bluuebunny/crossref_metadata_2025 huggingface dataset:
The Gun Policy Fork in the Road
Authors: Spitzer Robert J.
Published: September 2022

This chapter begins by demonstrating that contemporary gun dilemmas resemble those of a century ago. There the similarities end, however, as the chapter sets up the existing policy dilemma of a public strongly supportive of stronger gun laws, and overwhelmingly supporting of existing laws, while gun rights advocates press to repeal existing gun laws by expanding the definition of gun rights, a movement that finds new favor with a profoundly more conservative federal judiciary. That movement is led in part by Justice Clarence Thomas who has been joined on the high court by several recent very conservative appointees. While this legal movement is animated by the theory of constitutional Originalism, our actual gun law history tells a story at odds with that perspective as it pertains to the Second Amendment. The succeeding chapters lay out that argument.
Assault Weapons and Ammunition Magazines
Authors: Spitzer Robert J.
Published: September 2022

The contemporary debate over whether or how to regulate assault weapons and large capacity ammunition magazines has been framed as one where possession of both should properly fall under the Second Amendment rights umbrella. This argument is based on an interpretation of history and law that collides with evidence provided in this chapter. In particular, new evidence is offered here to demonstrate that ammunition magazine regulation was widespread when the technology began to spread a century ago. The same is true of the regulation of semi-automatic and fully automatic weapons, whose regulation predates the modern assault weapons controversy begun the 1980s. In fact, such regulations first appeared in the 1920s. The regulation question is then brought back to the modern era, where the most recent and extensive research available is assessed regarding the criminological and societal consequences of these devices.
What Is True?
Authors: Gat Azar
Published: September 2022

What is true? Is there truth? These are among the most profound questions that have preoccupied humanity since the dawn of civilization. The nature of truth needs to be clarified prior to any discussion of ideology, ideological differences, and ideological fixation. Sweeping through the history of thought, from the ancient Greeks (and the Buddhists) to the modern philosophy of mind and the postmodernists, the chapter argues that while the skeptical tradition concerning the existence of truth has a point, this point has been vastly overdrawn. Truth as correspondence to reality is a valid notion, but as vastly simplified and finite code representations of features of the world that cannot fully encompass reality’s infinite diversity and are intrinsically partial and incomplete. While some propositions are untrue, others can be perfectly true while never being the whole truth, as our conceptual grid of reality can always be further refined, elaborated, and contextualized.
Conclusion
Authors: Gat Azar
Published: September 2022

The Conclusion argues against the so-called Mannheim Paradox (which Mannheim did not share), according to which every factual statement about the world is inevitably tied up with, and therefore shaped by, value preferences; that there is no such thing as objectivity about the facts; and that any rejection of an ideological bias is supposedly grounded in the critic’s own ideological perspective and bias. The Conclusion further suggests why—as the historical record demonstrates—ideological fixations seems to be all the more associated with the intellectual profession.
Rational Democratic Deliberation
Authors: Fleck Leonard M.
Published: September 2022

Shaping the democratic deliberative process to address wicked problems of health care justice related to precision medicine requires a careful structuring of that process. The deliberative process needs very specific focal points for discussion, such as the use of CAR T-cell therapy with a front-end cost of $475,000 to attack hematologic cancers. Is that a cost-effective use of social resources? Is this a just use of limited health care resources compared to very expensive therapies for life-threatening disorders (heart failure, hemophilia, AIDS) outside cancer? If 30% of CAR T-cell therapy patients will gain less than an extra year of life and if there were a biomarker that could identify those patients before the fact, would it be unjust to deny them CAR T-cell therapy? These are the sort of wicked ethical challenges generated by precision medicine that must be the focus of specific deliberative conversations.
Demagoguery in Office
Authors: Zug Charles U.
Published: September 2022

This chapter shows how the U.S. Constitution was designed to incentivize desirable rhetorical conduct in public officials through institutional design, articulating the Constitution’s implicit standards of conduct for evaluating uses of demagoguery in different constitutional offices. These standards are easiest to glimpse in the Supreme Court because the public still has a fairly developed sense of what kinds of public speech are appropriate for Justices and for judges generally. This chapter articulates the constitutional understandings on which that sense of judicial conduct is based, and then proceeds to discuss Congress and the presidency as well. While members of Congress are authorized to deploy relatively aggressive rhetoric because of their role as advocates for their constituents and overseers of the rest of the state, presidents have Constitutional responsibilities that require holding them to a higher rhetorical standard.
Introducing Constitutional Specificity
Authors: Brown Adam R.
Published: September 2022

Detailed constitutions reduce institutional flexibility by establishing more complicated political machinery, and they reduce policy flexibility by reducing the range of options available to government officials. Developing a detailed constitution requires costly negotiation. Constitution writers are more willing to bear these costs when they wish to delegate authority more precisely—that is, when they have less trust in the elected officials who will eventually wield constitutional authority. State constitutions ballooned in length in the late 19th century, for example, when distrust of legislatures and of centralized authority peaked. Even today, state constitutions adopted at that time remain lengthier than others. However, this specificity also comes with long-term costs: adding detail to a constitution locks in current political compromises, making it harder for future generations to adapt to new circumstances. A brief case study of Alabama, with the world’s lengthiest written constitution, illustrates these challenges.
Principles of Cyber-Warfare
Authors: Moore Daniel
Published: September 2022

What is cyber-warfare, and where does it fit? What are the thresholds that cross from an espionage campaign or an influence operation to an act of cyber-warfare? This chapter tackles the above questions not through a legal lens, but by layering military analysis with the realities of attacking through networks. The chapter has two principal parts; one establishes a five-step model--targeting, impact, attacker, goals, and relationships--to consider any incident as cyber-warfare. Each step requires increasingly complex analysis and allows the reader to distinguish between acts of social activism, peacetime espionage, criminal pursuits or military conflict. The second part of the chapter then dives into the differences between cyberwar and cyber-warfare. More than semantics, the former is a vehicle for fearmongering while the latter explains the role offensive cyber operations play in conflict.
A Typology of Cyber Actors
Authors: Smeets Max
Published: September 2022

Chapter 4 subsequently provides a typology of four different kinds of states based on two key dimensions: the level of an actor's constraints when it comes to conducting cyber effect operations, and the amount of financial and organizational resources an actor has available to conduct cyber operations. The chapter explains that the majority of states that have established a military cyber organization are highly constrained yet have invested limited resources in conducting cyber operations.
The Elements of an Offensive Cyber Capability
Authors: Smeets Max
Published: September 2022

This chapter lists the requirements of developing an offensive cyber capability, categorizing five dimensions of such a capability: people, exploits, toolset, infrastructure and organizational structure (the PETIO framework). Through the introduction of this conceptual framework, the chapter explains that an organization seeking to conduct cyber effect operations requires a more diverse workforce than is often acknowledged. In the tools and exploits dimension, even though much attention has been paid to states' stockpiling of zero-day exploits and the development of custom tools, the reality is that known exploits and tools are also often highly effective. The key requirement is that the attacker has superior knowledge of the target systems and networks, and understands how their deployed attack capabilities behave in this environment. Investment in infrastructure--for targeting, development, testing and training--is another essential requirement and can come at a great cost. Lastly, there are trade-offs at the inter-organizational and intra-organizational levels.
Media Personalization in Domestic Political Contexts
Authors: Gattermann Katjana
Published: September 2022

Chapter 4 investigates the extent to which media personalization is conditional upon domestic political and institutional contexts. To do so, it analyses media personalization with respect to news coverage involving the European Commission and the Parliament in national newspapers from seven European countries between 1992 and 2019. Media personalization is operationalized as individualization, that is, an increasing focus on individual politicians at the expense of either institution, and presidentialization in terms of an increasing focus on the Commission President vis-à-vis the Commission. The chapter cannot confirm any universal trend towards greater media personalization in the news coverage of either institution. Domestic media systems—rather than electoral systems and politicization of EU affairs in domestic contexts—appear to be responsible for cross-country differences in personalization. The chapter concludes that these findings have consequences for the likelihood that European citizens become aware of individual politicians in EU politics.
On the Temporality of Emotions
Authors: Marušić Berislav
Published: September 2022

Many emotions attenuate more rapidly than the significance of the considerations that gives rise to them as we accommodate ourselves to what happens. Grief often diminishes quickly, even though the dead continue to matter to us; anger often evaporates, even though the injustice to which it responds remains undiminished. Nonetheless, such accommodation seems somehow all right: It would be a mistake to be persistently grieving or to be relentlessly angry. But how could it be all right, if the reasons for grief and anger remain significant? However, matters are different with love. Unlike grief and anger, whose diminution is puzzling, what seems puzzling in the case of love is its continuation. In its self-consciousness, love is endless: In loving someone, we foresee no end to our love. Yet we know that love can end: Hearts are broken, lovers betrayed, and people grow apart. Does the self-consciousness of love involve a mistake? Or can we reasonably think of our love as lasting? On the Temporality of Emotions argues that whereas grief and anger reasonably diminish, love can rationally be conceived as endless. The book draws on contemporary theories of the emotions, especially grief and love, as well as on recent accounts of reasons. It puts forward an account of emotional self-consciousness as, at once, embodied and rational. Nonetheless, it maintains that accommodation reveals an irreconcilable moment in our emotional life, a moment that philosophical reflection ought not seek to resolve, lest our emotions are conceived as too neat and philosophy as too comforting.
Public Scientific Testimony II
Authors: Gerken Mikkel
Published: September 2022

Chapter 6 concerns science reporting and begins with a critical assessment of some prominent principles of science communication that appeal to scientific consensus, recipient values, etc. This critical assessment serves as the background for a positive proposal, Justification Reporting, which has it that science reporters should seek to include appropriate aspects of the nature and strength of scientific justification in science reporting. The prospects and limitations of this norm are discussed by considering relevant empirical research. The chapter concludes with an ameliorative perspective regarding the journalistic principle of Balanced Reporting according to which science reporters should seek to report opposing hypotheses in a manner that does not favor any one of them. By an application of Justification Reporting, Gerken sets forth an alternative, Epistemically Balanced Reporting, according to which science reporters should report opposing hypotheses by indicating the nature and strength of their respective scientific justifications.
The Rise and Fall of Fortune
Authors: Degenhardt Jane Hwang
Published: September 2022

Chapter 1 pairs Christopher Marlowe’s Doctor Faustus (c.1588/89) and Robert Greene’s Friar Bacon and Friar Bungay (c.1589/90) to consider how the stage registers the dangers of empires amassed through greed and violent conquest and also celebrates the opportunity to forge a new model of commercial empire based on diplomacy, pan-European alliance, and the opening of England’s borders to global exchange. Foregrounding the critically unrecognized commercial and imperial preoccupations of these plays, the chapter exposes how both plays subscribe to a narrative of translatio imperii that links the continuous rise and fall of empire to shifts in fortune fueled in part by human ambition. While delivering two very different conclusions, these plays explore the intertwined speculative potential of fortune and empire by spotlighting the role of human actors in orienting themselves to the ongoing rise and fall of empire that constitutes world history.
Neutrality and Excellence
Authors: Reiff Mark R.
Published: September 2022

In Liberalism with Excellence, Matthew Kramer makes an argument for how excellence may enter into liberalism despite liberalism’s strong commitment to neutrality. Kramer seeks to challenge not only the uncompromising rejection of this position by liberals such as Jonathan Quong, but also the so-called “blended” approach of “soft-perfectionist” scholars such as Joseph Raz and George Sher. This essay does not so much challenge Kramer’s approach as offer an alternative for accomplishing the same thing. Under Kramer’s approach, support for a particular form of excellence does not violate neutrality if it promotes “warranted self-respect.” Under the proposal in this chapter, support for a particular form of excellence does not violate neutrality if pursuing it does not violate anyone’s individual rights, if the amount of support that it and competing forms of excellence receive is proportional to the support each receive within the relevant polity, and if supporting this particular form of excellence does not prevent anyone from pursuing any other supportable form of excellence. While Kramer justifies his support for certain forms of excellence by incorporating them into what Rawls calls “a thin theory of the good,” to which the principle of neutrality does not apply, the proposal here shows how even if neutrality does apply, it can be fully satisfied.
Does Edificatory Perfectionism Express a Quidnunc Mentality?
Authors: Tahzib Collis
Published: September 2022

Recently, Matthew Kramer has developed an intriguing and highly original objection to perfectionism in its mainstream “edificatory” form, namely that perfectionist states that seek the elevation and edification of the citizenry are guilty of a “quidnunc mentality.” This mentality, Kramer argues, is akin in important respects to the mentality of a village busybody who meddles in matters that are none of her business, and is objectionable in that it is both “a form of self-aggrandizement and a form of self-abasement.” The contention of this chapter is that Kramer’s quidnunc mentality objection to edificatory perfectionism fails. Section 1 explains what Kramer means by the quidnunc mentality and why he considers such a mentality objectionable. Section 2 argues that the quidnunc mentality objection fails because it begs the question against edificatory perfectionism by assuming precisely what needs to be shown, namely that the edification of the citizenry falls outside the proper bounds of government. In sections 3 and 4, two potential responses available to Kramer are considered and rejected. Finally, section 5 concludes by commenting on a sense in which Kramer’s quidnunc mentality objection, despite not succeeding in undermining edificatory perfectionism, nonetheless contains an underlying insight that opens up a fascinating and novel set of questions.
Election Campaigns and Welfare State Change
Authors: Kumlin Staffan , Goerres Achim
Published: September 2022

For over three decades, mature European welfare states have been on their way into an austerity phase marked by greater need and more insecure revenues. A number of reform pressures—including population ageing, unemployment, economic globalization, and increased migration—call into question the economic sustainability and normative underpinning of transfer systems and public services. And while welfare states long seemed resilient to growing challenges, it now seems clear that they are changing. This book examines how political leaders and the public respond to reform pressures at a pivotal moment in a mass democracy: the election campaign. Do campaigns facilitate debate and attention to welfare state challenges? Do political parties present citizens with distinct choices as to how challenges might be met? Do leaders prepare citizens for the idea that some policies may be painful? Do party messages have adaptive consequences for how the public perceives the need for reform? Do citizens adjust their normative support for welfare policies in the process? Overall, the answers to these questions affect how we understand welfare state change and the functioning of representative democracy in an era of mounting challenges. The book builds on an integrated set of data sources collected by the authors. These include information about campaign themes from a large number of countries across three decades, content analysis of party leader speeches from the largest parties in Germany, Norway, and Sweden in the 2000s, as well as experiments and panel survey data from these countries.
Cultural Ecosystem Services
Authors: James Simon P.
Published: September 2022

The means–end model is often applied to cases in which nature has cultural value because of its political, religious, mythic, personal, or historical meanings. Those who presuppose this model typically use the concept of a cultural ecosystem service to try to make sense of such cases. They suppose that when natural entities have cultural value, they supply us with cultural ecosystem services. Some object to this practice on the ground that ‘ecosystems’ is rarely an appropriate name for the provider of the relevant cultural service. Some object to attempts to price such services. Both those criticisms have some force, though neither provides a decisive reason to reject attempts to conceive of cultural value in terms of the provision of ecosystem services.
Limitations of the Standard Model
Authors: James Simon P.
Published: September 2022

To think in terms of the provision of cultural ecosystem services is to presuppose that when nature has cultural value, it serves as a causally efficient means to certain ends. Yet that presupposition fails to capture the intimacy of the relations between people and the natural entities they value. Take the cultural value of reindeer for the Saami people of northern Europe. One of the reasons reindeer are of value for the Saami is because they are integral to that people’s cultural identity. This is not to suggest that reindeer have a certain sort of instrumental value for the Saami, for that suggestion would imply, implausibly, that the reindeer could be replaced, without loss of value, by some alternative service provider. Nor is it to suggest that there are two distinct entities, the Saami on the one hand and the reindeer on the other, and a causal relation tying them together. On the contrary, one cannot describe who the Saami as a people are without referring to the fact that they are reindeer herders. To comprehend the value reindeer have for the Saami, one cannot restrict oneself to thinking in terms of causality and instrumental value. One must move beyond the means–end model. These arguments are developed through analyses of two case studies: Navajo relocation and Saami reindeer herding.
Value and Disvalue
Authors: James Simon P.
Published: September 2022

Many natural entities have cultural value, but some have cultural disvalue. An entity acquires this kind of disvalue when it undermines a meaningful and valuable whole, as when an earthquake destabilizes one’s religious faith. But entities can also acquire cultural disvalue by contributing to wholes that are meaningful but disvaluable, as when—for example—a particular flower is adopted as an emblem of an evil political cause. In cases of the latter sort, the whole will count as disvaluable, even though it is valued by devotees of the relevant cause. And those entities that contribute to that disvaluable whole will thereby acquire cultural disvalue. If, by contrast, a meaningful whole is not morally bad but merely based on false beliefs, it might nonetheless qualify as valuable and, accordingly, natural entities might acquire constitutive value because of the roles they play in it. The same may be said of traditions and other meaningful wholes that have recently been invented. They, too, might qualify as valuable, and natural entities might therefore have constitutive value because of the roles they play in them. These issues are explored by means of four further case studies: The Great Lisbon Earthquake, Cornflowers, Dark skies, and Eating whales.
Constitution and Rights
Authors: James Simon P.
Published: September 2022

The fact that some natural entity, x, has constitutive value does not entail that x ought, all things considered, to be protected. Nonetheless, in some cases such entities ought to be protected for precisely this reason. The point may be made in terms of rights. More precisely, when x has high constitutive value for Person A, the normative reasons for action that derive from its having that value may be appropriately expressed in the language of rights. One can say that x should be protected out of respect for A’s rights. In the book’s eleventh case study, Jumbo Valley, the relevant right is a right to religious freedom. In its twelfth and final one, Bauxite mining at Wane Kreek, it is a certain kind of property right.
Conclusion
Authors: James Simon P.
Published: September 2022

To understand nature’s contributions to human well-being, one needs a model of value centred on the concepts of cultural meaning and part-whole relations. This book presented one such model. The book’s other main conclusions are summarized. It is then suggested that natural entities are both remote and near: remote in the sense that they are largely unshaped by human actions, near in the sense that they shape our identities. The point is explained by referring to the case of Katherine Smith, the late Navajo activist.
Sex as Crime
Authors: Zellentin Holger M.
Published: September 2022

The second chapter focuses on prohibited and regulated impurity caused by human sexual activity. A continuous legal development can be traced that starts with the prescriptions on prohibited sexual impurity imposed on the gerim, on the non-Israelites, especially in Leviticus 18, throughout all forms of late antique Christianity, in this case even more fully shared with the rabbinic Noahide Laws, to the Qur’an. When it comes to prohibited sexual impurity, the Qur’an seems to dismiss Arabian practices and adopts a biblical model close to that of many late antique Christians. When considering the concept of regulated sexual impurity, by contrast, the Hebrew Bible, along with the Acts of the Apostles, explicates its rulings only for the Israelites, leaving their applicability to the gerim and respectively to gentile Christians open to diverging late antique interpretations. The Qur’an’s point of departure regarding regulated sexual impurity can be pinpointed at the confluence of pagan Arabian culture and the practices of those Christians who endorsed the expansive attitudes towards the Decree of the Apostles, and obeyed laws pertaining to regulated sexual impurity.
Co-evolution of Law and Economy
Authors: Verhagen Hendrik L. E.
Published: September 2022

This chapter provides the analytical framework for examining the co-evolution of Roman law and economy. It will first look at legal evolution from the perspective of social systems theory. This theory provides a useful interpretative scheme for analysing the interactions between law and economy in any society in which the legal system can be regarded as an autonomous subsystem of society. In particular, social systems theory provides a good model for analysing how the origin and evolution of legal rules and institutions are often triggered by economic circumstances, while at the same time they are conditioned by the internal structure of the legal system. The co-evolution of law and economy will be further analysed with reference to socio-cultural evolution theory. It will then carry out a closer examination of how Roman law co-evolved with the Roman economy. It will be concluded with a review of the economic functions of pignus and hypotheca.
Environmental Conditions After Fusarium Head Blight Visual Symptom Development Affect Contamination of Wheat Grain with Deoxynivalenol and Deoxynivalenol-3-Glucoside
Authors: Moraes Wanderson Bucker , Madden Laurence V. , Baik Byung-Kee , Gillespie James , Paul Pierce A.
Published: September 2022

Fusarium head blight (FHB) of wheat, caused by the fungus Fusarium graminearum, is associated with grain contamination with mycotoxins such as deoxynivalenol (DON). Although FHB is often positively correlated with DON, this relationship can break down under certain conditions. One possible explanation for this could be the conversion of DON to DON-3-glucoside (D3G), which is typically missed by common DON testing methods. The objective of this study was to quantify the effects of temperature, relative humidity (RH), and preharvest rainfall on DON, D3G, and the D3D/DON relationship. D3G levels were higher in grain from spikes exposed to 100% RH than to 70, 80, or 90% RH at 20 and 25°C across all tested levels of mean FHB index (percentage of diseased spikelets per spike). Mean D3G contamination was higher at 20°C than at 25 or 30°C. There were significantly positive linear relationships between DON and D3G. Rainfall treatments resulted in significantly higher mean D3G than the rain-free check and induced preharvest sprouting, as indicated by low falling numbers (FNs). There were significant positive relationships between the rate of increase in D3G per unit increase in DON (a measure of conversion) and sprouting. As FN decreased, the rate of D3G conversion increased, and this rate of conversion per unit decrease in FN was greater at relatively low than at high mean DON levels. These results provide strong evidence that moisture after FHB visual symptom development was associated with DON-to-D3G conversion and constitute valuable new information for understanding this complex disease-mycotoxin system.
Possible Increased Risk of Death from Blood Cancer Drug
Authors: Aschenbrenner Diane S.
Published: September 2022

The Food and Drug Administration (FDA) is warning that an increased risk of death is possible with the use of duvelisib (Copiktra) compared with the monoclonal antibody ofatumumab in the treatment of chronic lymphocytic leukemia. Serious adverse effects also appear to be more likely with duvelisib use.

Nurses should monitor for adverse effects and report them to the FDA's MedWatch program.
New Approval for Drug Treating Large B-Cell Lymphoma
Authors: Aschenbrenner Diane S.
Published: September 2022

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi) to treat large B-cell lymphoma in adults who relapsed or were refractory after first-line treatment.

Lisocabtagene maraleucel continues to be prescribed under the Risk Evaluation and Mitigation Strategy due to the risk of fatal or potentially fatal cytokine release syndrome and neurologic toxicities.

Nurses need to closely monitor patients for these and for other serious adverse effects for at least seven days after infusion of the drug.
Pathway to Becoming a Progressive Care Certified Nurse
Authors: Benike Linnea , Wozniak Janelle
Published: September 2022

Nurses working on progressive care units (PCUs) use specialized knowledge and skills to provide care to acutely ill patients. The literature suggests that specialty certification may have a positive impact on patient and nurse outcomes alike, although results are mixed. A project team set out to create a culture that encouraged nurses to pursue progressive care certified nurse (PCCN) certification on three cardiac medical PCUs at a large academic health center by implementing a Pathway to PCCN program, which is a structured, cohort-based approach to certification preparation.

The primary aim of the intervention was to achieve a 10% PCCN certification rate within one year. Additionally, the project team evaluated whether participating in the Pathway to PCCN program affected staff nurses' self-reported confidence in their clinical judgment in 10 patient care domains: cardiac, pulmonary, behavioral, neurological, musculoskeletal, hematological, endocrine, gastrointestinal, renal, and multisystem.

Project methods included structured strategies within a “4R” framework developed by the project team: recruitment, obtaining resources, providing reassurance, and celebrating certification through recognition. Project methods were evaluated using anonymous electronic surveys and staff interviews.

The percentage of staff with PCCN certification increased from 0% to 15.2%. The average confidence levels reported by nurses who participated in the project (N = 64) increased in eight out of nine (89%) of the clinical judgment domains tested on the PCCN examination in Cohort 2, and in nine of the clinical judgment domains in Cohorts 1 and 3. Implementing a structured cohort pathway for specialty certification using the 4R framework is a strategy that can increase rates of specialty certification among eligible nurses.
Outcomes Similar with Restricted vs. Standard IV Fluid Administration in Patients with Septic Shock
Authors: Rosenberg Karen
Published: September 2022

According to this study:

Among adults in the ICU with septic shock, restriction of IV fluids didn't result in fewer deaths at 90 days than standard IV fluid therapy.

The number of days alive without life support and days alive out of the hospital were also similar in the two groups.
New Data on Paxlovid Reported
Authors: Rosenberg Karen
Published: September 2022

According to this study:

In a phase 2/phase 3 study of Paxlovid use in patients at standard risk for developing severe COVID-19, the primary end point of self-reported sustained alleviation of all symptoms for four consecutive days wasn't met.

A nonsignificant risk reduction in hospitalizations and death was seen in a subgroup of patients who had at least one risk factor for severe COVID-19.
Response to osimertinib plus trametinib in a heavily treated epidermal growth factor receptor (EGFR)-positive NSCLC harboring a rare, acquired rapidly accelerated fibrosarcoma B-type (BRAF) p.D594N mutation: a case report
Authors: Li Sixiang , Lin Xinqing , Sun Shiyong , Li Shiyue , Zhou Chengzhi
Published: September 2022

Heterogeneity in the acquired genetic cause of osimertinib resistance leads to difficulties in understanding and addressing molecular mechanisms of resistance in clinical practice. Recent studies and clinical cases established that altered BRAF could drive osimertinib resistance in an EGFR-independent manner. Herein, we present a case in which an EGFR-positive, MET-amplified nonsmall cell lung cancer (NSCLC) patient acquired BRAF p.D594N mutation on third-line osimertinib plus crizotinib and responded to seventh-line treatment with osimertinib plus MEK inhibitor trametinib. Disease control was maintained for 6 months. BRAF p.D594N is a kinase impaired mutation but leads to increased MEK/ERK signaling, which could activate the downstream signaling of EGFR and induce drug resistance. There has been preclinical evidence supporting dual inhibition of MEK and EGFR for overcoming this resistance. To the best of our knowledge, our case is the first to provide clinical evidence that trametinib plus osimertinib was effective for EGFR-mutant NSCLC patients with acquired BRAF p.D594N mutation. More supporting data and systematic validation studies are needed for comprehensive understanding of this therapy strategy and future applications.
Injuries That Happen at Work Lead to More Opioid Prescriptions and Higher Opioid Costs
Authors: Asfaw Abay , Quay Brian , Bushnell Tim , Pana-Cryan Regina
Published: September 2022

Objectives

This study aimed to compare opioid prescription incidence, supply days, and cost associated with occupational injury and other injury-caused conditions.

Methods

We used Medical Expenditure Panel Survey (MEPS) data for 2010–2019. The MEPS provides information on medical conditions and associated medical encounters, treatments, and treatment costs, as well as demographic, education, health, working status, income, and insurance coverage information. We used descriptive statistics and logistic and 2-part regressions.

Results

Controlling for covariates and compared with other injury-caused conditions, occupational injury–caused conditions resulted in 33% higher odds of opioid prescribing, 32.8 more opioid prescription supply days, and $134 higher average cost.

Conclusions

Occupational injuries were associated with higher opioid incidence and costs, and more opioid supply days. These findings point to the need to focus on making work safer and the role employers may play in supporting worker recovery from injury and opioid use disorders.
Neuroendocrine Neoplasms of the Pancreas: Diagnostic Challenges and Practical Approach
Authors: Alipour Zahra , Sweeney Jacob R. , Zhang Qingzhao , Yang Zhaohai
Published: September 2022

Most pancreatic neuroendocrine neoplasms are slow-growing, and the patients may survive for many years, even after distant metastasis. The tumors usually display characteristic organoid growth patterns with typical neuroendocrine morphology. A smaller portion of the tumors follows a more precipitous clinical course. The classification has evolved from morphologic patterns to the current World Health Organization classification, with better-defined grading and prognostic criteria. Recent advances in molecular pathology have further improved our understanding of the pathogenesis of these tumors. Various issues and challenges remain, including the correct recognition of a neuroendocrine neoplasm, accurate classification and grading of the tumor, and differentiation from mimickers. This review focuses on the practical aspects during the workup of pancreatic neuroendocrine neoplasms and attempts to provide a general framework to help achieve an accurate diagnosis, classification, and grading.
Genome analysis of a new sulphur disproportionating species Thermosulfurimonas strain F29 and comparative genomics of sulfur-disproportionating bacteria from marine hydrothermal vents
Authors: Allioux Maxime , Yvenou Stéven , Godfroy Anne , Shao Zongze , Jebbar Mohamed , Alain Karine
Published: September 2022

This paper reports on the genome analysis of strain F29 representing a new species of the genus

Thermosulfurimonas

. This strain, isolated from the Lucky Strike hydrothermal vent field on the Mid-Atlantic Ridge, is able to grow by disproportionation of S0 with CO2 as a carbon source. Strain F29 possesses a genome of 2,345,565 bp, with a G+C content of 58.09%, and at least one plasmid. The genome analysis revealed complete sets of genes for CO2 fixation via the Wood–Ljungdahl pathway, for sulphate-reduction and for hydrogen oxidation, suggesting the involvement of the strain into carbon, sulphur, and hydrogen cycles of deep-sea hydrothermal vents. Strain F29 genome encodes also several CRISPR sequences, suggesting that the strain may be subjected to viral attacks. Comparative genomics was carried out to decipher sulphur disproportionation pathways. Genomes of sulphur-disproportionating bacteria from marine hydrothermal vents were compared to the genomes of non-sulphur-disproportionating bacteria. This analysis revealed the ubiquitous presence in these genomes of a molybdopterin protein consisting of a large and a small subunit, and an associated chaperone. We hypothesize that these proteins may be involved in the process of elemental sulphur disproportionation.
Audiovisual cues must be predictable and win-paired to drive risky choice
Authors: Hathaway Brett A. , Kim Dexter R. , Malhas Salwa B. A. , Hrelja Kelly M. , Kerker Lauren , Hynes Tristan J. , Harris Celyn , Langdon Angela J. , Winstanley Catharine A.
Published: September 2022

Risky or maladaptive decision making is thought to be central to the etiology of both drug and gambling addiction. Salient audiovisual cues paired with rewarding outcomes, such as the jackpot sound on a win, can enhance disadvantageous, risky choice in both rats and humans, yet it is unclear which aspects of the cue-reward contingencies drive this effect. Here, we implemented six variants of the rat Gambling Task (rGT), in which animals can maximise their total sugar pellet profits by avoiding options paired with higher per-trial gains but disproportionately longer and more frequent time-out penalties. When audiovisual cues were delivered concurrently with wins, and scaled in salience with reward size, significantly more rats preferred the risky options as compared to the uncued rGT. Similar results were observed when the relationship between reward size and cue complexity was inverted, and when cues were delivered concurrently with all outcomes. Conversely, risky choice did not increase when cues occurred randomly on 50% of trials, and decision making actually improved when cues were coincident with losses alone. As such, cues do not increase risky choice by simply elevating arousal, or amplifying the difference between wins and losses. It is instead important that the cues are reliably associated with wins; presenting the cues on losing outcomes as well as wins does not diminish their ability to drive risky choice. Computational analyses indicate reductions in the impact of losses on decision making in all rGT variants in which win-paired cues increased risky choice. These results may help us understand how sensory stimulation can increase the addictive nature of gambling and gaming products.
VASH1/2 inhibition accelerates functional recovery of injured nerves
Authors: Gobrecht Philipp , Gebel Jeannette , Hilla Alexander , Gisselmann Günter , Fischer Dietmar
Published: September 2022

Treatments accelerating axon regeneration in the nervous system are still unavailable in the clinic. However, in culture, parthenolide markedly promotes adult sensory neurons’ axon growth by inhibiting microtubule detyrosination. Here, we show that overexpression of vasohibins increases microtubule detyrosination in growth cones and compromises growth in culture and in vivo. Moreover, overexpression of these proteins increases the required parthenolide concentrations to promote axon regeneration, while the knockdown of vasohibins or their enhancer SVBP abolishes parthenolide’s effects, verifying them as pharmacological targets for promoting axon growth. In vivo, repeated intravenous application of parthenolide or its prodrug di-methyl-amino-parthenolide (DMAPT) markedly facilitates regeneration of sensory, motor, and sympathetic axons in injured murine and rat nerves and accelerates functional re-covery. Moreover, orally applied DMAPT was similarly effective in promoting nerve regeneration. Thus, pharmacological inhibition of vasohibins facilitates axon regeneration in different species and nerves, making parthenolide and DMAPT promising drugs for curing nerve injury.
Climate influences bill shape diversification in cavity-excavating birds
Authors: Chhaya Vaibhav , Reddy Sushma , Krishnan Anand
Published: September 2022

The remarkable structural and functional diversity of the avian bill serves as an ideal system to understand how ecological and environmental factors influence morphological diversification under physically demanding tasks. For example, in cavity-excavating birds where the bill experiences tremendous physical stresses, climate and habitat affect the mechanical properties of available nesting substrates and therefore can potentially influence the shape and performance of bills. Few studies have focused on the entire avian bill, a complex structure consisting of the rhamphotheca and bony core of the upper and lower mandibles, which may evolve as independent modules or as a single integrated unit. Here, we examined patterns and drivers of bill shape diversification in barbets using micro-computed tomography of museum study skins. We employed landmark-based geometric morphometrics and phylogenetic comparative methods to study the influence of climatic conditions, integration and phylogenetic constraints on bill shape diversification. Asian and African barbets have explored distinct maxillary shape spaces without corresponding change in mandibular shape after correcting for phylogenetic non-independence. Additionally, maxillary shape for both rhamphotheca and bony components was significantly correlated with climate variables and exhibited signatures of allometric scaling. All four bill components, however, covaried with each other and have evolved in a gradual and integrated fashion, exhibiting late-stage shape disparity. Through these findings, our study offers crucial insights into how ecological behaviors impact morphological evolution of complex, multifunctional features.
Finding the right balance of conservation effort in cultivated grasslands: A modelling study on protecting dispersers in a climatically changing and anthropogenically disturbed environment
Authors: Leins Johannes A.
Published: September 2022

Managing cultivated grasslands in a sustainable way is controversial, because it often goes along with economical loss and additional effort for local farmers. On the plus side, such a management could permit inhabiting species not only to survive but to thrive and expand their range. In order to satisfy both aspects, it can be helpful to minimize conservation effort to a degree that is still ecologically beneficial but intervenes as little as possible with regional land-use customs. Computer simulations are a useful tool to find such compromises prior to implementing management strategies. We simulated the population development of the large marsh grasshopper, a grassland species with limited dispersal abilities, in a disturbed and climatically changing environment of Germany up to the year 2080. Our results show that - in a spatially aggregated landscape - adapting the harvesting schedule in a relatively low number ≤ 7 % of (in)directly connected yet otherwise intensively managed grasslands suffices for species preservation and even expansion to some extent. The effect on dispersal success of additional conservation effort above this 7 % threshold is significantly lower than it is below the threshold. In terms of population size, however, every additional refuge benefits the grasshopper. Climate change enhances the positive effects on the target species even further. A higher level of fragmentation, however, requires a substantially larger conservation effort in terms of protected grassland proportion. Therefore, it is recommended and more effective to focus on the implementation of protected areas within spatially aggregated grasslands. Stakeholders should additionally be aware of the fact that it can take several years for a conservation effort to become apparent and measurable, especially if the goal is to support an isolated or reintroduced species in expanding into unpopulated territories.
Asymmetric inheritance of centrosomes maintains stem cell properties in human neural progenitor cells
Authors: Royall Lars N. , Denoth-Lippuner Annina , Jessberger Sebastian
Published: September 2022

During human forebrain development, neural progenitor cells (NPCs) in the ventricular zone (VZ) undergo asymmetric cell divisions to produce a self-renewed progenitor cell, maintaining the potential to go through additional rounds of cell divisions, and differentiating daughter cells, populating the developing cortex. Previous work in the embryonic rodent brain suggested that the preferential inheritance of the pre-existing (older) centrosome to the self-renewed progenitor cell is required to maintain stem cell properties, ensuring proper neurogenesis. If asymmetric segregation of centrosomes occurs in NPCs of the developing human brain, which depends on unique molecular regulators and species-specific cellular composition, remains unknown. Using a novel, recombination-induced tag exchange (RITE)-based genetic tool to birthdate and track the segregation of centrosomes over multiple cell divisions in human embryonic stem cell (hESC)-derived regionalized forebrain organoids, we show the preferential inheritance of the older mother centrosome towards self-renewed NPCs. Aberration of asymmetric segregation of centrosomes by genetic manipulation of the centrosomal, microtubule-associated protein Ninein alters fate decisions of NPCs and their maintenance in the VZ of human cortical organoids. Thus, the data described here use a novel genetic approach to birthdate centrosomes in human cells and identify asymmetric inheritance of centrosomes as a mechanism to maintain self-renewal properties and to ensure proper neurogenesis in human NPCs.

Impact Statement

Genetic birthdating in forebrain organoids shows asymmetric inheritance of centrosomes in human neural progenitor cells, required for proper human neurogenesis.