bluuebunny/crossref_metadata_2025_split 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

Abstract

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

Abstract
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

Abstract

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 &lt; .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.
Article 102
Authors: Whish Richard , Bailey David 
Published: September 2024

Abstract
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.
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

Abstract
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 &gt; 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

Abstract

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 &lt; 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

Abstract
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

Abstract
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

Abstract

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

Abstract

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

Abstract

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

Abstract
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 &lt;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

Abstract
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.