bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of drug safety warnings on drug sales and share prices
Authors: Białkowski Jędrzej , Clark Jeremy 
Published: October 2021

AbstractCurrent 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

AbstractThis 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.
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

AbstractThe 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

AbstractIntroductionWhile 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.MethodsSixty 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.ResultsThe 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.ConclusionThe 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

AbstractNanosecond (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

AbstractChildhood 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.
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

AbstractThe 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

AbstractCover 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

AbstractIt 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

AbstractAnalogy‐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.
Some Investigations with a Simple Actuarial Model for Infections Such as COVID-19
Authors: Wilkie A. D. 
Published: October 2021

AbstractIn 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

AbstractThe 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

AbstractLinking 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

Zusammenfassung
Zusammenfassung
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

Zusammenfassung
Zusammenfassung
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

Zusammenfassung
Zusammenfassung
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.