2009 to 18, the US based Center for Climate Strategies and Beijing based Global Environmental Institute led a cooperative US‐China relations program on low carbon development (LCD). The template for bilateral cooperation leveraged traditional policy innovation and mainstreaming procedures in China through early stage training and counterpart exchange, co‐development and piloting of tools, national endorsement for official use, training and capacity building, and cooperative planning actions. The experience suggests that the bilateral cooperation model through high level technical and institutional cooperation between governmental and nongovernmental experts worked well and can be replicated with customization to new bilateral relationships at different jurisdictional levels and for different issue areas. However, to succeed it requires years of stable investment and continuous counterpart engagement, and its application to new bilateral cooperation must address a variety of barriers. The China subnational LCD co‐development process was enabled by an existing US template for state level comprehensive climate action planning applied in over 20 US states. Its domestication in China resulted in creation of the China Subnational LCD Planning and Analysis Toolkit, a pilot in Chongqing, official endorsement by China's National Development and Reform Commission (NDRC), and further recognition through a US State Department – China NDRC EcoPartnership. Ultimately, it involved many partners, including the Chinese Academy of Sciences Institute for Policy and Management, the Guangzhou Institute of Energy Conversion, and over 30 provinces and cities. It led to new China efforts addressing renewable energy implementation in South China, and for LCD and renewable energy cooperation in Southeast Asia.
Seismic vulnerability modelling of building portfolios using artificial neural networks
Authors: Kalakonas Petros , Silva Vitor
Published: October 2021

The incorporation of machine learning (ML) algorithms in earthquake engineering can improve existing methodologies and enable new frameworks to solve complex problems. In the present study, the use of artificial neural networks (ANNs) for the derivation of seismic vulnerability models for building portfolios is explored. Large sets of ground motion records (GMRs) and structural models representing the building stock in the Balkan region were used to train ANNs for the prediction of structural response, damage and economic loss conditioned on a vector of ground shaking intensity measures. The structural responses and loss ratios (LRs) generated using the neural networks were compared with results based on traditional regression models using scalar intensity measures in terms of efficiency, sufficiency, bias and variability. The results indicate a superior performance of the ANN models over traditional approaches, potentially allowing a greater reliability and accuracy in scenario and probabilistic seismic risk assessment.
The effects of drug safety warnings on drug sales and share prices
Authors: Białkowski Jędrzej , Clark Jeremy
Published: October 2021

Current regulations require that when seeking approval for new drugs, pharmaceutical companies must demonstrate their short‐ but not long‐term safety and efficacy. Instead, post‐approval, clinicians report adverse reactions to regulators, who may issue additional safety warnings. We investigate the incentives this creates for pharmaceutical companies to seek approval for new drugs with unknown long‐term effects. We first construct models predicting that (1) long‐run effects can be reasonably approximated from observational follow‐up of short‐term randomized control trials, and (2) companies will trade‐off short‐term sales against possible later adverse demand effects. We then test whether regulator warnings over diabetic, analgesic, analeptic, or psychoanaleptic drugs sold in the US and UK hospital and retail sectors affect the sales of individual drugs or the share prices of companies that sell them. With some exceptions, we find that pharmaceutical companies generally face no adverse market reaction in sales or share price from newly issued warnings in these four drug categories.
Haste makes waste: A critical review of docking‐based virtual screening in drug repurposing for SARS‐CoV‐2 main protease (M‐pro) inhibition
Authors: Macip Guillem , Garcia‐Segura Pol , Mestres‐Truyol Júlia , Saldivar‐Espinoza Bryan , Ojeda‐Montes María José , Gimeno Aleix , Cereto‐Massagué Adrià , Garcia‐Vallvé Santiago , Pujadas Gerard
Published: October 2021

This review makes a critical evaluation of 61 peer‐reviewed manuscripts that use a docking step in a virtual screening (VS) protocol to predict SARS‐CoV‐2 M‐pro (M‐pro) inhibitors in approved or investigational drugs. Various manuscripts predict different compounds, even when they use a similar initial dataset and methodology, and most of them do not validate their methodology or results. In addition, a set of known 150 SARS‐CoV‐2 M‐pro inhibitors extracted from the literature and a second set of 81 M‐pro inhibitors and 113 inactive compounds obtained from the COVID Moonshot project were used to evaluate the reliability of using docking scores as feasible predictors of the potency of a SARS‐CoV‐2 M‐pro inhibitor. Using two SARS‐CoV‐2 M‐pro structures and five protein‐ligand docking programs, we proved that the correlation between the pIC50 and docking scores is not good. Neither was any correlation found between the pIC50 and the ∆G calculated with an MM‐GBSA method. When a group of experimentally known inactive compounds was added, neither the docking scores or the ∆G were able to distinguish between compounds with or without M‐pro experimental inhibitory activity. Performances improved when covalent and noncovalent inhibitors were treated separately, but were not good enough to fully support using a docking score as a cutoff value for selecting new putative M‐pro inhibitors or predicting the relative bioactivity of a compound by comparison with a reference compound. The two sets of known SARS‐CoV‐2 M‐pro inhibitors presented here could be used for validating future VS protocols which aim to predict M‐pro inhibitors.
Dynamics of a harvested stage‐structured predator–prey model with distributed maturation delay
Authors: Al‐Omari Jafar , Gumah Ghaleb , Al‐Omari Shrideh
Published: October 2021

A new delayed predator–prey model with stage‐structure and harvesting on prey and predator is proposed, where the stage‐structure is modeled by the introduction of distributed time delay. The positivity, boundedness and the conditions for uniform persistence have been derived. We investigate the dynamical behavior of the system in terms of local stability of each feasible equilibria, global stability, and persistence. We find that the dynamics of the model depends largely on the harvesting efforts on the two species and the specific form of the birth and death functions.
Liburnian lunches: New stable isotope data for the Iron Age community of Nadin‐Gradina, Croatia
Authors: Toyne J. Marla , Čelhar Martina , Nystrom Kenneth C.
Published: October 2021

The Iron Age in Central Europe is defined as a transformative time in local populations' lives including dietary patterns. Stable isotope analysis has become a valuable tool for investigating paleodietary and paleomobility patterns in ancient societies using samples of human and animal skeletal remains from individual burials. This is an isotopic study of collagen and apatite from Iron Age Liburian burials seventh to first century BC from Nadin‐Gradina, Croatia. Sixty human samples include 40 teeth and 20 bones. Fifteen individuals with paired tissues (teeth and bone) are used to explore differences between early and later life isotope compositions. Zooarchaeological remains from the site help approximate local dietary baselines of domesticated and hunted animal sources (n = 22 bones). Samples produced excellent collagen and uncontaminated carbonate yields to measure isotope ratios of carbon (13C/12C) and nitrogen (15N/14N). Overall, the dietary indicators are quite uniform,δ13C average −19.1 ± 0.6‰ andδ15N average +9.8 ± 0.6‰ for bone and almost identical values for sectioned crown and root tooth dentin. This suggests a consistent lifetime diet with strong reliance on C3plants such as wheat, oats, and other vegetables and that there was a moderate amount of animal protein, but unlikely including marine sources. This isotopically homogeneous dataset suggests that Iron Age hillforts and agricultural settlements in this region had relatively stable diets that were distinct compared with other nearby inland sites where millet was more prevalent. This research expands our understanding of a shift toward more localized subsistence strategies in the region and Nadin‐Gradina itself.
Bone health in pediatric transfusion‐dependent beta‐thalassemia: Circulating osteoprotegerin and RANKL system
Authors: Youssry Ilham , Saad Nahla , Madboly Mohamed , Samy Rania M. , Hamed Soha T. , Tawfik Hanaa , Elbatrawy Salwa R. , Kaddah Normeen , Abd Elaziz Dalia
Published: October 2021

Introduction

While the mechanism of bone disease in thalassemia is multifactorial and still under investigation, the receptor activator of nuclear factor kappa B (RANK), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) have pivotal roles in regulating bone metabolism. This study aimed to measure RANKL and OPG serum levels, and to detect the incidence of RANKL rs9533156, OPG rs2073618, and OPG rs2073617 genotypes in pediatric β‐thalassemia patients and to assess their relation to bone mineral density.

Methods

Sixty patients with transfusion‐dependent β‐thalassemia (TBT) patients ages 5 to 14 years were included, and 60 healthy, age‐ and sex‐matched volunteers contributed as a control group. The patients were scanned for bone mineral density.

Results

The mean of spine dual‐energy X‐ray absorptiometry (DXA) Z‐score in patients was −1.66 ± 1.02 standard deviation (SD). Twenty‐four of them had low spine DXA Z‐scores. The patients showed significantly lower OPG levels and OPG/RANKLs ratios than the control group (3.28 ± 9.11 ng/ml and 11.38 ± 14.93 ng/ml, and 0.01 ± 0.03 and 0.07 ± 0.09, respectively). The RANKL SNP rs9533156 TC heterozygous genotype was detected more with statistical significance in patients than controls. The incidence of OPG rs2073618 and OPG rs2073617 genotypes were 2.3 times and 1.9 times more frequent in patients than controls, respectively.

Conclusion

The RANK/RANKL/OPG system may have an important role in regulating bone metabolism in TBT patients, although further studies are needed to clarify its role.
Enhanced aerosol deposition by a low‐cost compact nanosecond‐pulsed plasma system
Authors: Gao Haotian , Li Jiacheng , Liu Dawei
Published: October 2021

Nanosecond (ns)‐pulsed air plasmas are promising for environmental and biomedical applications. This paper presented a low‐cost ns‐pulsed plasma system that consists of a two‐stage Cockcroft–Walton voltage multiplier, a spark gap gas switch, and a plasma reactor. This ns power supply generated a uniform air plasma with a volume of 25 × 25 × 2 cm and a maximum ion wind of 0.8 m/s. The ion wind transported aerosols through plasma volume. Aerosols were charged and deposited on the grounded mesh electrode. The direct interactions between reactive ns plasma and deposited aerosols can promote the development of plasma applications.
Association between asthma and enamel defects in primary and young permanent teeth – A systematic review
Authors: Rizzardi Karina F. , da Silva Toledo Elora , Ferraz Lucio F. C. , Darrieux Michelle , Girardello Raquel , de Lima Marson Fernando A. , Parisotto Thaís M.
Published: October 2021

Childhood respiratory diseases, such as asthma, are important public health problems worldwide and could be associated with tooth enamel defects. This study aimed to verify the relationship between asthma and enamel defects in teeth, to answer the following question: “Could asthma in children be significantly associated with enamel defects in deciduous dentition and young permanent teeth?.” PUBMED‐MEDLINE, EMBASE, LILACS, and COCHRANE databases were systematically searched and assessed articles (2000–2021) were cautiously scored according to a predetermined criterion. The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses were considered. Twenty‐two articles were critically appraised and used as a basis for conclusions. The relationship between asthma and enamel defects was confirmed in the majority of appraised papers, one with a high level of evidence, nine with a moderate level, and four with a low level. Out of the eight manuscripts investigating the influence of asthma medication on enamel defects, only three (one with high, one moderate, and another with a low level of evidence) suggested an association. It can be concluded that asthma is closely connected with enamel defects in young permanent teeth. However, as most of the papers appraised were of cross‐sectional or case‐control design, further well‐designed clinical investigations with a prospective design are welcome to reinforce our findings.
A Review of Platinum Diffusion in Silicon and Its Application for Lifetime Engineering in Power Devices
Authors: Johnsson Anna , Schmidt Gerhard , Hauf Moritz , Pichler Peter
Published: October 2021

In silicon power semiconductors, platinum is used to improve the switching characteristics of the devices by adjusting the lifetime of the minority charge carriers. Platinum diffusion in silicon has been a research topic for many scientists over the past decades. Herein, the current state of knowledge is presented together with the concepts developed for its use in silicon power devices. The relevant processes include diffusion from a platinum silicide, postimplantation annealing, and phosphorus‐diffusion gettering. The evaluation of corresponding experiments and the calibration of the models have not only resulted in more narrow limits for the equilibrium concentrations of vacancies and self‐interstitials in silicon and the transport capacity of interstitial platinum, but also in improved devices.
Safety and potency of BIV1‐CovIran inactivated vaccine candidate for SARS‐CoV‐2: A preclinical study
Authors: Abdoli Asghar , Aalizadeh Reza , Aminianfar Hossein , Kianmehr Zahra , Teimoori Ali , Azimi Ebrahim , Emamipour Nabbi , Eghtedardoost Marzieh , Siavashi Vahid , Jamshidi Hamidreza , Hosseinpour Mohammadreza , Taqavian Mohammad , Jalili Hasan
Published: October 2021

The development of effective and safe COVID‐19 vaccines is a major move forward in our global effort to control the SARS‐CoV‐2 pandemic. The aims of this study were (1) to develop an inactivated whole‐virus SARS‐CoV‐2 candidate vaccine named BIV1‐CovIran and (2) to determine the safety and potency of BIV1‐CovIran inactivated vaccine candidate against SARS‐CoV‐2. Infectious virus was isolated from nasopharyngeal swab specimen and propagated in Vero cells with clear cytopathic effects in a biosafety level‐3 facility using the World Health Organization’s laboratory biosafety guidance related to COVID‐19. After characterisation of viral seed stocks, the virus working seed was scaled‐up in Vero cells. After chemical inactivation and purification, it was formulated with alum adjuvant. Finally, different animal species were used to determine the toxicity and immunogenicity of the vaccine candidate. The study showed the safety profile in studied animals including guinea pig, rabbit, mice and monkeys. Immunisation at two different doses (3 or 5 μg per dose) elicited a high level of SARS‐CoV‐2 specific and neutralising antibodies in mice, rabbits and nonhuman primates. Rhesus macaques were immunised with the two‐dose schedule of 5 or 3 μg of the BIV1‐CovIran vaccine and showed highly efficient protection against 104 TCID50 of SARS‐CoV‐2 intratracheal challenge compared with the control group. These results highlight the BIV1‐CovIran vaccine as a potential candidate to induce a strong and potent immune response that may be a promising and feasible vaccine to protect against SARS‐CoV‐2 infection.
Can cover crops improve soil ecosystem services in water‐limited environments? A review
Authors: Blanco‐Canqui Humberto , Ruis Sabrina J. , Holman Johnathon D. , Creech Cody F. , Obour Augustine K.
Published: October 2021

Cover crops (CCs) are considered to deliver multiple soil ecosystem services, but such potential could vary by climatic region. This leads to the question: can CCs improve soil ecosystem services in low precipitation regions? To answer this, we reviewed published data up to 27 July 2021 regarding CC impacts on CC biomass production, soil organic C (SOC) accumulation, water and wind erosion, soil water, nitrate leaching potential, soil microbial biomass, weed management, crop yields, and livestock production (i.e., CCs as forage) across regions with <500 mm precipitation. Literature indicates that CCs produce 2.37 ± 2.30 Mg ha−1 of aboveground biomass, but belowground biomass data are unavailable. Cover crops increased soil wet aggregate stability (63% of CC vs. no CC comparisons), suggesting reduced water erosion potential with CCs. Also, CCs reduced nitrate leaching potential (74% of comparisons) and soil water (50%), increased soil microbial biomass (73%), and did not affect dry aggregate stability (67%) and crop yields (56%). Cover crops accumulated SOC in 59% of comparisons. Averaged across all comparisons, CCs accumulated 0.43 Mg SOC ha−1 yr−1 in the upper 30‐cm depth. This SOC accumulation rate is within the range of SOC accumulation across all regions in previous reviews. Cover crops can reduce weed biomass by 89%. Also, when hayed or grazed, CCs could provide net economic returns without negating soil benefits. Overall, CCs improve most soil ecosystem services without many detrimental effects on crop yields in water‐limited environments, although more long‐term (>10 yr) data are needed for definitive conclusions.
Linking natural resources and performance of small agricultural businesses: Do entrepreneurial orientation and environmental sustainability orientation matter?
Authors: Dias Claudia , Rodrigues Ricardo Gouveia , Ferreira João J.
Published: October 2021

It is still unclear how the natural environment influences the firm's performance. It is needed to understand how business activities that strongly depend on natural resources, as it is agriculture, manage their scarcity and uncertainty. Based on a sample of 150 small agricultural businesses, hierarchical regression was used to analyze how entrepreneurial orientation (EO) and environmental sustainability orientation (ESO) can shape the influence of natural resources on environmental performance (EP) and financial performance (FP). Supported by the Natural Resource‐Dependence Theory (NRDT), our study found that natural resources availability is determinant for FP. At the same time, EP depends on Land but not on water and climatic conditions. The results also support the resource‐based view (RBV), since EO and ESO are mediators in the association between natural resources and FP, representing powerful internal responses to agricultural businesses face the natural environment constraints.
An evolutionary ensemble analogy‐based software effort estimation
Authors: Shahpar Zahra , Bardsiri Vahid Khatibi , Bardsiri Amid Khatibi
Published: October 2021

Analogy‐based estimation (ABE) is the most commonly applied method for estimating using software. Although there are several analogy‐based estimation techniques, there is no consistent conclusion of which technique is the best in all circumstances. Therefore, this article presents an evolutionary ensemble ABE (EEABE) for software cost estimation. Ensemble effort estimation (EEE) models forecast software development endeavors through using multiple estimation methods. In this article, EEABE combines GA as an evolutionary algorithm with six ABE models. The proposed method has been evaluated on four well‐known datasets comprising Maxwell, Albrecht, Kemerer, and Desharnais, by the k‐fold cross‐validation technique and based on the performance criteria of MRE, MMRE, MDMRE, BMMRE, and PRED(0.25). The simulation results demonstrate that the use of EEABE increases the accuracy of estimation and reduces the cost. Besides, EEABE is a flexible and adaptable model with any type of dataset and software development project, and it has been optimized with the possibility of using various ABE techniques.
Formation Mechanism and Control Strategy of Edge Seam Defects for Hot Rolling Interstitial‐Free Steel
Authors: Wang Dongcheng , Xu Yanghuan , Zhang Tongyuan , Duan Bowei , Yu Huaxin , Liu Hongmin
Published: October 2021

During the process of hot rolling, seam defects often appear on the edges of the interstitial‐free (IF) steel, which seriously affects product quality and yield. To this end, the macro‐ and micromorphology of edge seam defects are analyzed, their specific characteristics are summarized, and the defect cast slab rolling experiment is conducted. The experiment shows that the pore, crack, and slag inclusion are not the causes of the seam defects. Then, through a combination of theoretical analysis, actual parameters’ detection, and experiments, the formation mechanisms of the seam defects are evidently side folding of the intermediate slab and flipping of the corner metal. The mechanisms of the two types of folds are also described in detail. Finally, in view of the mechanisms, the advantages and disadvantages of control measures are analyzed, and the concave anvil of the slab sizing press is selected at last. To determine the effectiveness of the scheme, a pass experiment is conducted on a slab sizing press at the production site. Results show that the steel coils without slab sizing press generally have seam defects, whereas the coils with a concave anvil slab sizing press do not. The defects are almost totally eliminated.
Study on Oxidation Behavior of Industrial Basic Oxygen Furnace Slag and Recovery of Magnetic Iron‐Containing Phase
Authors: He Zhanwei , Lan Mo , Hu Xiaojun , Xue Xiangxin , Chou Kuo-Chih
Published: October 2021

The BOF slag contains a lot of iron‐containing species and its efficient recovery is a difficult problem in metallurgy. Herein, the oxidation behavior of industrial BOF slag under air atmosphere is investigated to explore the optimal oxidation conditions for transforming nonmagnetic FeO into magnetic MgFe2O4, including oxidation temperature, oxidation time, and airflow rate. The raw slag and oxidized slags are analyzed using chemical analysis, X‐ray diffraction (XRD) analysis, scanning electron microscope (SEM)‐energy dispersive spectroscopy (EDS) analysis, and Factsage thermodynamic simulation. The results show that the formation of MgFe2O4 phase is closely related to the oxidation temperature, oxidation time, and airflow rate. With the increase in temperature, the conversion rate of MgFe2O4 increases, and reaches the maximum at 1050 °C. However, the conversion rate of MgFe2O4 decreases and part of β‐C2S is converted to α‐C2S above 1050 °C. When the oxidation time and airflow rate increase, the conversion rate of MgFe2O4 increases and reaches the maximum value at 100 min and 1.25 L min−1, respectively. Correspondingly, the grade increased from 16.3% of the raw slag to 27.86% of the magnetic slag, an increase of 11.5%. This is a more convenient and effective method, which can not only bring economic benefits for relevant enterprises but also reduce environmental pollution.
Some Investigations with a Simple Actuarial Model for Infections Such as COVID-19
Authors: Wilkie A. D.
Published: October 2021

In this chapter the author adds an infection feature to an actuarial multiple state model to give a simple model for an infection such as COVID-19. The model is simple enough to be replicated in an Excel worksheet, with one row per day of calculations. The whole population is treated as homogenous, with no distinction by age, sex or anything else; to that extent it is unrealistic, but to include these features would complicate it considerably. To fit it to observed data requires successive optimisation by programme, and this is described. Different variations of the model allow it to fit better and take account of, for example, immunisation by vaccine. It is shown to fit the past events in the United Kingdom (U.K.) quite well, and it has also been fitted to other countries, but this is not shown in this chapter. It is also observed that this, or any other model, is of less use for forecasting the future, because it cannot predict the behaviours of governments or of populations. But various assumptions can be made about the future, as at the latest date of calculation (1 March 2021), and interesting consequences are shown.
Changes in Behaviour Induced by COVID-19: Obedience to the Introduced Measures
Authors: Badenes-Plá Nuria
Published: October 2021

The pandemic of COVID-19 that has plagued our planet since the beginning of 2020, has disrupted the way of life of society in general. As in other pandemics suffered throughout history, isolation has been a crucial measure to avoid contagion, causing effects beyond health, in many areas of life. How society obtains economic resources, spends them, enjoys leisure, or simply interacts, is now different. The political and economic context has changed, freedom of movements and expectations are also different. All this generates changes in the behaviour of society that does not react uniformly in all countries. This chapter reviews some of the modifications in behaviour caused by the present circumstances, as what will happen in future pandemics is not predictable for sure. The emphasis is placed on obedience observed in different contexts to imposed restrictions. Homes have become workplaces, consumption patterns have changed, and the derived effects are not always beneficial or distributed equally across the social strata.
Patent Linkages and Its Impact on Access to Medicines: Challenges, Opportunities for Developing Countries
Authors: Raju K. D.
Published: October 2021

Linking patent protection to generics’ regulatory approvals is a heated topic of discussions and a friction point among countries proposing higher protection for patented drugs. Patent linkage has been pushed through bilateral and regional agreements outside of the WTO system. It is widely understood that patent linkage is implemented to delay the market entry of generic medicines. It is argued here that developing countries are not obliged to take up TRIPs plus patent-linkage obligations.

A list of approved drugs and their therapeutic equivalence can be published by every country. The patent information can also be published to be made known to everybody. Regulatory mechanisms and patent protection should be kept in separate parallel tracks. Any attempt to link the two streams to prevent the registration of generics based solely on alleged patent infringement would negatively affect access to medicines worldwide.

Patent linkage provisions are TRIPS-plus commitments, as there is no such obligation under the WTO TRIPS Agreement. The analysis of 16 countries which provide for patent linkage shows that it is, in most cases, a resulting commitment from regional trade agreements or bilateral agreements. Patent linkage provisions are not acceptable to the developing world, and any attempt to introduce these will affect the accessibility and affordability of generic medicines in the developing world.
Hochpreisige Arzneimittel: Mehr Perspektive als Herausforderung – Anmerkungen zu Preisen, Gewinnen und Fortschritten in der Arzneimitteltherapie
Authors: Steutel Han
Published: October 2021

Das Innovationsmodellder pharmazeutischen Industrie ist ein Kreislaufmodell. Die Umsätze von heute finanzieren den Fortschritt von morgen.

Arzneimittelpreise können nicht nach Kriterien der Fairness und Gerechtigkeit beurteilt werden. Sie sollten nicht auf Basis von Entwicklungs-, Produktions- und Vertriebskosten bemessen werden. Vielmehr sollten Preise den Wert von Arzneimitteln widerspiegeln, um gesellschaftlich optimale Innovationsanreize setzen zu können.

Bei der Wahl geeigneter adjustierter Maßgrößen für den Gewinn ergibt sich im Branchendurchschnitt eine dem Risiko angemessene Verzinsung des eingesetzten Kapitals auch im Vergleich zu anderen Branchen.

Arzneimittel haben einen großen Beitrag geleistet, unsere Lebenserwartung zu erhöhen und unsere Lebensqualität zu verbessern. Bei Arzneimitteln handelt es sich daher um Investitionsgüter, die eine höhere wirtschaftliche Produktivität, Einsparungen von Kosten in anderen Bereichen (z. B. Krankenhaus- und Pflegekosten) und vor allem ein längeres und besseres Leben für uns alle ermöglichen. Bei Reformen sollten Arzneimittel deshalb auch als Investitionsgüter behandelt werden.
AMNOG: Ziel, Funktionsweise und Ergebnisse
Authors: Erdmann Daniel , Wittmüß Wiebke , Schleeff Jörn
Published: October 2021

Seit nunmehr zehn Jahren werden neu eingeführte Arzneimittel in Deutschland auf ihren Zusatznutzen untersucht und Preise auf Basis dieser Bewertung vereinbart. Der Artikel fasst zunächst die veröffentlichten Nutzenbewertungen des G-BA zusammen und analysiert diese auf Ebene der Therapiegebiete. Hierbei wird ein verstärktes Augenmerk auf die regulativ bedingte Sonderrolle von Orphan Drugs gelegt. Im zweiten Teil werden die Verhandlungsergebnisse und der zu beobachtende starke Ausgabenanstieg neuer patentgeschützter Arzneimittel betrachtet. Der Artikel schließt mit einer Betrachtung zum AMNOG als weiterhin lernendes System.
Entwicklung der Arzneimittelkosten und -preise in der Versorgung
Authors: Schröder Melanie , Telschow Carsten
Published: October 2021

Arzneimittelpreise von mehr als 10.000 €, 100.000 € oder gar Preise jenseits der Millionengrenze waren noch vor wenigen Jahren eine absolute Ausnahme, werden aber seitdem immer häufiger zur Realität. Während es die einen gelassen sehen und auf die unproblematische Umsatzentwicklung der ambulanten Arzneimittelverordnungen hinweisen, sehen die anderen eine Gefährdung der heutigen und vor allem der zukünftigen Finanzierbarkeit. Aber welchen Einfluss haben diese hochpreisigen, meist patentgeschützten Arzneimittel auf den deutschen Arzneimittelmarkt und haben wir wirklich (k)ein Problem? Der Beitrag zeigt eine rasante Preisentwicklung insbesondere bei neuen patentgeschützten Arzneimitteln und auch eine steigende Ausgabenrelevanz von sogenannten Hochpreisern, die ihre Preisanker in immer mehr Indikationsgebieten setzen können. Zudem wird deutlich, dass die Fokussierung auf den ambulanten Markt zu kurz greift, um die Kostenauswirkung dieser neuen Arzneimittel einzuschätzen. Die Kosten der zusätzlich notwendigen Berücksichtigung für die Anwendung von Marktneueinführungen im Krankenhaus können aus der Perspektive der Zahlenden durchaus Besorgnis hervorrufen. Der Blick auf die umsatzstarken und gewinnstärksten Pharmakonzerne schließlich zeigt, dass sich deren Geschäftsfeld überwiegend auf hochpreisige und patentgeschützte Arzneimittel konzentriert.
Diagnosing complications following cochlear implantation using transcutaneous ultrasound
Authors: Rupp Robin , Thimsen Vivian , Balk Matthias , Mueller Sarina K. , Sievert Matti , Mantsopoulos Konstantinos , Hoppe Ulrich , Hornung Joachim , Iro Heinrich , Gostian Antoniu-Oreste
Published: October 2021

Purpose

The aim of this study was to investigate the feasibility and reliability of transcutaneous ultrasound for the detection of complications after cochlear implantation.

Methods

In a single center retrospective cohort study, 115 consecutive cases of suspected complications after cochlear implantation (intervention group) were examined. The rate of pathologic ultrasound findings for specific leading symptoms and diagnoses was compared to a control group comprising twenty consecutive cochlear implants in symptom-free patients.

Results

Diagnostic ultrasound showed distinctly more pathologic findings in the intervention group (n = 67; 58.3%; p < 0.001) compared to the control group (n = 1; 5%). Ultrasound revealed significantly more pathologic findings in haematoma or seroma around the implant (n = 17; 100%; p < 0.001; ϕ = 0.94) and magnet dislocation (n = 44; 97.7%; p < 0.001; ϕ = 0.92) confirmed by a strong effect. Ultrasound examination showed a medium to high effect size in patients presenting with local infections (n = 3; 21.4%; p = 0.283; ϕ = 0.25) and skin flap oedema (n = 2; 50%; p = 0.061; ϕ = 0.51). In contrast, ultrasound examinations displayed a low effect size in undefined cephalgia (0%; p = 0.444; ϕ = 0.17) and device malfunction or failure (0%; p > 0.999; ϕ = 0.13).

Conclusion

Transcutaneous ultrasound can be advocated as a feasible and effective method in the diagnostic work-up of magnet dislocation and haematoma or seroma around the implant following cochlear implantation. Contrary, ultrasound findings can be expected to be inconspicuous in patients presenting with undefined cephalgia and device malfunction or failure.
Judicial consequences in Spain for the completion of the medical death certificate
Authors: Pinto Pastor Pilar , Dorado Fernández Enrique , Herreros Benjamín , Albarrán Juan Elena , Santiago-Sáez Andrés
Published: October 2021

The completion of the death certificate is indispensable in Spain for a death to be recorded in the civil registry. Occasionally, doctors may be reluctant to sign a death certificate due to possible legal consequences. This study seeks to analyse the possible judicial consequences doctors may face upon filling out this medico-legal document. Sentences published on the Judicial Power’s website between 2009 and 2019 containing the term “death certificate” were analysed. From a total of 2100 sentences examined, only 15 were found to contain the term “death certificate” as part of the claim. In only 7 of these cases the claim was made against the physician, and in 5 the physician was found guilty. Three of them concluded falsity via criminal proceedings, one via administrative proceedings for refusing to sign the certificate and one through civil proceedings for filling out an erroneous antecedent cause of death. In view of the above, it can be inferred that the completion of the death certificate poses few judicial consequences for physicians. In addition, this study reveals the importance of the death certificate document as evidence in judicial proceedings.
Ethical Guidance for Hard Decisions: A Critical Review of Early International COVID-19 ICU Triage Guidelines
Authors: Aquino Yves Saint James , Rogers Wendy A. , Scully Jackie Leach , Magrabi Farah , Carter Stacy M.
Published: October 2021

This article provides a critical comparative analysis of the substantive and procedural values and ethical concepts articulated in guidelines for allocating scarce resources in the COVID-19 pandemic. We identified 21 local and national guidelines written in English, Spanish, German and French; applicable to specific and identifiable jurisdictions; and providing guidance to clinicians for decision making when allocating critical care resources during the COVID-19 pandemic. US guidelines were not included, as these had recently been reviewed elsewhere. Information was extracted from each guideline on: 1) the development process; 2) the presence and nature of ethical, medical and social criteria for allocating critical care resources; and 3) the membership of and decision-making procedure of any triage committees. Results of our analysis show the majority appealed primarily to consequentialist reasoning in making allocation decisions, tempered by a largely pluralistic approach to other substantive and procedural values and ethical concepts. Medical and social criteria included medical need, co-morbidities, prognosis, age, disability and other factors, with a focus on seemingly objective medical criteria. There was little or no guidance on how to reconcile competing criteria, and little attention to internal contradictions within individual guidelines. Our analysis reveals the challenges in developing sound ethical guidance for allocating scarce medical resources, highlighting problems in operationalising ethical concepts and principles, divergence between guidelines, unresolved contradictions within the same guideline, and use of naïve objectivism in employing widely used medical criteria for allocating ICU resources.
Why do women more often intend to study abroad than men?
Authors: Cordua Fine , Netz Nicolai
Published: October 2021

In many Western countries, women are more likely to study abroad than men. At present, there is a lack of theory-guided empirical studies searching explanations for this pattern. We address this research gap by examining gender differences in study abroad intent among first-semester students in Germany. To derive a comprehensive theoretical framework, we draw on social role theory of sex differences, cognitive development theory, new home economics and statistical discrimination theory. Using data from the nationally representative 2010 DZHW School Leavers Survey, we test our hypotheses by estimating logistic regressions and non-linear effect decompositions. We find that women more often intend to study abroad primarily because of the gender-specific interest profiles they develop throughout their early life course: Related to their subject choice at school, women tend to acquire competences (e.g., language skills) that ease later stays abroad. To some extent, women’s better educational performance during school also explains their better chances to study abroad. Once in higher education, women tend to choose fields of study in which studying abroad is considered more valuable for competence acquisition. Losing time due to studying abroad is less of an obstacle for women but—against theoretical expectations—not because of a lower labour market orientation. Finally, the expectation to interrupt the professional career for taking care of the family deters women—especially those from a low social background—from studying abroad, but not men. We do not find evidence that women understand studying abroad as a strategy to counteract this anticipated discrimination. Overall, our results underscore the particular importance of social role and cognitive development theory for explaining gender differences in the spatial mobility of students.
Influence of Raspberry and Its Dietary Fractions on the In vitro Activity of the Colonic Microbiota from Normal and Overweight Subjects
Authors: Núñez-Gómez Vanesa , Periago Ma Jesús , Navarro-González Inmaculada , Campos-Cava Ma Piedad , Baenas Nieves , González-Barrio Rocío
Published: October 2021

Raspberry is a source of dietary fibre and phenolic compounds, which are metabolised by the gut microbiota, resulting in the production of short chain fatty acids (SCFAs) and phenolic catabolites; but the formation of these compounds depends on the microbiota composition. The aim of this study was to investigate whether the raspberry and its fractions (phenolic extract, total and insoluble dietary fibre) affect the microbial activity depending on the body weight condition. For this, in vitro fermentations of raspberry fractions were carried out using faeces from normal-weight (NW) and overweight volunteers (OW) during 48 h, and phenolic catabolites and SCFAs were analysed at 0, 6, 24 and 48 h. The whole raspberry and the phenolic extract produced greater quantities of urolithins and total SCFAs when compared with fibre fractions, reaching the highest amount between 24 and 48 h. The body weight condition was an important factor, since faeces from NW led to greater production of urolithins from non-extractable phenolic compounds bound to fibre fractions, whereas in OW the urolithins production was higher from the fractions with more extractable polyphenols. In summary, the whole raspberry has been shown to have a prebiotic effect, mainly due to its phenolic compounds content rather than its fibre content.
Phase II MS4 challenges: moving toward effective stormwater management for small municipalities
Authors: Rieck Leslie , Carson Craig , Hawley Robert J. , Heller Madison , Paul Mike , Scoggins Mateo , Zimmerman Mel , Smith Robert F.
Published: October 2021

Federal regulations for municipal separate storm sewer systems (MS4s) in the United States have been in place since 1990 as part of the Nation Pollutant Discharge Elimination System (NPDES), aiming to reduce sediment and pollutant loads originating from urban areas. However, small-municipality (Phase II) MS4s frequently grapple with several challenges, resulting in a lack of stakeholder buy-in and actionable stormwater management plans. We identify five common challenges concerning MS4 requirements based on literature review, professional experience, and feedback solicited from stakeholders, municipal managers, and fellow professionals and offer real-world examples of efficient, effective MS4 frameworks and/or solutions. The five challenges are summarized as beliefs that: (1) agricultural land use is the largest pollutant contributor and the root cause of pollution problems; (2) stormwater management only benefits downstream communities; (3) large, expensive projects are required to comply with regulations; (4) maintenance, monitoring, and inspection of best management practices (BMPs) is overwhelmingly complex and expensive; and (5) a lack of direct funding makes complying with regulations an impossible task. These challenges are universal in nature for Phase II MS4 permittees and can create real barriers for effective stormwater management. However, we found many examples of methods or techniques to effectively address these five specific challenges, making them well-suited and important for discussion. BMPs can create tangible improvements for surrounding communities (e.g., reduced streambank erosion and flooding), and improved understanding of the structure and options within the MS4 program will help small municipalities make informed choices about management plans.
The utilization of positron emission tomography in the evaluation of renal health and disease
Authors: Amoabeng Kwame Anokye , Laurila Sanna , Juárez-Orozco Luis Eduardo , Marthinsen Anne Beate Langeland , Moczulski Dariusz , Rebelos Eleni , Dadson Prince
Published: October 2021

Purpose

Positron emission tomography (PET) is a nuclear imaging technique that uses radiotracers to visualize metabolic processes of interest across different organs, to diagnose and manage diseases, and monitor therapeutic response. This systematic review aimed to characterize the value of PET for the assessment of renal metabolism and function in subjects with non-oncological metabolic disorders.

Methods

This review was conducted and reported in accordance with the PRISMA statement. Research articles reporting “kidney” or “renal” metabolism evaluated with PET imaging between 1980 and 2021 were systematically searched in Medline/PubMed, Science Direct, and the Cochrane Library. Search results were exported and stored in RefWorks, the duplicates were removed, and eligible studies were identified, evaluated, and summarized.

Results

Thirty reports met the inclusion criteria. The majority of the studies were prospective (73.33%, n = 22) in nature. The most utilized PET radiotracers were 15O-labeled radio water (H215O, n = 14) and 18F-fluorodeoxyglucose (18F-FDG, n = 8). Other radiotracers used in at least one study were 14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid (18F-FTHA), 18F-Sodium Fluoride (18F-NaF), 11C-acetate, 68-Gallium (68Ga), 13N-ammonia (13N-NH3), Rubidium-82 (82Rb), radiolabeled cationic ferritin (RadioCF), 11C‐para-aminobenzoic acid (11C-PABA), Gallium-68 pentixafor (68Ga-Pentixafor), 2-deoxy-2-F-fluoro-d-sorbitol (F-FDS) and 55Co-ethylene diamine tetra acetic acid (55Co-EDTA).

Conclusion

PET imaging provides an effective modality for evaluating a range of metabolic functions including glucose and fatty acid uptake, oxygen consumption and renal perfusion. Multiple positron emitting radiolabeled racers can be used for renal imaging in clinical settings. PET imaging thus holds the potential to improve the diagnosis of renal disorders, and to monitor disease progression and treatment response.