bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial oestrogen–myocardial cyclic guanosine monophosphate axis critically determines angiogenesis and cardiac performance during pressure overload
Authors: Fukuma Nobuaki , Tokiwa Hiroyuki , Numata Genri , Ueda Kazutaka , Liu Pang-Yen , Tajima Miyu , Otsu Yu , Kariya Taro , Hiroi Yukio , Liao James K , Komuro Issei , Takimoto Eiki
Published: September 2024

Aims

Oestrogen exerts beneficial cardiovascular effects by binding to specific receptors on various cells to activate nuclear and non-nuclear actions. Oestrogen receptor α (ERα) non-nuclear signalling confers protection against heart failure remodelling, involving myocardial cyclic guanosine monophosphate (cGMP)–cGMP-dependent protein kinase G (PKG) activation; however, its tissue-specific role remains elusive. Herein, we examine the cell type–specific role of ERα non-nuclear signalling in oestrogen-conferred protection against heart failure.

Methods and results

We first assessed the tissue-specific impacts of ERα on the cardiac benefits derived from oestrogen, utilizing endothelial ERα deletion (ERαf/f/Tie2Cre+) and myocyte ERα deletion (ERαf/f/αMHCCre+) female mice. Female mice were ovariectomized and the effect of estradiol (E2) was assessed in hearts exposed to 3 weeks of pressure overload [transverse aortic constriction (TAC)]. E2 failed to improve cardiac function in ERαf/f/Tie2Cre+ TAC hearts but provided benefits in ERαf/f/αMHCCre+ TAC hearts, indicating that endothelial ERα is essential. We next assessed the role of non-nuclear signalling in endothelial cells (ECs), employing animals with endothelial-specific inactivation of ERα non-nuclear signalling (ERαKI/KI/Tie2Cre+). Female ovariectomized mice were supplemented with E2 and subjected to 3-week TAC. ERαKI/KI/Tie2Cre+TAC hearts revealed exacerbated cardiac dysfunction and reduced myocardial PKG activity as compared to littermate TAC hearts, which were associated with attenuated myocardial induction of vascular endothelial growth factor (VEGF) and angiogenesis as assessed by CD31-stained capillary density. This phenotype of ERαKI/KI/Tie2Cre+was rescued by myocardial PKG activation from chronic treatment with a soluble guanylate cyclase (sGC) stimulator. We performed co-culture experiments to determine endothelial–cardiomyocyte interactions. VEGF induction by E2 in cardiac myocytes required a co-existence of intact endothelial ERα signalling in a nitric oxide synthase-dependent manner. On the other hand, VEGF was induced in myocytes directly with an sGC stimulator in the absence of ECs.

Conclusion

An endothelial oestrogen–myocardial cGMP axis stimulates angiogenic response and improves cardiac performance during pressure overload.
GDPR and the indefinable effectiveness of privacy regulators: Can performance assessment be improved?
Authors: Buckley Gerard , Caulfield Tristan , Becker Ingolf
Published: September 2024

Data protection regulations like the General Data Protection Regulation (GDPR) are increasingly important in securing individuals’ privacy as society goes digital. The success of any regulation, however good, ultimately depends on how well it is executed. Existing literature fails to answer what good execution means in this context. We research what practitioners think are the objectives of data protection regulators and how they evaluate their effectiveness. We explore novel ways to assess regulator performance more systematically. We surveyed 70 chief information security officers and conducted 23 structured interviews. The interviewees included informed business executives, lawyers, digital rights activists, and four national regulators. We supplement it with an analysis of diverse enforcement databases. Our findings indicate a mismatch between the broad presumed objectives attributed to regulators and the narrow criteria used to judge them in practice. Perception of the regulator’s effectiveness is subjective, sanctions-focused, and influenced by one’s role and responsibilities. Moreover, the independence of regulators, intentionally designed to insulate them from daily politics, raises serious questions of accountability. We examine the historical, cultural, and organizational motivations behind the current byzantine complexity of the GDPR regime. Lastly, we contribute a series of key performance indicators and make structural suggestions around centralized and standardized reporting of cases to deliver improved learning, legitimacy, transparency, and comparability. We believe our findings have important implications for the future development of regulator assessment and accountability in Europe and in the growing number of GDPR-like regimes outside Europe.
Social Isolation and Healthcare Utilization in Older Adults Living With Dementia and Mild Cognitive Impairment in the United States
Authors: Bartley Mairead M , St. Sauver Jennifer L , Schroeder Darrell R , Khera Nandita , Griffin Joan M
Published: September 2024

Background and Objectives

Social isolation is commonly experienced by older people and is associated with adverse health outcomes. Little is known about the influence of social isolation on the risk of acute care utilization among people living with mild cognitive impairment (MCI) or dementia. Our objective was to investigate the impact of social isolation on the risk of death, hospitalization, and emergency department (ED) use among people living with MCI or dementia who are followed in our Community Internal Medicine practice at Mayo Clinic, Rochester, Minnesota.

Research Design and Methods

We included people living with MCI or dementia, 55 years and older, who had a clinic visit between June 1, 2019, and June 30, 2021, and who had completed questions about social connections. The risk of death, hospitalization, and ED use was examined by levels of social connection (socially isolated, moderately isolated, moderately integrated, or socially integrated).

Results

Of 2,320 people included (1,010 with MCI and 1,310 with dementia), 455 (19.6%) were classified as socially isolated and 591 (25.5%) were moderately isolated. Compared with those who were socially integrated, people who were socially isolated were at higher risk of death, hospitalization, and ED visits (p < .001).

Discussion and Implications

Social isolation is associated with an increased risk of acute health care utilization and death in people living with MCI or dementia. Interventions to address social isolation in this population are needed.
8. Environmental crime and enforcement
Authors: Bell Stuart , McGillivray Donald , Pedersen Ole W. , Lees Emma , Stokes Elen
Published: September 2024

This chapter explores what happens when environmental laws are not complied with. This is done through an examination of key terms such as environmental crime, the role of criminal law, and the increasingly popular use of civil enforcement tools. The chapter also discusses the effectiveness of enforcement.
9. Public participation
Authors: Bell Stuart , McGillivray Donald , Pedersen Ole W. , Lees Emma , Stokes Elen
Published: September 2024

This chapter discusses the significance of public participation in environmental law with specific focus on access to environmental information and public participation in environmental decision-making. The arguments for and against public participation are discussed in detail as is the historical importance afforded participation. A central focus of the chapter is the Aarhus Convention and its implementation into UK law. The chapter also discusses environmental reporting and the role of labelling schemes aimed at helping consumers make environmentally sound choices.
16. Air Pollution
Authors: Bell Stuart , McGillivray Donald , Pedersen Ole W. , Lees Emma , Stokes Elen
Published: September 2024

This chapter examines the many legal and regulatory challenges arising from the problem of air pollution. As shown in the chapter, air pollution has been a regulatory problem for centuries and remains a significant threat to human health. The focus of the chapter is on the main sources of air pollution, internationally and domestically, and the regulatory responses which are largely anchored in EU rules. Finally, the chapter analyses the air quality targets brought in by the Environment Act 2021.
9. The European Union and Brexit
Authors: Elliott Mark , Thomas Robert
Published: September 2024

This chapter focuses on the constitutional implications of the UK’s membership of the European Union and the constitutional implications of its exit from the EU (or ‘Brexit’). The chapter examines how EU law was accommodated within the UK legal system during the period of the UK’s membership of the EU, and in particular considers the consequences of the primacy of EU law for the doctrine of parliamentary sovereignty. The chapter also considers the extent to which lessons learned about the UK constitution as a result of EU membership will remain relevant now that the UK has left the EU.
13. The Grounds of Judicial Review
Authors: Elliott Mark , Thomas Robert
Published: September 2024

This chapter discusses the grounds upon which it is possible to challenge administrative decisions by way of judicial review, and shows that there are many and varied grounds on which courts may review decisions taken by public bodies. Administrative law, for all of its technicality and detail, is part of our wider constitutional fabric, and represents the working out, in a particular legal context, of much broader debates about the proper relationship between the different branches of the constitution. A notable theme in this area concerns the deepening, in recent years, of judicial scrutiny of the executive. New grounds of review—such as legitimate expectation and proportionality—have emerged, often involving a greater degree of judicial oversight of executive decisions than has traditionally existed.
8. The African Human Rights System
Authors: Cançado Trindade Antônio Augusto , González-Salzberg Damián A.
Published: September 2024

Complementing the previous two chapters on regional systems, Chapter 8 focuses on the African regime, delving into its unique characteristics, shaped by the historical and geographical context of its creation and development under the auspices of the Organization of African Unity (OAU) and the African Union (AU). After drawing attention to the work of the African Children’s Committee, the chapter engages with both the African Commission and Court of Human and Peoples’ Rights, discussing their composition and powers. It explores how these bodies can deal with claims concerning the violations of human and peoples’ rights brought before them. As in the previous chapter, particular challenges faced by the system are selected for discussion.
11. The Use of Force, Collective Security and Peacekeeping
Authors: Dixon Martin , McCorquodale Robert , Williams Sarah
Published: September 2024

International law aims to regulate the use of force in two ways. First, it stipulates that there is a paramount obligation not to use force to settle disputes, with only limited exceptions; and second, it has at its disposal a procedure whereby the international community itself may use force against those using violence. These are known respectively as the rules on the ‘unilateral use of force’ and the rules of ‘collective security’, both of which are discussed in this chapter. This chapter also explores individual criminal responsibility for the crime of aggression.
Smith, Hogan, and Ormerod's Criminal Law
Authors: Ormerod David , Laird Karl , Gibson Matthew
Published: September 2024

This textbook, now in its 17th edition, has been completely updated to include all recent legislative and case law developments, together with detailed analysis of those developments. Part I begins with an introduction to criminal law, with reference to definitions, context, and sources, followed by discussion of the elements of a crime (actus reus and mens rea), before moving on to considering crimes of negligence and strict liability. It then assesses accessorial liability, along with corporate and vicarious liability. Subsequently, it discusses mental condition defences, alongside issues relating to mistake and intoxication, as well as general defences. The final chapter of Part I provides a detailed review of inchoate offences. Part II examines specific offences, beginning with murder, manslaughter, and other homicide and related offences. Next, it focuses on non-fatal offences and sexual offences. It then reviews a range of property, fraud, and related offences, notably: theft, robbery, offences of temporary deprivation, making off without payment, general and ancillary fraud offences, blackmail, burglary, handling stolen goods, and offences of damages to property. Finally, a range of online chapters address computer misuse, forgery, obscene communication and publication offences, offences against public order, road traffic offences, money laundering, and offensive weapons.
5. Crimes of strict liability
Authors: Ormerod David , Laird Karl , Gibson Matthew
Published: September 2024

Offences of strict liability are those crimes that do not require mens rea or even negligence as to one or more elements in the actus reus. Where an offence is interpreted to be one of strict liability, a person will be criminally liable even if they could not have avoided the prescribed harm despite attempting to do so. Where someone is accused of strict liability, it is not necessary for the prosecution to bring evidence of mens rea as to the matter of strict liability. This chapter discusses strict liability and its distinction from ‘absolute’ liability, crimes of strict liability in common law and statutes, strict liability and the presumption of innocence, the presumption of mens rea, the severity of punishment for strict liability, arguments for and against strict liability, the imposition of liability for negligence, and statutory due diligence defences.
Land Law
Authors: McFarlane Ben , Hopkins Nicholas , Nield Sarah
Published: September 2024

All books in this flagship series contain carefully selected substantial extracts from key cases, legislation, and academic debate, providing able students with a stand-alone resource. The sixth edition of Land Law: Text, Cases, and Materials covers all core aspects of land law, including the nature of land and of property rights, registration, human rights, legal estates, legal interests, equitable interests, acquisition of interests in land, trusts of land, the priority of interests in land, co-ownership and interests in the home, leases, easements, covenants, commonhold, and security interests in land. The book provides students with the detailed knowledge and analytical tools required to understand and engage fully with the current topical debates surrounding the subject, including recent reform proposals. The book comprises of eight parts, and it looks at the content question, the acquisition question, and priority and the defences question. It also covers different contexts, such as the shared home and neighbours and neighbourhoods.
12. Interests in the Home: The Acquisition Question
Authors: McFarlane Ben , Hopkins Nicholas , Nield Sarah
Published: September 2024

All books in this flagship series contain carefully selected substantial extracts from key cases, legislation, and academic debate, providing able students with a stand-alone resource. This chapter explores the acquisition question in relation to the family home through an analysis of the doctrines of resulting and constructive trusts. It explains the different initial presumptions drawn in cases of joint and sole legal ownership and the particular approach that has been adopted in the case of a home purchased ‘in joint names for joint occupation by a married or unmarried couple, where both are responsible for any mortgage’. The chapter considers how the ‘common intention’ of parties in relation to the common intention constructive trust is determined differently in relation to the primary acquisition question (in cases of sole legal ownership) and the secondary question of the quantification of beneficial shares (applicable in cases of joint and sole beneficial ownership). The contentious issue of the extent to which the courts’ broader approach to common intention in relation to quantification may be carried over to the primary acquisition question is addressed. Finally, the chapter considers statutory rights to occupy and current Law Commission proposals for reform.
15. The Priority Triangle
Authors: McFarlane Ben , Hopkins Nicholas , Nield Sarah
Published: September 2024

All books in this flagship series contain carefully selected substantial extracts from key cases, legislation, and academic debate, providing able students with a stand-alone resource. This chapter addresses the question of when C can have a defence to B’s pre-existing property right. It thus covers the basic principles that apply when answering the priority question. It examines how a court determines which of two competing property rights arose first. It also examines exceptions to the basic rule, acknowledged by s 28 of the Land Registration Act 2002, that B’s property right, where it arises before C’s property right, will take priority.
21. Leasehold Covenants
Authors: McFarlane Ben , Hopkins Nicholas , Nield Sarah
Published: September 2024

All books in this flagship series contain carefully selected substantial extracts from key cases, legislation, and academic debate, providing able students with a stand-alone resource. This chapter explores the concept of a leasehold covenant. It investigates the mechanisms by which both negative and positive leasehold covenants bind subsequent purchasers of the lease from the original tenant and subsequent purchasers of the freehold reversion from the landlord. It also considers the law governing the enforcement of leasehold covenants and the process of forfeiture by which a landlord can bring the lease to an end for a failure by the tenant to perform the tenant’s covenants. Forfeiture is the process by which a landlord can extinguish a lease by exercising a right to re-enter the premises. It provides ‘an essential management tool, particularly in relation to commercial and long residential leases’, but it can also be a heavy-handed response.
7. Parties to crime
Authors: Allen Michael J. , Edwards Ian
Published: September 2024

Course-focused and comprehensive, the Textbook on series provides an accessible overview of the key areas on the law curriculum. This chapter discusses the meaning of accomplices, vicarious liability, joint enterprise liability, and corporate liability. All the parties to a crime are accomplices. The person who perpetrates the crime is referred to as the principal. Others, not being principals, who participate in the commission of an offence are referred to as accessories or secondary parties and will be liable to conviction if it is proved that they aided, abetted, counselled, or procured the commission of the crime by the principal. A Law in Context feature examines the implications of the Supreme Court’s important decision in R v Jogee [2016] UKSC 8. Vicarious liability is a form of strict liability arising from the master–servant relationship, without reference to any fault of the employer. A corporation is a legal person and therefore may be criminally liable even though it has no physical existence and cannot act or think except through its directors or servants.
15. Confessions
Authors: Keane Adrian , McKeown Paul
Published: September 2024

This chapter discusses the admissibility of confessions under the Police and Criminal Evidence Act 1984 (the 1984 Act). It considers how, under s 76(2) of the 1984 Act, confessions may be excluded as a matter of law where obtained by oppression or in consequence of something said or done which was likely to render any such confession unreliable. It also considers the discretion to exclude confessions under s 78(1) of the 1984 Act; the effect of breaches of the Codes of Practice issued under the 1984 Act; the voir dire; statements made in the presence of the accused; and facts discovered in consequence of inadmissible confessions.
Article 102
Authors: Whish Richard , Bailey David
Published: September 2024

This chapter discusses the main features of Article 102 of the Treaty of Functioning of the European Union (TFEU), which is concerned with the abusive conduct of dominant firms. It begins by discussing the meaning of ‘undertaking’ and ‘effect on trade between Member States’ in the context of Article 102. It then considers what is meant by a dominant position and looks at the requirement that any dominant position must be held in a substantial part of the internal market. Thereafter it discusses some general considerations relevant to the concept of abuse of dominance, followed by an explanation of what is meant by ‘exploitative’, ‘exclusionary’ and ‘single market’ abuses. It then discusses possible defences to allegations of abuse, and concludes by considering the consequences of infringing Article 102.
5. The authority of the agent
Authors: Beheshti Reza , Saintier Séverine , Thomas Sean
Published: September 2024

This chapter explores the authority of the agent. It tackles the interplay of authority between an agent, a principal, and third parties, and the distinction between actual and apparent authorities. In most cases of apparent authority, the ‘principal’ makes a representation that the ‘agent’ has authority which the third party relies upon by entering into a contract. In certain circumstances, a person who acts in an emergency to preserve the property or interests of another may be treated as an agent of necessity regardless of the principal's absent consent. The chapter then overviews the impact of ratification on the rights and liabilities of third parties.
6. Relations with third parties
Authors: Beheshti Reza , Saintier Séverine , Thomas Sean
Published: September 2024

This chapter focuses on third parties. It specifically looks at the differences between disclosed and undisclosed agencies. The agency is disclosed where the agent reveals that they are acting as an agent; the agency is undisclosed where the agent does not reveal the fact of the agency at all and purports to be acting in their name and on their behalf. The chapter then discusses the agent's warranty of authority to the third party who contracts with the agent's principal. It considers the liability for misstatements as any misrepresentation may give the representee a right to rescind any contract made in reliance on it.
16. Risk, frustration and mistake
Authors: Beheshti Reza , Saintier Séverine , Thomas Sean
Published: September 2024

This chapter presents the key concepts of risk, frustration, and mistake in line with the ownership or possession of property. It starts with the notion of risk by acknowledging that any commercial operation involves risk, but risks can be allocated between parties by the terms of the contract. Additionally, a contract of sale can be affected by mistake or frustration in the same way as any other contract. The Sale of Goods Act 1979 (SGA) provides provisions to deal with mistakes and frustrations in several circumstances. The chapter also considers the Consumer Rights Act 2015 (CRA 2015), which altered and simplified the position of consumer buyers of goods.
19. Contracts for the supply of services
Authors: Beheshti Reza , Saintier Séverine , Thomas Sean
Published: September 2024

This chapter covers the contracts for the supply of services. It explains that the provision of services is itself an important commercial activity, but many services are provided in the course of other commercial transactions. The Supply of Goods and Services Act 1982 (SGSA) applies to all non-consumer contracts involving the supply of services. The scope of the SGSA 1982 extends to all contracts involving the supply of services, including those for professional services and those which involve the supply or bailment of goods. The chapter also looks at the notion of product-as-service and circular economy before considering the future of goods and services of contracts.
Investigation of the α9-nicotinic receptor single nucleotide polymorphisms induced oncogenic properties and molecular mechanisms in breast cancer
Authors: Liao You-Cheng , Wang Lu-Hai , Hung Mien-Chie , Cheng Tzu-Chun , Lin Ying-Chi , Chang Jungshan , Tu Shih-Hsin , Wu Chih-Hsiung , Yen Yun , Hsieh Yi-Chen , Chen Li-Ching , Ho Yuan-Soon
Published: September 2024

α9-nAChR, a subtype of nicotinic acetylcholine receptor, is significantly overexpressed in female breast cancer tumor tissues compared to normal tissues. Previous studies have proposed that specific single nucleotide polymorphisms (SNPs) in the CHRNA9 (α9-nAChR) gene are associated with an increased risk of breast cancer in interaction with smoking. The study conducted a breast cancer risk assessment of the α9-nAChR SNP rs10009228 (NM_017581.4:c.1325A > G) in the Taiwanese female population, including 308 breast cancer patients and 198 healthy controls revealed that individuals with the heterozygous A/G or A/A wild genotype have an increased susceptibility to developing breast cancer in the presence of smoking compared to carriers of the G/G variant genotype. Our investigation confirmed the presence of this missense variation, resulting in an alteration of the amino acid sequence from asparagine (N442) to serine (S442) to facilitate phosphorylation within the α9-nAchR protein. Additionally, overexpression of N442 (A/A) in breast cancer cells significantly enhanced cell survival, migration, and cancer stemness compared to S442 (G/G). Four-line triple-negative breast cancer patient-derived xenograft (TNBC-PDX) models with distinct α9-nAChR rs10009228 SNP genotypes (A/A, A/G, G/G) further demonstrated that chronic nicotine exposure accelerated tumor growth through sustained activation of the α9-nAChR downstream oncogenic AKT/ERK/STAT3 pathway, particularly in individuals with the A/G or A/A genotype. Collectively, our study established the links between genetic variations in α9-nAChR and smoking exposure in promoting breast tumor development. This emphasizes the need to consider gene–environment interactions carefully while developing effective breast cancer prevention and treatment strategies.
Characterisation of global and regional mitral annular strains in an acute porcine model
Authors: Persson Robert Matongo , Aguilera Hans Martin Dahl , Grong Ketil , Kvitting John-Peder Escobar , Stangeland Lodve , Haaverstad Rune , Urheim Stig , Prot Victorien Emile
Published: September 2024

OBJECTIVES

This study aimed to explore regional mitral annular strain using a novel computational method.

METHODS

Eight pigs underwent implantation with piezoelectric transducers around the mitral annulus. Interventions of pre- and afterload were performed by inferior vena cava constriction and endovascular balloon occlusion of the descending aorta. The mitral annulus was reconstructed in a mathematical model and divided into 6 segments. Global and segmental annular strain were calculated from a discrete mathematical representation.

RESULTS

Global annular strain gradually decreased after isovolumetric contraction until late systole. Mitral annular end-systolic strain demonstrated shortening in all segments except the anterior segment, which showed the least deformation. The P2 annular segment demonstrated the most end-systolic shortening (–7.6 ± 1.1% at baseline, P < 0.001 compared to anterior segment). Systolic global annular strain showed no significant change in response to load interventions but correlated positively with left ventricular contractility at baseline and after preload reduction.

CONCLUSIONS

Mitral annular systolic strain demonstrates cyclical variations with considerable regional heterogeneity, with the most pronounced deformation in posterior annular segments. Measurements appear independent of changes to pre- and afterload.
Robust implicit regularization via weight normalization
Authors: Chou Hung-Hsu , Rauhut Holger , Ward Rachel
Published: September 2024

Overparameterized models may have many interpolating solutions; implicit regularization refers to the hidden preference of a particular optimization method towards a certain interpolating solution among the many. A by now established line of work has shown that (stochastic) gradient descent tends to have an implicit bias towards low rank and/or sparse solutions when used to train deep linear networks, explaining to some extent why overparameterized neural network models trained by gradient descent tend to have good generalization performance in practice. However, existing theory for square-loss objectives often requires very small initialization of the trainable weights, which is at odds with the larger scale at which weights are initialized in practice for faster convergence and better generalization performance. In this paper, we aim to close this gap by incorporating and analysing gradient flow (continuous-time version of gradient descent) with weight normalization, where the weight vector is reparameterized in terms of polar coordinates, and gradient flow is applied to the polar coordinates. By analysing key invariants of the gradient flow and using Lojasiewicz’s Theorem, we show that weight normalization also has an implicit bias towards sparse solutions in the diagonal linear model, but that in contrast to plain gradient flow, weight normalization enables a robust bias that persists even if the weights are initialized at practically large scale. Experiments suggest that the gains in both convergence speed and robustness of the implicit bias are improved dramatically using weight normalization in overparameterized diagonal linear network models.
Shard Theory for g-Fans
Authors: Mizuno Yuya
Published: September 2024

For a finite dimensional algebra $A$, the notion of $g$-fan $\Sigma (A)$ is defined from two-term silting complexes of $\textsf{K}^{\textrm{b}}(\textsf{proj} A)$ in the real Grothendieck group $K_{0}(\textsf{proj} A)_{\mathbb{R}}$. In this paper, we discuss the theory of shards to $\Sigma (A)$, which was originally defined for a hyperplane arrangement. We establish a correspondence between the set of join-irreducible elements of torsion classes of $\textsf{mod}A$ and the set of shards of $\Sigma (A)$ for $g$-finite algebra $A$. Moreover, we show that the semistable region of a brick of $\textsf{mod}A$ is exactly given by a shard. We also give a poset isomorphism of shard intersections and wide subcategories of $\textsf{mod}A$.
Clinically important interactions of macrolides and tetracyclines with dietary interventions—a systematic review with meta-analyses
Authors: Wiesner Agnieszka , Zagrodzki Paweł , Gawalska Alicja , Paśko Paweł
Published: September 2024

Background

Effective management of drug–food interactions is crucial for enhancing antibiotics’ efficacy/safety. Adhering to PRISMA guidelines, we conducted a systematic review to assess the impact of dietary interventions on the bioavailability of 15 macrolides and 10 tetracyclines.

Methods

We included studies examining the influence of food, beverages, antacids, and mineral supplements on the pharmacokinetic parameters of orally administered macrolides and tetracyclines. We searched Medline (via PubMed), Embase and Cochrane Library databases up to December 2022. Risk of bias was assessed using Cochrane and NIH tools. Quantitative analyses were conducted if two or more comparable food-effect studies were available; otherwise, a qualitative summary was provided.

Results

We included 120 studies from 97 reports. Meta-analyses were conducted for 8 macrolides and 4 tetracyclines, with qualitative synthesis for 10 and 9, respectively. About 64% of the studies were open-label, crossover designs. Our assessment found that 37% of the studies had a high risk of bias, while only 6% had low risk. Food significantly affected 10 of 13 macrolides (77%) and 6 of 7 tetracyclines (86%). High positive effects on bioavailability were seen with extended-release azithromycin and clarithromycin, and erythromycin estolate. High negative impacts were observed with erythromycin propionate and stearate, azithromycin capsules, demeclocycline and omadacycline. Antacids and mineral supplements significantly decreased tetracyclines absorption. Milk and grapefruit juice showed variable impacts on absorption.

Discussion

Interactions depend on antibiotics’ physicochemical characteristics, intervention type, drug formulation and potential patient factors. The quality of evidence was rated low due to outdated studies, methodological diversity and unequal data availability.
Population pharmacokinetics of unbound cefazolin in infected hospitalized patients requiring intermittent high-flux haemodialysis: can a three-times-weekly post-dialysis dosing regimen provide optimal treatment?
Authors: Duke Carleigh , Parker Suzanne L , Zam Betty B , Chiong Fabian , Sajiv Cherian , Pawar Basant , Ashok Aadith , Cooper Brynley P , Tong Steven Y C , Janson Sonja , Wallis Steven C , Roberts Jason A , Tsai Danny
Published: September 2024

Objectives

To describe the population pharmacokinetics of cefazolin in infected hospitalized patients requiring intermittent haemodialysis (IHD).

Methods

This prospective population pharmacokinetic study was conducted in IHD patients prescribed cefazolin 2 g three times weekly. Plasma samples were collected at prespecified timepoints and assayed for total and unbound concentrations using validated LC. Pharmacokinetic modelling and dosing simulations were performed using Pmetrics®. PTA in plasma suitable for MSSA (unbound trough concentrations of ≥2 mg/L for the final 24 h of a 72 h interval) were simulated for different dosing regimens. A PTA of ≥95% was deemed acceptable.

Results

A total of 260 cefazolin concentrations (130 total, 130 unbound) were collected from 16 patients (14 female) with a median age of 51 years. The median (IQR) pre-dialysis unbound cefazolin concentration for a 3 day dose interval trough was 17.7 (13.5–31.4) mg/L. The median (IQR) unbound fraction was 0.38 (0.32–0.46). The lowest pre-dialysis unbound concentration was 9.1 mg/L. A two-compartment model with a complex protein-binding component adequately described the data. The mean unbound cefazolin CL during IHD was 16.4 ± 4.26 L/h, compared with 0.40 ± 0.19 L/h when dialysis was off. Duration of time on haemodialysis (TOH) was the only covariate supported in the final model. The 2 g three-times-weekly regimen was associated with a PTA of 99.7% on dosing simulations to maintain unbound concentrations of ≥2 mg/L with TOH of 6 months. The 1 g three-times-weekly post-dialysis was associated with a PTA of 95.4%.

Conclusions

A 2 g three-times-weekly post-dialysis cefazolin regimen is supported for MSSA infections.
Risk factors for positive follow-up blood cultures in critically ill adults with Gram-negative bacteraemia
Authors: Mayes Rebecca A , Siegrist Emily A , Mathew Julia , Neely Stephen B , McCloskey Cindy B , White Bryan P
Published: September 2024

Objectives

To evaluate the utility of follow-up blood cultures (FUBCs) for Gram-negative bloodstream infection (BSI) in ICU patients and identify risk factors for repeat positive cultures.

Methods

This was a single-centre, retrospective cohort study of critically ill adults with Gram-negative BSI between 1 January 2015 and 1 January 2020. Critically ill patients with one or more blood cultures positive for a Gram-negative organism were included. Descriptive and inferential statistics were performed with an alpha of 0.05.

Results

A total of 148 critically ill patients with Gram-negative BSI were included, with 42 patients (28.4%) having one or more positive FUBCs. The majority (66.2%) were admitted to a medical ICU. The most common organisms isolated were Escherichia coli (n = 56, 37.8%) and Klebsiella pneumoniae (n = 26, 17.6%). Significant patient risk factors associated with a positive FUBC on univariate regression included: MDR organisms, immunocompromised status, fever, vasopressor use at time of FUBC, lack of source control attainment, and higher quick Pitt bacteraemia score. Multivariable penalized logistic regression indicated that lack of source control containment and less time from index to FUBC remained significantly associated with repeat positive FUBC.

Conclusions

This is the first study to investigate the use of FUBC for Gram-negative BSI in exclusively ICU patients. Risk factors for repeat positive FUBC in this population include lack of source control and less time between index and FUBC. Prospective studies are needed to fully elucidate the role of FUBCs in critically ill patients with Gram-negative BSI.
Multi-class analysis of 57 drugs quantitatively in blood and qualitatively in urine by LC–MS–MS to complement comprehensive DFC, DUID, and postmortem testing
Authors: Rodda Luke N , Farley Megan , Towler Steven , Devincenzi Tyler , Pearring Sue
Published: September 2024

A streamlined LC–MS–MS method utilizing protein precipitation and filtration extraction was developed to consolidate analyses for drug-facilitated crimes (DFCs), postmortem (PM) investigations, and driving under the influence of drug (DUID) testing. Fifty-seven target drug and metabolite analytes eluted in <6 minutes and were compromised of gamma-hydroxybutyric acid precursors (1), hallucinogens (3), muscle relaxants (3), anticonvulsants (7), antidepressants (20), antihistamines (5), antipsychotics (11), antihypertensives and alpha-adrenergics (3), analgesics and anesthetics (3), and miscellaneous (1) in blood (quantitatively) and urine (qualitatively). Limits of detection were set to meet the more challenging sensitivity requirements for DFC and are therefore also suitable for PM investigations and other forensic casework, including DUID. Comprehensive Academy Standards Board / American National Standards Institute (ASB/ANSI) validation was performed, and applicability studies examined 72 proficiency test blood and urine samples, along with 9206 unique blood and urine samples from 5192 authentic forensic cases that resulted in 11,961 positive analytes in samples. By expanding the analytical reach across multiple drug classes through a unified approach and screening a wider number of drugs, the technique can identify substances that might have previously evaded detection, thereby enhancing laboratory efficiency by minimizing the need for multiple tests. When combined with a recently developed in-house method, this integrated testing strategy meets the testing requirements outlined in ASB/ANSI standards and recommendations for DFC, PM, and Tier 1 DUID analyses.
Independent contribution of gonads and sex chromosomes to sex differences in bone mass and strength in the four-core genotypes mouse model
Authors: Ramirez Gabriel , Okpara Chiebuka , Arnett Matthew , Segvich Dyann M , Deosthale Padmini , González Paola Ortiz , Kritikos Alexander E , Melo Julian Balanta , Sanz Natasha , Pin Fabrizio , Wallace Joseph M , Plotkin Lilian I
Published: September 2024

Vertebrate sexual dimorphism is ascribed to the presence of testes or ovaries, and, hence, to the secretion of gonad-specific hormones. However, mounting evidence indicates that sex differences in tissues and organs also stem from the presence of sex chromosomes (XX or XY). To tease out the contribution of gonads from sex chromosomes to the musculoskeletal system, we used the Four-Core Genotypes (FCG) mouse model, in which the Sry gene, which dictates testis formation, was either deleted from the Y chromosome, resulting in XY mice with ovaries (XY-SryO), or overexpressed in XX mice, resulting in XX mice with testes (XXT), together with gonadal males with XY-SryT (Sry deletion and overexpression of the Sry transgene in chromosome 3) and females with XXO. The FCG mice are generated by crossing XXO with XY-SryT mice, all of C57BL/6 J background. We now show that the musculoskeletal phenotype of 2- to 4-mo-old FCG mice varies based on both gonads and sex chromosomes, depending on the age and the organ/tissue/cell analyzed. The effect of sex chromosomes on body weight, fat and lean/skeletal muscle mass, and bone mass and structure is minor in 2-/3-mo-old mice, soon after sexual maturation. The contribution of sex chromosomes (XX vs XY-Sry in mice with the same gonads and sex hormones) to several of our measurements becomes apparent in adult 4-mo-old mice. The contribution of 1X and 1Y-Sry vs 2X chromosomes varies among different measurements in gonadal males or females, and mice with XY-Sry chromosomes might have higher or lower values that XX mice. Our study shows XX vs XY-Sry chromosome contribution to the musculoskeletal phenotype, which becomes more evident as the animals reach peak bone mass, suggesting that although gonadal sex has a major role, sex chromosomes are also an unrecognized contributor to musculoskeletal mass and bone strength.
Quality-of-life outcomes from NRG Oncology NSABP B-39/RTOG 0413: whole-breast irradiation vs accelerated partial-breast irradiation after breast-conserving surgery
Authors: Ganz Patricia A , Cecchini Reena S , White Julia R , Vicini Frank A , Arthur Douglas W , Rabinovitch Rachel A , Kuske Robert R , Julian Thomas B , Parda David S , Scheier Michael F , Winter Kathryn A , Paik Soonmyung , Kuerer Henry M , Vallow Laura A , Pierce Lori J , Mamounas Eleftherios P , McCormick Beryl , Bear Harry D , Germain Isabelle , Gustafson Gregory S , Grossheim Linda , Petersen Ivy A , Hudes Richard S , Curran Jr Walter J , Wolmark Norman
Published: September 2024

Background

NRG Oncology NSABP B-39/RTOG 0413 compared whole-breast irradiation (WBI) to accelerated partial-breast irradiation (APBI). APBI was not equivalent to WBI in local tumor control. Secondary outcome was quality of life (QOL).

Methods

The QOL sub-study used validated self-report questionnaires, including the Breast Cancer Treatment Outcome Scale (BCTOS) and the 36-Item Short Form Health Survey (SF-36) vitality scale. Assessments occurred before random assignment, at treatment completion (chemotherapy or radiotherapy), 4 weeks later, at 6, 12, 24, and 36 months. Primary aims: cosmesis change equivalency (baseline to 3 years; a priori margin of equivalence 0.4 standard deviations) and fatigue change superiority (baseline to end of treatment [EOT]) for APBI vs WBI, by patient groups treated with or without chemotherapy when appropriate.

Results

From March 21, 2005 to May 25, 2009, 975 patients enrolled in this sub-study; 950 had follow-up data. APBI had 3-year cosmesis equivalent to WBI (95% CI = -0.0001 to -0.16; equivalence margin -0.22 to -0.22) in all patients. The APBI group without chemotherapy had less EOT fatigue (P = .011; mean score APBI 63 vs WBI 59); the APBI group receiving chemotherapy had worse EOT fatigue (P = .011; APBI 43 vs WBI 49). The APBI group reported less pain (BCTOS) at EOT (WBI 2.29 vs APBI 1.97) but worse pain at 3 years (WBI 1.62 vs APBI 1.71). APBI patients reported greater convenience of care than with WBI and reported less symptom severity at EOT and 4 weeks later.

Conclusion

Cosmetic outcomes were similar for the APBI and WBI groups, with small statistically significant differences in other outcomes that varied over time. Differences in fatigue and other symptoms appeared to resolve by ≥6 months. APBI may be preferred by some patients, for whom extended treatment is burdensome.

ClinicalTrials.gov

NCT00103181.
DIRT/µ: automated extraction of root hair traits using combinatorial optimization
Authors: Pietrzyk Peter , Phan-Udom Neen , Chutoe Chartinun , Pingault Lise , Roy Ankita , Libault Marc , Saengwilai Patompong Johns , Bucksch Alexander
Published: September 2024

As with phenotyping of any microscopic appendages, such as cilia or antennae, phenotyping of root hairs has been a challenge due to their complex intersecting arrangements in two-dimensional images and the technical limitations of automated measurements. Digital Imaging of Root Traits at Microscale (DIRT/μ) is a newly developed algorithm that addresses this issue by computationally resolving intersections and extracting individual root hairs from two-dimensional microscopy images. This solution enables automatic and precise trait measurements of individual root hairs. DIRT/μ rigorously defines a set of rules to resolve intersecting root hairs and minimizes a newly designed cost function to combinatorically identify each root hair in the microscopy image. As a result, DIRT/μ accurately measures traits such as root hair length distribution and root hair density, which are impractical for manual assessment. We tested DIRT/μ on three datasets to validate its performance and showcase potential applications. By measuring root hair traits in a fraction of the time manual methods require, DIRT/μ eliminates subjective biases from manual measurements. Automating individual root hair extraction accelerates phenotyping and quantifies trait variability within and among plants, creating new possibilities to characterize root hair function and their underlying genetics.
Rubidium and Cesium Ion-Induced Electron and Ion Signals for Scanning Ion Microscopy Applications
Authors: Li Yang , Xu Sheng , Loeber Thomas H , Vredenbregt Edgar J D
Published: September 2024

Scanning ion microscopy applications of novel focused ion beam (FIB) systems based on ultracold rubidium (Rb) and cesium (Cs) atoms were investigated via ion-induced electron and ion yields. Results measured on the Rb+ and Cs+ FIB systems were compared with results from commercially available gallium (Ga+) FIB systems to verify the merits of applying Rb+ and Cs+ for imaging. The comparison shows that Rb+ and Cs+ have higher secondary electron (SE) yields on a variety of pure element targets than Ga+, which implies a higher signal-to-noise ratio can be achieved for the same dose in SE imaging using Rb+/Cs+ than Ga+. In addition, analysis of the ion-induced ion signals reveals that secondary ions dominate Cs+ induced ion signals while the Rb+/Ga+ induced signals contain more backscattered ions.
Posting Holistic Health and Fitness Reels on Social Media Platforms to Improve Soldier Health in the Brigade
Authors: Culley Katelyn , DaLomba Elaina
Published: September 2024

Introduction

As of 2020 Holistic health and fitness (H2F) teams have been embedded into brigades to engage Soldiers in Preventative Mental, Physical, Nutritional, Spiritual, and Sleep Readiness services. This represents a change in Army culture from a focus on testing to one of wellness because of increasing sleep concerns, mental health concerns, and injury rates. Soldier awareness of H2F services, where to find them, how to use them, and command endorsement of H2F professional’s services has been limited and not well studied. Most soldiers fall into the Generations Y and Z categories, and this population tends to access information primarily from social media sources. Social media platforms therefore represent potentially effective ways to reach these individuals to increase their awareness of H2F services.

Materials and Methods

This quality improvement project used therapist produced brief interactive videos covering the topics of sleep hygiene and consequences of sleep supplement use and sleep deprivation, mental readiness, and journaling as a form of mindfulness. Video reels were posted to one brigade H2F’s social media (Facebook and Instagram) platforms to improve Soldier awareness and engagement in wellness activities in these areas. Data were tracked before and after the initiation of the reel series via Facebook and Instagram MetaBusiness Suite, and via utilization tracking for H2F occupational therapy group and 1:1 visits.

Results

Data tracked before and after the initiation of the video series revealed an 898.2% increase in Facebook access, including reel reach, and increases in 1:1 and group sleep and mental readiness visits to the H2F occupational therapist.

Conclusions

The use of social media to facilitate soldier awareness and use of H2F mental and sleep readiness services is a viable option for H2F units seeking to enhance their reach in these areas. The project created very little demand on the local therapist’s time or to brigade resources and may help increase Soldier accessing of H2F resources online and directly.