bluuebunny/crossref_metadata_2025 huggingface dataset:
4. Regulating the information society
Authors: Murray Andrew
Published: August 2023

This chapter examines whether the actions of individuals in the digital environment could be regulated. It first considers John Perry Barlow’s 1996 publication of his Declaration of Independence for Cyberspace, in which he asserts that cyberspace was a separate sovereign space where real-world laws and real-world governments were of little or no effect. Barlow’s forceful challenge to lawmakers and law enforcement bodies gave rise to a school of thought known as cyberlibertarianism. The chapter compares cyberlibertarianism with another school of thought called cyberpaternalism, which rejected the notion that cyberspace was immune from regulatory intervention by real-world regulators. It also explains Lawrence Lessig’s modalities of internet regulation, network communitarianism, private regulators of cyberspace, and states’ supranational regulation of cyberspace. The chapter goes on to examine contemporary theories of internet governance and regulation including libertarian paternalism, platform and intermediary regulation and algorithmic regulation.
5. Cyber-speech
Authors: Murray Andrew
Published: August 2023

This chapter examines cyber-speech and its implications for free expression. It first provides an overview of the technologies involved, from simple systems such as web pages, blogs, and internet fora to social media platforms (SMPs), and media-sharing sites. The chapter then highlights the social implications of the shift in power from centralized media organizations to users. It also considers the responsibilities that users owe to each other in this environment and how regulators may balance freedom of expression with social responsibility. To determine whose values predominate when regulating a global media tool which does not recognize traditional borders, the chapter presents two case studies: political speech and hate speech.
8. Intellectual property rights and the information society
Authors: Murray Andrew
Published: August 2023

This chapter examines intellectual property rights (IPRs) in relation to the information society. The discussion begins with an overview of IPRs involving copyright, patents, trade marks, and the database right, and then considers IPRs and the process of digitization within the framework of cyberlaw. It mentions the criticism received for overprotecting content or systems in the information society and discusses the idea of an over-reliance on models developed for a previous age and for different challenges in dealing with the information economy and society. It concludes by highlighting the tension between the information society and the intellectual property industry in terms of what each wants and expects: liberty, free use of content, and unfettered free expression for the former; and protection, control over use, and abuse and reward for the latter.
13. Databases
Authors: Murray Andrew
Published: August 2023

This chapter examines database right, a sui generis form of intellectual property protection, the roots of which are to be found in copyright law. It first compares copyright and database rights before turning to cases in which the UK’s Copyright, Designs and Patents Act 1988 was applied to listings of information in the form of a simple database. The chapter then considers the European Union’s Database Directive and analyses the Fixtures Marketing, British Horseracing Board Ltd v William Hill, and Football Dataco v Yahoo! cases. Finally, it looks at databases, along with the intellectual property issues that they generate, within the framework of the information society.
15. Brand identities, search engines, and secondary markets
Authors: Murray Andrew
Published: August 2023

This chapter examines brand identities, search engines, and secondary markets and their operation in the information society. It considers jurisdiction and online trade mark disputes, as well as search engine optimization and the role of Google and the impact of its search engine services on brand profile and market presence. The chapter goes on to examine secondary markets and the liability of sellers of counterfeit products for the abuse of trade marks. The chapter concludes with a summary of the changing nature of online branding and the diminishing impact of domain names to cement brand identity, as well as the growing influence of developments to web browser functionality on consumer behaviour.
22. Data protection: the legal framework
Authors: Murray Andrew
Published: August 2023

This chapter examines data protection, digitization of data, its implications for personal privacy, and the regulation of data industries. It begins by discussing the current law found, post Brexit in the UK General Data Protection Regulation and the Data Protection Act 2018. It examines the key concepts of data controllers, data processors, and data subjects, and discusses the conditions for the processing of personal data. This includes an examination of key cases such as Nowak v Data Protection Commissioner, the Facebook fan page case, and Bodil Lindqvist. It looks at the geographical scope of UK GDPR and the extra-territorial effect of the Regulation and examines the domestic purposes exemption after Ryneš. It examines questions of fairness and lawfulness of processing as discussed in Johnson v Medical Defence Union.
2. Constitutional Foundations of the Powers of the Courts
Authors: Wade Sir William , Forsyth Christopher , Ghosh Julian
Published: August 2023

This chapter begins with a discussion of the concept of the rule of law, covering the meaning of legality and discretionary power, judicial independence and fairness. It then explains the sovereignty of Parliament, the elements of judicial control and the doctrine of ultra vires.
6. The European Union
Authors: Wade Sir William , Forsyth Christopher , Ghosh Julian
Published: August 2023

This chapter discusses the legal framework of the EU, and the interaction between European law and British constitutional and administrative law. In particular, it considers the post-Brexit UK regime, retained EU law and the EU–UK Trade and Cooperation Agreement.
10. Retention of Discretion
Authors: Wade Sir William , Forsyth Christopher , Ghosh Julian
Published: August 2023

This chapter examines the rules which govern discretionary power. It focuses on the rules which ensure that discretionary power should be wielded only by those to whom it is given and that they should retain it unhampered by improper constraints or restrictions. Topics discussed include delegation; surrender, abdication, dictation; over-rigid policies; restriction by contract or grant; and estoppel.
11. Abuse of Discretion
Authors: Wade Sir William , Forsyth Christopher , Ghosh Julian
Published: August 2023

This chapter examines the sovereign principle that powers must be exercised reasonably and in good faith and on proper grounds—in other words, that they must not be abused. This is one of the twin pillars that uphold the structure of administrative law. Topics discussed include the justification for review on substantive grounds; the rule of reason; the principle of proportionality; categories of unreasonableness; good faith; and statutory reasonableness.
12. Natural Justice and Legal Justice
Authors: Wade Sir William , Forsyth Christopher , Ghosh Julian
Published: August 2023

This chapter first discusses how the courts have devised a code of fair administrative procedure based on doctrines which are an essential part of any system of administrative justice. It then explains the concept of administrative justice and natural justice; natural justice in the common law; the European Convention and natural justice in administrative proceedings; and the curative effect of access to a court of ‘full jurisdiction’.
14. The Right to a Fair Hearing
Authors: Wade Sir William , Forsyth Christopher , Ghosh Julian
Published: August 2023

This chapter discusses the right to a fair hearing, which has been used by the courts as a base on which to build a kind of code of fair administrative procedure, comparable to ‘due process of law’ under the Constitution of the United States. Topics covered include administrative cases, the retreat from natural justice, the right to be heard, the protection of legitimate expectations and exceptions to the right to a fair hearing.
18. Procedure of Judicial Review
Authors: Wade Sir William , Forsyth Christopher , Ghosh Julian
Published: August 2023

This chapter discusses the application for judicial review. The development of the application is complicated and intertwined with the historical deficiencies and peculiarities of the remedies themselves. Thus, the chapter begins with an account of the defects in the prerogative remedies that spurred the creation of the application. It then discusses the creation of the application for judicial review and subsequent developments; and the divorce of public and private law.
19. Restriction of Remedies
Authors: Wade Sir William , Forsyth Christopher , Ghosh Julian
Published: August 2023

Remedies are awarded only to litigants who have sufficient locus standi, or standing. The law starts from the position that remedies are correlative with rights, and that only those whose own rights are at stake are eligible to be awarded remedies. No one else will have the necessary standing before the court. This chapter discusses the old and new law of standing; discretionary power of the court to withhold remedies; exhaustion of remedies; protective and preclusive (ouster) clauses; exclusive statutory remedies; and ‘default powers’, i.e. special powers under which ministers may take steps to compel local authorities to carry out their functions properly.
9. Article 6: The Right to a Fair Trial
Authors: Harris David , O’boyle Michael , Bates Ed , Buckley Carla M. , Kamber KreŠimir , Bryanston-Cross ZoË , Cumper Peter , Green Heather
Published: August 2023

This chapter discusses Article 6 of the European Convention on Human Rights, which guarantees the right to a fair trial in both criminal and non-criminal cases. In all cases, it guarantees the right to a fair and public hearing trial within a reasonable time by an independent and impartial tribunal established by law. There are particular guarantees for persons subject to a criminal charge, including the right to be presumed innocent, to be informed of the charge, to adequate time and facilities to prepare the accused’s defence, to legal assistance, to examine and cross-examine witnesses, and to an interpreter.
12. Article 9: Freedom of Thought, Conscience, and Religion
Authors: Harris David , O’boyle Michael , Bates Ed , Buckley Carla M. , Kamber KreŠimir , Bryanston-Cross ZoË , Cumper Peter , Green Heather
Published: August 2023

This chapter discusses Article 9 of the European Convention on Human Rights, which covers forms of both religious and non-religious belief. Few Articles of the Convention have generated as much controversy as Article 9, from complaints about curbs on religious dress and displays of religious symbols to conflicts over faith in the workplace. In the past three decades, the Court has made important strides in formulating its own guidelines in relation to freedom of thought, conscience, and religion. The chapter considers the restrictions on belief permitted by Article 9.
15. Article 12: The Right to Marry and to Found a Family
Authors: Harris David , O’boyle Michael , Bates Ed , Buckley Carla M. , Kamber KreŠimir , Bryanston-Cross ZoË , Cumper Peter , Green Heather
Published: August 2023

This chapter discusses Article 12 of the European Convention on Human Rights, which protects the right to marry and to found a family, subject to a wide power on the part of states to regulate the exercise of the right. National law may regulate the form and capacity to marry, but procedural or substantive limitations must not remove the essence of the right. The right to marry does not extend to same-sex marriage and there is no right to divorce. However, persons who are transgender are guaranteed the right to marry persons of their now opposite sex.
1. Introduction
Authors: Ormerod David , Child John
Published: August 2023

This book focuses on substantive criminal law, that is, how offences such as theft and murder are defined. This introductory chapter sets in context criminal offences and defences, first by considering the basis upon which certain conduct is criminalised and other conduct is not. In continuing to set the context, the chapter goes on to consider criminal justice and criminology, criminal evidence, criminal process (including the court structure and central actors), sentencing, civil law protections, and so on. Narrowing to our focus on substantive criminal law—how offences and defences are defined—the chapter moves on to discuss the sources of criminal law, the internal structure of offences and defences, principles of the substantive criminal law, and the subjects to which it applies. Finally, the chapter introduces features on reform and legal application.
2. Actus reus
Authors: Ormerod David , Child John
Published: August 2023

This chapter provides an overview of actus reus, which refers to the ‘external elements’ of an offence. These external elements do not simply relate to D’s conduct. Rather, as we will see, the actus reus of an offence includes any offence elements outside the fault element (‘mens rea’) of the offence. Before discussing the elements that form the actus reus, this chapter considers the distinction between actus reus and mens rea. It then describes the three elements of actus reus: conduct, circumstances, and results. It also explains the categories of actus reus offences, omissions liability, and causation before concluding with sections that outline potential options for legal reform and a structure for analysing the actus reus of an offence when applying the law in a problem-type question. Relevant cases are highlighted throughout the chapter, with a brief summary of the main facts and judgments.
3. Mens rea
Authors: Ormerod David , Child John
Published: August 2023

This chapter provides an overview of mens rea, loosely translated as ‘guilty mind’. Whereas the concept of actus reus focuses on the external elements of an offence, mens rea focuses on state of mind or fault. The mens rea of the offence describes the fault element with which D acted: D intended, believed, foresaw as a risk the proscribed element(s), and so on. The chapter first considers how offences differ in the role mens rea plays. For some offences, a mens rea element may be required in relation to each actus reus element; for other offences there are actus reus elements that do not have a corresponding mens rea and vice versa. The chapter moves on to discuss the legal meaning of central mens rea terms such as ‘intention’, ‘negligence’, ‘dishonesty’, and ‘recklessness’. Finally, it outlines reform debates, and a structure for analysing the mens rea of an offence when applying the law in a problem-type question. Relevant cases are highlighted throughout the chapter.
6. Shares
Authors: French Derek
Published: August 2023

This chapter considers one way of becoming a shareholder of a company with a share capital: by taking shares from the company in exchange for a contribution of capital. The number and class of shares of the company that the member holds determines the extent of the member’s undertaking to contribute capital, and of entitlement to share in distributions and vote at meetings. Share allotment in exchange for a capital contribution is explained, and the need for public companies to have a minimum contributed capital is emphasised. The chapter also looks at possible remedies available to a person who has been induced to take an allotment of shares by a misrepresentation, including rescission of contract. Finally, it examines ways of altering a company’s share capital.
11. Borrowing and security
Authors: French Derek
Published: August 2023

This chapter considers borrowing as an important method of financing a company’s activities, and security as a right of recourse against company property if the loan is not repaid on time. It begins by discussing security for financial obligations, paying particular attention to security contracts, the redemption or discharge of security and the realisation of security. It then turns to the registration of non-possessory security contracts, the priorities of legal and equitable charges and floating charges as a form of security and their crystallisation. The extent to which the assets of a company, to which anyone is considering extending credit, are already charged as security is also explained. The chapter considers three particularly significant court cases: Evans v Rival Granite Quarries Ltd [1910] 2 KB 979; Re Spectrum Plus Ltd [2005] UKHL 41, [2005] 2 AC 680; and Re Yorkshire Woolcombers Association Ltd [1903] 2 Ch 284.
Transparency
Authors: French Derek
Published: August 2023

This chapter discusses the obligations imposed on companies and their officers to provide information about the company, other than accounts. Information about a company’s constitution, membership, officers and finances must be provided to Companies House, which makes the information available for inspection by anyone at its website. Much of that information must also be made available for inspection at the company’s registered office or an alternative inspection place. Some other information, including directors’ service contracts, must be kept available for inspection by the company’s members at its registered office or inspection place. Any company must identify itself by its registered name at its registered office, inspection place, and places of business. Further identifying information, including its registered number, must be given on business letters, order forms and websites. The chapter discusses the general rules on disclosure and how they are enforced.
C. Marketable loans
Authors: French Derek
Published: August 2023

This chapter deals with arrangements by which a company borrows a large sum of money long term. The money is put up by a number of investors who are entitled to receive interest payments (usually twice a year) and, at the end of the term of the loan, repayment of principal. Sale of all or part of an investor’s entitlements is possible and arrangements are usually made for trading on a stock exchange. Marketable loans were once issued to the general public in the same way as shares, but nowadays they are usually held in large quantities by financial institutions and specialist investors. They are described as ‘wholesale’ rather than ‘retail’ investments. Interests in marketable loans are called ‘debt securities’, ‘bonds’ or ‘debentures’.
5. Members
Authors: Roach Lee
Published: August 2023

This chapter focuses on one of the vital roles played by members of a company, namely their ability to make decisions. A significant amount of power is placed in the hands of members, and numerous key decisions are reserved for them alone. This chapter looks at the rules by which general meetings are run and discusses the effectiveness of the general meeting.
1. The English Legal System
Authors: Gillespie Alisdair , Weare Siobhan
Published: August 2023

This chapter provides an introduction to the English Legal System. Specifically, it explains the meaning of the terms ‘English’, ‘legal’, and ‘system’. It first provides an overview of the constituent parts of the United Kingdom of Great Britain and Northern Ireland, namely England, Wales, Scotland, and Northern Ireland. It describes the types of law that exist and attempts to define what law is. It then discusses the English legal system, which is based on common law and is an adversarial system.
10. The Legal Professions
Authors: Gillespie Alisdair , Weare Siobhan
Published: August 2023

This chapter explains what the legal professions are, what they do, and how to qualify as a member of the professions. It examines the rules governing practice as a member of the professions and, in particular, the issue of ethical behaviour. There are three principal branches to the legal profession in England and Wales. The first consists of barristers, the second of solicitors, and the third of chartered legal executives. The routes to qualification vary for each of the branches, but broadly speaking all involve an academic stage and work-based training. When considering the current routes to qualification for each of the branches of the profession, the chapter also explores potential qualification reforms, in particular those proposed by the Solicitors Regulation Authority with the introduction of the Solicitors’ Qualifying Exam (SQE). Diversity within each branch of the profession is also explored in relation to gender, ethnicity, and socio-economic backgrounds.
20. The Future
Authors: Gillespie Alisdair , Weare Siobhan
Published: August 2023

This chapter considers the impact that Covid-19 has had on the English Legal System. The chapter is broken down into sections that mirror the parts of this book. The chapter begins by noting that the manner in which laws are passed differed because of coronavirus. The government was given wide-ranging powers to introduce new laws that restricted liberty. In many instances, these were not subject to parliamentary debate or judicial analysis. The chapter also considers how the courts had to adjust to new ways of working. While traditionally the courts rely on live proceedings, with everyone gathered in court, this was not possible throughout the pandemic. Remote hearings became the new normal until so-called ‘Nightingale courts’ were introduced to allow for socially distant trials to resume. However, this has led to significant delays in both the civil and criminal justice systems that will have a lasting impact. The chapter considers not only what happened during the coronavirus pandemic, but also what lessons have been learnt that can carry through to the future.
Use of adenine base editing and homology-independent targeted integration strategies to correct the cystic fibrosis causing variant, W1282X
Authors: Mention Karen , Cavusoglu-Doran Kader , Joynt Anya T , Santos Lúcia , Sanz David , Eastman Alice C , Merlo Christian , Langfelder-Schwind Elinor , Scallan Martina F , Farinha Carlos M , Cutting Garry R , Sharma Neeraj , Harrison Patrick T
Published: August 2023

Small molecule drugs known as modulators can treat ~90% of people with cystic fibrosis (CF), but do not work for premature termination codon variants such as W1282X (c.3846G>A). Here we evaluated two gene editing strategies, Adenine Base Editing (ABE) to correct W1282X, and Homology-Independent Targeted Integration (HITI) of a CFTR superexon comprising exons 23–27 (SE23–27) to enable expression of a CFTR mRNA without W1282X. In Flp-In-293 cells stably expressing a CFTR expression minigene bearing W1282X, ABE corrected 24% of W1282X alleles, rescued CFTR mRNA from nonsense mediated decay and restored protein expression. However, bystander editing at the adjacent adenine (c.3847A>G), caused an amino acid change (R1283G) that affects CFTR maturation and ablates ion channel activity. In primary human nasal epithelial cells homozygous for W1282X, ABE corrected 27% of alleles, but with a notably lower level of bystander editing, and CFTR channel function was restored to 16% of wild-type levels. Using the HITI approach, correct integration of a SE23–27 in intron 22 of the CFTR locus in 16HBEge W1282X cells was detected in 5.8% of alleles, resulting in 7.8% of CFTR transcripts containing the SE23–27 sequence. Analysis of a clonal line homozygous for the HITI-SE23–27 produced full-length mature protein and restored CFTR anion channel activity to 10% of wild-type levels, which could be increased three-fold upon treatment with the triple combination of CF modulators. Overall, these data demonstrate two different editing strategies can successfully correct W1282X, the second most common class I variant, with a concomitant restoration of CFTR function.
What drives network evolution? Comparing R&D project and patent networks in the EU
Authors: Akçomak İbrahim Semih , Çetinkaya Umut Yılmaz , Erdil Erkan , Gossart Müge Özman
Published: August 2023

Collaboration networks are the main mechanisms through which regional innovation capacities are enhanced. These networks have been analyzed by using data either on research projects or patents. However, analyzing only one type of network can limit our understanding of regional innovation dynamics. In this paper, we investigate the drivers of network evolution in two inter-regional network types within the European Union: R&D project networks and co-patenting networks. Specifically, we examine data on Framework Program project collaborations and patent collaborations at the NUTS2 regional level between 2011 and 2019. Our empirical strategy is based on Stochastic Actor-Oriented Model where we analyze and compare the factors that affect the evolution of two networks. We find that path-dependent processes resulting from past networks, such as triadic closure, preferential attachment, and tie repetition, play a more important role in explaining the evolution of R&D project networks compared with patent networks. On the other hand, regional characteristics, particularly the patenting intensity of a region and similarity in patenting between regions appear to be more influential in shaping patent networks. These results have important implications for the future evolution of knowledge networks in Europe.
Trajectories of kidney function and risk of mortality
Authors: van der Burgh Anna C , Sedaghat Sanaz , Ikram M Arfan , Hoorn Ewout J , Chaker Layal
Published: August 2023

Background

We aimed to identify patterns within the rate of kidney function decline, determinants of these patterns and their association with all-cause mortality risk in the general population.

Methods

Participants aged ≥ 45 years with at least one assessment of creatinine-based estimated glomerular filtration rate (eGFR) taken between 1997 and 2018 were selected from a population-based cohort study. Analyses were performed using several distinct latent class trajectory modelling methods. Cumulative incidences were calculated with 45 years of age as the starting point.

Results

In 12 062 participants (85 922 eGFR assessments, mean age 67.0 years, 58.7% women, median follow-up 9.6 years), four trajectories of eGFR change with age were identified: slow eGFR decline [rate of change in mL/min/1.73 m2 per year (RC), –0.9; 95% CI, –0.9 to –0.9; reference group], intermediate eGFR decline (RC, –2.5; 95% CI, –2.7 to –2.5) and fast eGFR decline (RC, –4.3; 95% CI, –4.4 to –4.1), and an increase/stable eGFR (RC, 0.3; 95% CI, 0.3 to 0.4). Women were more likely to have an increase/stable eGFR [odds ratio (OR), 1.94; 95% CI, 1.53 to 2.46] whereas men were more likely to have a fast eGFR decline (OR, 1.86; 95% CI, 1.33 to 2.60). Participants with diabetes, cardiovascular disease (CVD) or hypertension were more likely to have an intermediate or fast eGFR decline. All-cause mortality risks (cumulative incidence at age of 70 years) were 32.3% (95% CI, 21.4 to 47.9, slow eGFR decline), 6.7% (95% CI, 3.5 to 12.4, intermediate eGFR decline), 68.8% (95% CI, 44.4 to 87.8, fast eGFR decline) and 9.5% (95% CI, 5.5 to 15.7, increase/stable eGFR).

Conclusion

Sex, hypertension, diabetes and CVD were identified as trajectory membership determinants. Having fast eGFR decline was associated with the highest risk of all-cause mortality, highlighting the need for extensive monitoring and prevention of kidney function decline in individuals at risk of having fast eGFR decline.
Characterizing Boundedness of Metaplectic Toeplitz Operators
Authors: Coburn Lewis , Hitrik Michael , Sjöstrand Johannes
Published: August 2023

We study Toeplitz operators on the Bargmann space, with Toeplitz symbols given by exponentials of complex quadratic forms. We show that the boundedness of the corresponding Weyl symbols is necessary for the boundedness of the operators, thereby completing the proof of the Berger–Coburn conjecture in this case. We also show that the compactness of such Toeplitz operators is equivalent to the vanishing of their Weyl symbols at infinity.
Immune Status and SARS-CoV-2 Viral Dynamics
Authors: Li Yijia , Moser Carlee , Aga Evgenia , Currier Judith S , Wohl David A , Daar Eric S , Ritz Justin , Greninger Alexander L , Sieg Scott , Parikh Urvi M , Coombs Robert W , Hughes Michael D , Eron Joseph J , Smith Davey M , Chew Kara W , Li Jonathan Z ,   for the ACTIV-2/A5401 Study Team, Hosey Lara , Roa Jhoanna , Patel Nilam , Degli-Angeli Emily , Goecker Erin , Daza Glenda , Harb Socorro , Dragavon Joan , Aldrovandi Grace , Murtaugh William , Cooper Marlene , Gutzman Howard , Knowles Kevin , Bowman Rachel , Erhardt Bill , Warring Lorraine , Hessinger Diane , Adams Stacey
Published: August 2023

Immunocompromised individuals are disproportionately affected by severe coronavirus disease 2019, but immune compromise is heterogenous, and viral dynamics may vary by the degree of immunosuppression. In this study, we categorized ACTIV-2/A5401 participants based on the extent of immunocompromise into none, mild, moderate, and severe immunocompromise. Moderate/severe immunocompromise was associated with higher nasal viral load at enrollment (adjusted difference in means: 0.47 95% confidence interval, .12–.83 log10 copies/mL) and showed a trend toward higher cumulative nasal RNA levels and plasma viremia compared to nonimmunocompromised individuals. Immunosuppression leads to greater viral shedding and altered severe acute respiratory syndrome coronavirus 2 viral decay kinetics.

Clinical Trials Registration. NCT04518410.
Statistical Challenges When Analyzing SARS-CoV-2 RNA Measurements Below the Assay Limit of Quantification in COVID-19 Clinical Trials
Authors: Moser Carlee B , Chew Kara W , Giganti Mark J , Li Jonathan Z , Aga Evgenia , Ritz Justin , Greninger Alexander L , Javan Arzhang Cyrus , Bender Ignacio Rachel , Daar Eric S , Wohl David A , Currier Judith S , Eron Joseph J , Smith Davey M , Hughes Michael D ,   for the ACTIV-2/A5401 Study Team, Hosey Lara , Roa Jhoanna , Patel Nilam , Aldrovandi Grace , Murtaugh William , Science Frontier , Cooper Marlene , Gutzman Howard , Knowles Kevin , Bosch Ronald , Harrison Linda , Erhardt Bill , Adams Stacey
Published: August 2023

Most clinical trials evaluating coronavirus disease 2019 (COVID-19) therapeutics include assessments of antiviral activity. In recently completed outpatient trials, changes in nasal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA levels from baseline were commonly assessed using analysis of covariance (ANCOVA) or mixed models for repeated measures (MMRM) with single imputation for results below assay lower limits of quantification (LLoQ). Analyzing changes in viral RNA levels with singly imputed values can lead to biased estimates of treatment effects. In this article, using an illustrative example from the ACTIV-2 trial, we highlight potential pitfalls of imputation when using ANCOVA or MMRM methods, and illustrate how these methods can be used when considering values <LLoQ as censored measurements. Best practices when analyzing quantitative viral RNA data should include details about the assay and its LLoQ, completeness summaries of viral RNA data, and outcomes among participants with baseline viral RNA ≥ LLoQ, as well as those with viral RNA < LLoQ.

Clinical Trials Registration. NCT04518410.
Long COVID After Bamlanivimab Treatment
Authors: Evering Teresa H , Moser Carlee B , Jilg Nikolaus , Yeh Eunice , Sanusi Busola , Wohl David A , Daar Eric S , Li Jonathan Z , Klekotka Paul , Javan Arzhang Cyrus , Eron Joseph J , Currier Judith S , Hughes Michael D , Smith Davey M , Chew Kara W ,   for the ACTIV-2/A5401 Study Team, Hosey Lara , Roa Jhoanna , Patel Nilam , Coombs Robert , Greninger Alexander , Degli-Angeli Emily , Goecker Erin , Daza Glenda , Harb Socorro , Dragavon Joan , Aldrovandi Grace , Murtaugh William , Cooper Marlene , Gutzman Howard , Knowles Kevin , Bowman Rachel , Erhardt Bill , Waring Lorraine , Hessinger Diane , Adams Stacey , Kallianpur Asha R
Published: August 2023

Background

Prospective evaluations of long COVID in outpatients with coronavirus disease 2019 (COVID-19) are lacking. We aimed to determine the frequency and predictors of long COVID after treatment with the monoclonal antibody bamlanivimab in ACTIV-2/A5401.

Methods

Data were analyzed from participants who received bamlanivimab 700 mg in ACTIV-2 from October 2020 to February 2021. Long COVID was defined as the presence of self-assessed COVID symptoms at week 24. Self-assessed return to pre-COVID health was also examined. Associations were assessed by regression models.

Results

Among 506 participants, median age was 51 years. Half were female, 5% Black/African American, and 36% Hispanic/Latino. At 24 weeks, 18% reported long COVID and 15% had not returned to pre-COVID health. Smoking (adjusted risk ratio [aRR], 2.41 [95% confidence interval {CI}, 1.34– 4.32]), female sex (aRR, 1.91 [95% CI, 1.28–2.85]), non-Hispanic ethnicity (aRR, 1.92 [95% CI, 1.19–3.13]), and presence of symptoms 22–28 days posttreatment (aRR, 2.70 [95% CI, 1.63–4.46]) were associated with long COVID, but nasal severe acute respiratory syndrome coronavirus 2 RNA was not.

Conclusions

Long COVID occurred despite early, effective monoclonal antibody therapy and was associated with smoking, female sex, and non-Hispanic ethnicity, but not viral burden. The strong association between symptoms 22–28 days after treatment and long COVID suggests that processes of long COVID start early and may need early intervention.

Clinical Trials Registration

NCT04518410.
Association Between Anterior Nasal and Plasma SARS-CoV-2 RNA Levels and Hospitalization or Death in Nonhospitalized Adults With Mild-to-Moderate COVID-19
Authors: Giganti Mark J , Chew Kara W , Eron Joseph J , Li Jonathan Z , Pinilla Mauricio , Moser Carlee , Javan Arzhang Cyrus , Fischer William A , Klekotka Paul , Margolis David , Wohl David Alain , Coombs Robert W , Daar Eric S , Smith Davey M , Currier Judith S , Hughes Michael D ,   for the ACTIV-2/A5401 Study Team, Hosey Lara , Roa Jhoanna , Patel Nilam , Greninger Alexander , Degli-Angeli Emily , Goecker Erin , Daza Glenda , Harb Socorro , Dragavon Joan , Aldrovandi Grace , Murtaugh William , Science Frontier , Cooper Marlene , Gutzman Howard , Knowles Kevin , Bowman Rachel , Erhardt Bill , Waring Lorraine , Hessinger Diane , Adams Stacey
Published: August 2023

Background

There is little information regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA as a predictor for clinical outcomes in outpatients with mild-to-moderate coronavirus disease 2019 (COVID-19).

Methods

Anterior nasal (AN) and plasma SARS-CoV-2 RNA data from 2115 nonhospitalized adults who received monoclonal antibodies (mAbs) or placebo in the ACTIV-2/A5401 trial were analyzed for associations with hospitalization or death.

Results

One hundred two participants were hospitalized or died through 28 days of follow-up. Higher day 0 (pretreatment) AN RNA was associated with increasing risk of hospitalization/death (risk ratio [RR], 1.24 per log10 copies/mL [95% confidence interval {CI}, 1.04–1.49]) among placebo recipients, ranging from 3% to 16% for <2 to ≥6 log10 copies/mL. Although only 1% had quantifiable levels, there was a similar trend across day 0 plasma RNA categories. Higher day 3 AN RNA was associated with subsequent hospitalization/death among placebo recipients (RR, 1.42 per log10 copies/mL [95% CI, 1.00–2.03]), but not mAb recipients (RR, 1.02 per log10 copies/mL [95% CI, 0.68–1.56]). The proportion of treatment effect (reduction in hospitalizations/deaths after day 3 for mAb vs placebo) explained by day 3 AN RNA was 8%.

Conclusions

SARS-CoV-2 RNA levels are predictive of hospitalization/death in the natural history setting, but AN RNA levels may not be a reliable surrogate marker of mAb treatment effect in COVID-19 trials.

Clinical Trials Registration. NCT04518410.
Validity and Characterization of Time to Symptom Resolution Outcome Measures in the ACTIV-2/A5401 Outpatient COVID-19 Treatment Trial
Authors: Chew Kara W , Moser Carlee , Yeh Eunice , Wohl David A , Daar Eric S , Ritz Justin , Javan Arzhang Cyrus , Eron Joseph J , Currier Judith S , Smith Davey M , Hughes Michael D ,   for the ACTIV-2/A5401 Study Team
Published: August 2023

Background

Time to symptom resolution measures were used in outpatient coronavirus disease 2019 (COVID-19) treatment trials without prior validation.

Methods

ACTIV-2/A5401 trial participants completed a COVID-19 diary assessing 13 targeted symptoms and global experience (overall COVID-19 symptoms, return to pre–COVID-19 health) daily for 29 days. We evaluated concordance of time to sustained (2 days) resolution of all targeted symptoms (TSR) with resolution of overall symptoms and return to health in participants receiving placebo.

Results

The analysis included 77 high-risk and 81 standard-risk participants with overall median 6 days of symptoms at entry and median age 47 years, 50% female, 82% white, and 31% Hispanic/Latino. Correlation between TSR and resolution of overall symptoms was 0.80 and 0.68, and TSR and return to health, 0.66 and 0.57 for high- and standard-risk groups, respectively. Of the high- and standard-risk participants, 61% and 79%, respectively, achieved targeted symptom resolution, of which 47% and 43%, respectively, reported symptom recurrence. Requiring >2 days to define sustained resolution reduced the frequency of recurrences.

Conclusions

There was good internal consistency between TSR and COVID-19–specific global outcomes, supporting TSR as a trial end point. Requiring >2 days of symptom resolution better addresses natural symptom fluctuations but must be balanced against the potential influence of non-COVID-19 symptoms.

Clinical Trials Registration

NCT04518410.
Dengue virus infection in mice induces bone marrow myeloid cell differentiation and generates Ly6Glow immature neutrophils with modulated functions
Authors: Duggal Shweta , Rawat Surender , Siddqui Gazala , Vishwakarma Preeti , Samal Sweety , Banerjee Arup , Vrati Sudhanshu
Published: August 2023

While neutrophil activation during dengue virus infection is known, the effect of dengue virus infection on neutrophil biogenesis has not been studied. We demonstrate that dengue virus serotype 2 induces the differentiation of mice progenitor cells ex vivo toward the CD11b+Ly6C+Ly6G+ granulocyte population. We further observed an expansion of CD11b+Ly6CintLy6Glow myeloid cells in the bone marrow of dengue virus serotype 2–infected AG129 mice with low CXCR2 expression, implying an immature population. Additionally, dengue virus serotype 2 alone could induce the differentiation of promyelocyte cell line HL-60 into neutrophil-like cells, as evidenced by increased expression of CD10, CD66b, CD16, CD11b, and CD62L, corroborating the preferential shift toward neutrophil differentiation by dengue virus serotype 2 in the mouse model of dengue infection. The functional analysis showed that dengue virus serotype 2–induced neutrophil-like cells exhibited reduced phagocytic activity and enhanced NETosis, as evidenced by the increased production of myeloperoxidase, citrullinated histones, extracellular DNA, and superoxide. These neutrophil-like cells lose their ability to proliferate irreversibly and undergo arrest in the G0 to G1 phase of the cell cycle. Further studies show that myeloperoxidase-mediated signaling operating through the reactive oxygen species axis may be involved in dengue virus serotype 2–induced proliferation and differentiation of bone marrow cells as ABAH, a myeloperoxidase inhibitor, limits cell proliferation in vitro and ex vivo, affects the cell cycle, and reduces reactive oxygen species production. Additionally, myeloperoxidase inhibitor reduced NETosis and vascular leakage in dengue virus serotype 2–infected AG129 mice. Our study thus provides evidence that dengue virus serotype 2 can accelerate the differentiation of bone marrow progenitor cells into neutrophils through myeloperoxidase and modulate their functions.
Macrophage extracellular traps promote tumor-like biologic behaviors of fibroblast-like synoviocytes through cGAS-mediated PI3K/Akt signaling pathway in patients with rheumatoid arthritis
Authors: Weng Weizhen , Liu Yan , Hu Zuoyu , Li Zhihui , Peng Xiaohua , Wang Manli , Dong Bo , Zhong Shuyuan , Jiang Yutong , Pan Yunfeng
Published: August 2023

Rheumatoid arthritis is an autoimmune disease characterized by synovium hyperplasia and bone destruction. Macrophage extracellular traps are released from macrophages under various stimuli and may generate stable autoantigen–DNA complexes, as well as aggravate autoantibody generation and autoimmune responses. We aimed to investigate the role of macrophage extracellular traps on the biologic behaviors of rheumatoid arthritis fibroblast-like synoviocytes. Synovial tissues and fibroblast-like synoviocytes were obtained from patients with rheumatoid arthritis. Extracellular traps in synovium and synovial fluids were detected by immunofluorescence, immunohistochemistry, and SYTOX Green staining. Cell viability, migration, invasion, and cytokine expression of rheumatoid arthritis fibroblast-like synoviocytes were assessed by CCK-8, wound-healing assay, Transwell assays, and quantitative real-time polymerase chain reaction, respectively. RNA sequencing analysis was performed to explore the underlying mechanism, and Western blot was used to validate the active signaling pathways. We found that extracellular trap formation was abundant in rheumatoid arthritis and positively correlated to anti-CCP. Rheumatoid arthritis fibroblast-like synoviocytes stimulated with purified macrophage extracellular traps demonstrated the obvious promotion in tumor-like biologic behaviors. The DNA sensor cGAS in rheumatoid arthritis fibroblast-like synoviocytes was activated after macrophage extracellular trap stimuli. RNA sequencing revealed that differential genes were significantly enriched in the PI3K/Akt signaling pathway, and cGAS inhibitor RU.521 effectively reversed the promotion of tumor-like biologic behaviors in macrophage extracellular trap–treated rheumatoid arthritis fibroblast-like synoviocytes and downregulated the PI3K/Akt activation. In summary, our study demonstrates that macrophage extracellular traps promote the pathogenically biological behaviors of rheumatoid arthritis fibroblast-like synoviocytes through cGAS-mediated activation of the PI3K/Akt signaling pathway. These findings provide a novel insight into the pathogenesis of rheumatoid arthritis and the mechanisms of macrophages in modulating rheumatoid arthritis fibroblast-like synoviocyte tumor-like behaviors.
Thoracic spinal extradural arachnoid cyst causing Brown-Sequard-like syndrome: a rare case report and review of literature
Authors: Ajoku Uchenna , Nwekeala Bright Uche
Published: August 2023

Spinal extradural arachnoid cysts are rare benign lesions occurring along the cerebrospinal axis. They may be associated with pain or varying degrees of neurological compressive symptoms. Brown-Sequard syndrome is a rare sequalae, where there is ipsilateral upper motor neuron paralysis with loss of proprioception as well as contralateral loss of pain and temperature sensation below the lesion. We present a 33-year-old female with a 6-month history of worsening right lower limb weakness and a 2-month history of right lower limb pain. Motor examination revealed right lower limb weakness as well as exaggerated knee and ankle jerk reflexes. A magnetic resonance imaging (MRI) was done, which showed an eccentrically located T4–7 cystic extradural mass causing severe cord compression. She had T4–7 laminectomies with total excision of the cyst and disconnection of the fistulous tract between the cyst and the subarachnoid space. She made full neurologic recovery with no complications.
De Novo Mutation Rates in Sticklebacks
Authors: Zhang Chaowei , Reid Kerry , Sands Arthur F , Fraimout Antoine , Schierup Mikkel Heide , Merilä Juha
Published: August 2023

Mutation rate is a fundamental parameter in population genetics. Apart from being an important scaling parameter for demographic and phylogenetic inference, it allows one to understand at what rate new genetic diversity is generated and what the expected level of genetic diversity is in a population at equilibrium. However, except for well-established model organisms, accurate estimates of de novo mutation rates are available for a very limited number of organisms from the wild. We estimated mutation rates (µ) in two marine populations of the nine-spined stickleback (Pungitius pungitius) with the aid of several 2- and 3-generational family pedigrees, deep (>50×) whole-genome resequences and a high-quality reference genome. After stringent filtering, we discovered 308 germline mutations in 106 offspring translating to µ = 4.83 × 10−9 and µ = 4.29 × 10−9 per base per generation in the two populations, respectively. Up to 20% of the mutations were shared by full-sibs showing that the level of parental mosaicism was relatively high. Since the estimated µ was 3.1 times smaller than the commonly used substitution rate, recalibration with µ led to substantial increase in estimated divergence times between different stickleback species. Our estimates of the de novo mutation rate should provide a useful resource for research focused on fish population genetics and that of sticklebacks in particular.
Bacillus subtilis NrnB is expressed during sporulation and acts as a unique 3′-5′ exonuclease
Authors: Myers Tanner M , Ingle Shakti , Weiss Cordelia A , Sondermann Holger , Lee Vincent T , Bechhofer David H , Winkler Wade C
Published: August 2023

All cells employ a combination of endo- and exoribonucleases to degrade long RNA polymers to fragments 2–5 nucleotides in length. These short RNA fragments are processed to monoribonucleotides by nanoRNases. Genetic depletion of nanoRNases has been shown to increase abundance of short RNAs. This deleteriously affects viability, virulence, and fitness, indicating that short RNAs are a metabolic burden. Previously, we provided evidence that NrnA is the housekeeping nanoRNase for Bacillus subtilis. Herein, we investigate the biological and biochemical functions of the evolutionarily related protein, B. subtilis NrnB (NrnBBs). These experiments show that NrnB is surprisingly different from NrnA. While NrnA acts at the 5′ terminus of RNA substrates, NrnB acts at the 3′ terminus. Additionally, NrnA is expressed constitutively under standard growth conditions, yet NrnB is selectively expressed during endospore formation. Furthermore, NrnA processes only short RNAs, while NrnB unexpectedly processes both short RNAs and longer RNAs. Indeed, inducible expression of NrnB can even complement the loss of the known global 3′-5′ exoribonucleases, indicating that it acts as a general exonuclease. Together, these data demonstrate that NrnB proteins, which are widely found in Firmicutes, Epsilonproteobacteria and Archaea, are fundamentally different than NrnA proteins and may be used for specialized purposes.