bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of cardiovascular imaging surrogate endpoints in heart failure clinical trials: a systematic review
Authors: Vavere A , Lopez Juan V , Millegard M , Gustafsson K , Gunnarsson L , Roso Llorach A , Surkova E 
Published: January 2025

Abstract

Background
Cardiovascular imaging is commonly used for assessment of surrogate endpoints in early phase clinical trials in heart failure (HF). Treatment-induced change in left ventricular (LV) volumes and ejection fraction (EF) were validated against change in outcomes in a meta-analysis from 2011 [1]. However, cardiovascular imaging has evolved significantly since then with new modalities and endpoints introduced in interventional trials.

Purpose
To analyse temporal trends in implementation of cardiovascular imaging modalities and endpoints in HF trials in the last 15 years and identify endpoints with existing data on relationship between short-term change in imaging endpoint and long-term change in hard outcomes.

Methods
Firstly, we performed a systematic review of cardiovascular outcome trials (CVOTs) evaluating treatment effects on outcomes in HF. Secondly, we reviewed remodelling trials (RTs) evaluating effect of drugs identified in CVOTs search on imaging parameters.

Results
The CVOTs search yielded 64 records. Seventeen CVOTs evaluating effect of 10 different interventions on cardiovascular outcomes were considered eligible and included in the final analysis. The RTs search yielded 80 records, 34 publications were considered eligible (Fig.1).
Out of 34 RTs, 29 trials employed transthoracic echocardiography (Echo), 1– low dose Dobutamine stress-Echo, 5– cardiac magnetic resonance (CMR), 1– Dobutamine stress-CMR, 1– Phosphorus CMR spectroscopy, and 1– PET. With exception of one study, Echo was the only imaging modality used in selected RTs until 2020. Four studies utilised &gt;1 imaging modality.
Data on relationship between therapy-induced changes in remodelling parameters and changes in clinical outcomes are mostly available for conventional markers of the LV and left atrium (LA) (LV EF, volumes, mass, E/e’, e’, LA volume), followed by LV global longitudinal strain. Data on how the therapy-induced changes in other novel endpoints (LV global circumferential strain, right ventricular function, or surrogates of myocardial fibrosis), can translate into change in clinical outcomes in HF has been investigated for single interventions only (Fig.2).

Conclusions
While Echo had been dominating the field in interventional HF trials, new imaging modalities and endpoints have been introduced in trials recently. Conventional parameters of LV remodelling and function remain the most validated regarding relationship between change in surrogate endpoint in response to treatment and change in clinical outcomes. More evidence on translatability of changes in imaging markers of LV and LA myocardial deformation, right ventricular function and myocardial tissue characterisation with clinical outcomes need to be generated in future trials.
Fig.1. PRISMA Flow chart diagram
Fig. 2. Imaging endpoints in HF trials
Diagnostic accuracy of echomics in patients with transthyretin-related cardiacamyloidosis
Authors: Mori S , Montobbio N , Sormani M P , Campi C , Vianello P F , Mandoli G E , Zanoletti M , Mazzoni C , Rella V , Crotti L , Cameli M , Cappelli F , Porto I , Badano L P , Canepa M 
Published: January 2025

Abstract

Background/Introduction
The diagnosis of transthyretin-related cardiac amyloidosis (ATTR-CA), while often suggested by red flags observed in echocardiography, still requires a lengthy and multi-step process. Recent evidence indicates the feasibility of using radiomics on echocardiographic images (i.e., echomics) for the early characterization of myocardial texture anomalies in ATTR-CA.

Aims
This study aims to develop a radiomic-based model for the diagnosis of transthyretin-related cardiac amyloidosis (ATTR-CA) by characterizing myocardial tissue through echocardiography (echomics).

Methods
We retrospectively collected echocardiographic images in parasternal long-axis and apical 4-chamber views from ATTR-CA and control patients at four Italian centers. The largest possible region-of-interest (ROI) within the interventricular septum was delineated. Ninety-four radiomic features were extracted, including 9 shape-related features and 85 texture features, 21 of which depend on ROI dimensions and 73 purely texture-based (ROI-independent). Five logistic regression models were used to analyse data from three centres (229 ATTR-CA, 224 controls). The models estimated the diagnostic accuracy and area-under-the-curve (AUC) of different sets of radiomic features. The developed five models were finally tested on a cohort of patients from the fourth centre (32 ATTR-CA and 32 age- and sex-matched control patients) for external validation.

Results
The models that included shape and all texture features, whether separately or in combination, demonstrated very high cross-validated accuracies (93-95%) and AUC values (0.97-0.99). However, when using a fixed-size 0.5x0.5 cm ROI, these values decreased to 85% and 0.91, respectively. This confirms that some measurement depends on ROI size. The chosen model used 73 ROI independent features on the largest ROI and demonstrated significantly better accuracy and AUC (92% and 0.97, respectively, p&lt;0.001). These results were confirmed in the external validation cohort (87% and 0.95, respectively). Removing the least informative features resulted in a slight model improvement 90% accuracy and 0.95 precision when 40 out of 73 features were used.

Conclusions
This study demonstrates the potential of echomics (i.e., radiomics applied to echocardiography data) to distinguish between ATTR-CA and control patients by identifying disease-specific textural features that are independent of ROI dimensions.
Workflow
Results
Valve-sparing aortic root replacement for valves with paracommissural fenestrations: which valve will fail?
Authors: Kari Fabian A , Czerny Martin , Borger Michael , Misfeld Martin , Rylski Bartosz , Zimmer Emmanuel , Siepe Matthias , Hagl Christian , Detter Christian , Petersen Johannes , Richardt Doreen , Ensminger Stephan , Werner Paul , Andreas Martin , Peterss Sven , Pichlmaier Maximilian , Mueller Christoph S 
Published: January 2025

Abstract

OBJECTIVES
To define morphologic risk constellations during valve-sparing aortic root replacement (VSARR) for aortic valves with paracommissural fenestrations.

Patients and Methods
Patients from the multicentre prospective intention-to-treat VSARR- registry German Aortic Root Repair Registry (GEARR) were screened for paracommissural cusp fenestrations. We studied a combined end-point of residual aortic regurgitation (rAR) on post-CPB TEE, mid-term progress of rAR (TTE) and aortic valve replacement for AR.

RESULTS
Of a total of 762 registry patients (operated 2016–2024), 145 were identified with ≥1 paracommissural cusp fenestration. Eighteen patients (12%) were not treated as planned but underwent composite valved graft (CVG) implantation. Mean follow-up time was 3 years. Upon post-CPB TEE rAR grade 1 or 2 were present in 44 (33%) and 3 (2%) patients. 50% of patients with fenestrations in more than one cusp showed early progression of rAR. At three years, freedom from the combined end-point was 78% (99% CI 74–79%) for the complete study cohort. Patients with a maximum free margin length difference of &lt; 5mm, reflecting balanced root anatomy with respect to sinus and cusp sizes, had a significantly better outcome than those with ≥5mm: at three years, freedom from the combined end-point was 86% (99% CI 80–91%) vs 41% (99% CI 38–46%, p = 0.011). Outcome was worst for patients with cusp prolapse and a free margin length difference of &gt; 5mm (30% vs 70%, p = 0.018).

CONCLUSIONS
Fenestrations in more than one cusp, inhomogeneities of cusp free margin lengths, and additional prolapse are associated with inferior outcome after VSARR for valves with paracommissural fenestrations.
Sex-related differences in prosthesis-patient mismatch after surgical aortic valve replacement and long-term outcomes
Authors: Springhetti Paolo , Abdoun Kathia , Dumont Éric , Dagenais François , Kalavrouziotis Dimitri , Mohammadi Siamak , Pibarot Philippe , Clavel Marie-Annick 
Published: January 2025

Abstract

Background and Aims
Prosthesis-patient mismatch (PPM) is associated with dismal prognosis after aortic valve replacement (AVR). Sex differences in PPM outcomes remain poorly explored. Therefore, this study aims to evaluate sex-specific impact in PPM after surgical AVR.

Methods
Between 2000 and 2021, 7319 patients underwent surgical AVR at the Institut Universitaire de Cardiologie et de Pneumologie de Québec. Prosthesis-patient mismatch was defined by using the indexed effective orifice area (EOAi) and by applying the Valve Academic Research Consortium-3 (VARC-3) criteria. The cohort was followed up prospectively from surgical AVR until November 2023. The primary endpoint was defined as long-term mortality and the secondary endpoint as long-term cardiovascular (CV) and perioperative mortality. Mortality was established and CV mortality was adjudicated by Quebec national database.

Results
Any-degree PPM resulted more prevalent in women than in men (31.9% vs. 19.7%, P &lt; .0001) with rare incidence of severe PPM (2.4% vs. 0.6%, P &lt; .0001) according to VARC-3 definition. Over a median follow-up of 12.6 years, there were 3231 (44.1%) all-cause deaths, with 1238 (16.9%) from CV causes. Prosthesis-patient mismatch was associated with all-cause mortality (hazard ratio 1.30, 95% CI 1.20–1.40; P &lt; .0001) and CV mortality (hazard ratio 1.39, 95% CI 1.23–1.57; P &lt; .0001) in the whole cohort without interaction between sexes (P ≥ .74). After comprehensive multivariable adjustment, VARC-3 PPM remained independently associated with outcome only in women (P ≤ .04). Adapting PPM definition according to spline-derived EOAi thresholds disaggregated by sex, PPM was independently associated with outcome in both sexes (P ≤ .04).

Conclusions
Sex-specific EOAi thresholds associated with outcomes emerged in this large regional study. This finding suggests that PPM definition in men may follow higher EOAi thresholds than in women.
The Application of Mechanical Circulatory Support in Special Conditions
Authors: Scandroglio Anna Mara , Baldetti Luca , Oezkur Mehmet , Mahajna Ahmad , Pieri Marina , Kowalewski Mariusz , Pilarczyk Kevin , Lorusso Roberto 
Published: January 2025

Abstract
Special conditions, though not typically associated with cardiovascular distress, may be considered for treatment with temporary mechanical circulatory support (tMCS) devices. Such non-classical examples of cardiovascular compromise include trauma, sepsis, and peripartum cardiomyopathy, among others, and may require urgent treatment with a tMCS device for hemodynamic stabilization and tentatively saving the patient’s life. In this section, examples of the use of tMCS in several special circumstances is presented to garner awareness for such conditions, which have previously been overlooked or even considered contraindications, and highlight the benefit of tMCS devices during treatment of these patients and the need for more research into these circumstances.
Abuse of Relative Dominance by Digital Platforms: A Law and Economics Perspective
Authors: Li Qian , Cauffman Caroline 
Published: January 2025

Abstract
In the age of AI, digital platforms are likely to hold significant market power, giving them a superior bargaining position over their business partners and enabling them to impose unfair trading terms. However, proving that a platform holds a dominant position under Art. 102 of the Treaty on the Functioning of the European Union (TFEU) is challenging. The multi-sided nature of platforms complicates the definition of the relevant market, and their innovative digital business models makes it difficult to assess lasting market power. This could lead to false negatives, resulting in under-enforcement from an economic perspective. To address this market reality, the Digital Markets Act (DMA) has been adopted as an ex ante instrument to, inter alia, complement competition law enforcement. However, since the DMA’s quantitative thresholds remain high, numerous platforms with superior market power vis-à-vis their trading partners may not qualify as ‘gatekeepers’, leaving the risk of under-enforcement unresolved. This article explores the desirability of introducing a prohibition on ‘abuse of relative dominance’, drawing on this long-standing concept in some EU Member States. Such a measure could help tackle the concerns arising from the superior bargaining position of digital platforms.
Human TSC2 mutant cells exhibit aberrations in early neurodevelopment accompanied by changes in the DNA Methylome
Authors: Chalkley Mary-Bronwen L , Guerin Lindsey N , Iyer Tenhir , Mallahan Samantha , Nelson Sydney , Sahin Mustafa , Hodges Emily , Ess Kevin C , Ihrie Rebecca A 
Published: January 2025

Abstract
Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. While benign tumors in the heart, lungs, kidney, and brain are all hallmarks of the disease, the most severe symptoms of TSC are often neurological, including seizures, autism, psychiatric disorders, and intellectual disabilities. TSC is caused by loss of function mutations in the TSC1 or TSC2 genes and consequent dysregulation of signaling via mechanistic Target of Rapamycin Complex 1 (mTORC1). While TSC neurological phenotypes are well-documented, it is not yet known how early in neural development TSC1/2-mutant cells diverge from the typical developmental trajectory. Another outstanding question is the contribution of homozygous-mutant cells to disease phenotypes and whether phenotypes are also present in the heterozygous-mutant populations that comprise the vast majority of cells in patients. Using TSC patient-derived isogenic induced pluripotent stem cells (iPSCs) with defined genetic changes, we observed aberrant early neurodevelopment in vitro, including misexpression of key proteins associated with lineage commitment and premature electrical activity. These alterations in differentiation were coincident with hundreds of differentially methylated DNA regions, including loci associated with key genes in neurodevelopment. Collectively, these data suggest that mutation or loss of TSC2 affects gene regulation and expression at earlier timepoints than previously appreciated, with implications for whether and how prenatal treatment should be pursued.
BMP4-GPX4 can improve the ferroptosis phenotype of retinal ganglion cells and enhance their differentiation ability after retinal stem cell transplantation in glaucoma with high intraocular pressure
Authors: Fang Chuankai , He Di , Qian Yafen , Shen Xiaomei 
Published: January 2025

Abstract
Activation of bone morphogenetic protein (BMP) 4 signaling promotes the survival of retinal ganglion cell (RGC) after acute injury. In this study, we investigated the role of the BMP4 signaling pathway in regulating the degeneration of retinal ganglion cells (RGCs) in a mouse glaucoma model and its potential application in retinal stem cell. Our results demonstrate that BMP4-GPX4 not only reduces oxidative stress and iron accumulation but also promotes neuroprotective factors that support the survival of transplanted RSCs into the host retina. These findings suggest a novel therapeutic approach for glaucoma involving the modulation of the BMP4-GPX4 pathway to protect RGCs and improve visual function through enhanced RSC differentiation.
The Impact of Light Availability on the Functional Traits of Quercus Robur L. and Acer Platanoides L. First-Year Seedlings by Direct and Indirect Methods
Authors: Blinkova Olena , Żytkowiak Roma , Jagodziński Andrzej M 
Published: January 2025

Abstract
The resource strategy of seedlings is an important aspect for understanding the adaptation of trees at this ontogenetic phase to abiotic changes. In this study, we sought to determine the patterns of response of functional traits of a shade-tolerant (A. platanoides) and a shade-intolerant (Q. robur) species along natural environmental light gradients. We conducted trait-based analyses at both individual and community levels using direct (leaf area index, LAI; diffuse non-interceptance, DIFN) and indirect (Ellenberg-indicator values, LC) methods in the Arboretum at Kórnik (Poland). Differences between the two species were found for some variables. Analysis of phenotypic plasticity indices of leaf, stem and root traits of seedlings had high values for both species. The values of plasticity indices of A. platanoides root traits were lower compared to the corresponding traits for Q. robur. Relationships between measures obtained from individual-level trait data were stronger than relationships with measures obtained from community-level trait data. The data obtained from the direct method, which included light measurements both at the community level (experimental plots) and at the individual level (seedlings), revealed the closest relationships between functional traits of seedlings and light changes at the individual level trait data for both species. Correlation links between LAI and leaf (leaf mass per area; specific leaf area) and stem (specific stem length; stem mass fraction) traits were less tight for Q. robur compared to A. platanoides. The indirect Ellenberg-indicator analysis revealed relationships between LC and leaf mass per area, and stem-to-root ratio of seedlings based on community-level trait data. Close relationships between LC and leaf mass fraction, and specific leaf area were not established, in contrast to LAI and DIFN. The closest relationships, representing among traits within the same organ system, and links, describing interactions between traits of different organ systems, were established at the community-level trait data.
Bayesian assessment of profitability for products with highly uncertain demand based on multiple samples
Authors: Su Rung-Hung , Yang Hsiu-Han , Hsu Yu-Han 
Published: January 2025

Abstract
Accepted by: M. Zied BABAI
The achievable capacity index (ACI) is well suited to measuring the profitability of a newsboy-type product, wherein profitability is defined as the probability of achieving a target profit under the optimal order quantity. In retail/manufacturing situations where storage and production capacity are limited, profitability evaluation using ACI can be considered to select advantageous products. Although frequentist approaches are useful towards estimating the true ACI, the Bayesian approach may be preferable when prior information about the demand is available. In estimating the ACI, it may be necessary to deal with situations in which the demand is highly uncertain, the sample data consist of distinct subsets drawn from a demand population (i.e., multiple samples), and sampling error must be eliminated to avoid overestimates of profitability. This study seeks to overcome these issues by developing a Bayesian procedure for testing profitability based on multiple samples, focusing on exponentially distributed demand that can exhibit high uncertainty. The lower confidence bound of ACI is derived to express profitability estimates without sampling error. We also provide some tables to facilitate decision-making in evaluating profitability. We find that variations in confidence level and the evaluated criterion significantly influence the direction of decision-making, guiding managers to focus on controlling these factors. The practicality of the proposed method was demonstrated through a case study.
Balanced Metrics and Gauduchon Cone of Locally Conformally Kähler Manifolds
Authors: Ornea Liviu , Verbitsky Misha 
Published: January 2025

Abstract
A complex Hermitian $n$-manifold $(M,I, \omega )$ is called locally conformally Kähler (LCK) if $d\omega =\theta \wedge \omega $, where $\theta $ is a closed 1-form, balanced if $\omega ^{n-1}$ is closed, and SKT if $dId\omega =0$. We conjecture that any compact complex manifold admitting two of these three types of Hermitian forms (balanced, SKT, LCK) also admits a Kähler metric, and prove partial results towards this conjecture. We conjecture that the (1,1)-form $-d(I\theta )$ is Bott–Chern homologous to a positive (1,1)-current. This conjecture implies that $(M,I)$ does not admit a balanced Hermitian metric. We verify this conjecture for all known classes of LCK manifolds.
Surveying genetic markers of antibiotic resistance and genomic background in Chlamydia trachomatis: insights from a multiplex NGS-based approach in clinical strains from Portugal
Authors: Lodhia Zohra , Costa Da Silva Jorge , Correia Cristina , Cordeiro Dora , João Inês , Carreira Teresa , Schäfer Sandra , Aliyeva Elzara , Portugal Clara , Monge Isabel , Gonçalves Elsa , Matos Susana , Dias Ana Paula , Côrte-Real Rita , Carpinteiro Dina , Duarte Sílvia , Vieira Luís , Gomes João Paulo , Borges Vítor , Borrego Maria José 
Published: January 2025

Abstract

Objectives
To survey genetic markers of potential antimicrobial resistance (AMR) to macrolides and fluoroquinolones among Chlamydia trachomatis–positive samples from the collection of the Portuguese National Reference Laboratory for Sexually Transmitted Infections (STIs), and explore a multiplex PCR approach coupled with NGS to provide complementary information regarding a strain’s genomic backbone.

Methods
A total of 502 C. trachomatis–positive samples, mostly anorectal exudates, were subjected to PCR and sequencing of five targets, including loci potentially driving AMR (23S rRNA, gyrA and parC) and loci potentially informative about a strain’s genomic backbone with emphasis on differentiation of lymphogranuloma venereum (LGV)/non-LGV and L2/L2b (a 9 bp insertion in pmpH, a 74 bp insertion upstream from CT105 and the polymorphic CT442).

Results
No samples evidenced 23S rRNA mutations recognizably linked to macrolide resistance. Three samples harboured the Ser83Ile mutation in GyrA putatively driving fluoroquinolone resistance: two recombinant L2-L2b/D-Da (0.4%) and one L2 (0.2%). The screened regions in pmpH, upstream CT105 and CT442 were fully concordant with LGV/non-LGV differentiation. As expected, the pmpH L2b-specific genetic trait locus was detected in all L2b and recombinant L2-L2b/D-Da ompA genotypes, but also in 96.0% of L2 specimens, which also likely possess an L2b genomic backbone. The insertion upstream from CT105 exhibited full LGV specificity, constituting a promising target for the development of rapid LGV diagnostic assays.

Conclusions
This study contributes to enhancing the knowledge of C. trachomatis molecular epidemiology, suggesting that the known genetic determinants of AMR are not disseminated in clinical C. trachomatis strains, and presents an exploratory approach that can be suitable for LGV/non-LGV and L2/L2b genomic background differentiation.