bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Authors: Eiken Alexandria P. , Smith Audrey L. , Skupa Sydney A. , Schmitz Elizabeth , Rana Sandeep , Singh Sarbjit , Kumar Siddhartha , Mallareddy Jayapal Reddy , de Cubas Aguirre A , Krishna Akshay , Kalluchi Achyuth , Rowley M. Jordan , D'Angelo Christopher R. , Lunning Matthew A. , Bociek R. Gregory , Vose Julie M. , Natarajan Amarnath , El-Gamal Dalia 
Published: April 2024

Abstract

Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacologic agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NFκB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its antileukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NFκB signaling and the UPR, culminating in profound antitumor properties independent of TME stimuli.

Significance:
SpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NFκB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NFκB pathway and UPR) highlighting its use in drug-resistant CLL.
Managerialización en políticas de protección a infancia en Chile: óptica de trabajadores
Authors: Ribeiro de Souza Josiane Teresinha , Mok-Aravena Camila , Baleriola-Escudero Enrique , Morales-Muñoz Karol , Núñez-Parra Lorena , Sisto-Campos Vicente 
Published: April 2024

(analítico)Chile ha sido considerado como un caso emblemático de políticas de protección a la niñez y adolescencia siguiendo los postulados del nuevo management público, tales como tercerización privatizada con financiamiento del Estado o el énfasis en instrumentos de control y la rendición de cuentas de altas consecuencias. Esta investigación abordó las experiencias de profesionales que trabajan en este ámbito, mediante el análisis de 16 entrevistas semiestructuradas. Losresultados muestran que los instrumentos de gestión que instala la política ocupan un lugar central, demandando un exceso de trabajo administrativo y promoviendo una visión competitiva propia de la empresa privada en su quehacer con niñez y adolescencia, que desmotiva, afectando el sentido del trabajo que realizan y sus prácticas orientadas al cuidado.
Palabras clave: Tercerización; niñez; política; gestión. Tesauro de Ciencias Sociales de la Unesco.
Evaluation of a Clinical Decision Support Tool to Guide Adoption of the American Heart Association Telemetry Monitoring Practice Standards
Authors: Bergstedt Allen , Hilliard Brian , Alabsi Sarah , Usher Michael G. , Peters Maya , Grace James , Melton Genevieve B. , Beebe Timothy J. , Pestka Deborah L. 
Published: April 2024

Background
The objectives of this study were to (1) evaluate telemetry use pre‐ and postimplementation of clinical decision support tools to support American Heart Association practice standards for telemetry monitoring and (2) understand the factors that may contribute to variation of telemetry monitoring in practice.

Methods and Results
First, we captured overall variability in telemetry use pre‐ and postimplementation of the clinical decision support intervention. We then conducted semistructured interviews with telemetry‐ordering providers to identify key barriers and facilitators to adoption. During the study period, 399 physicians met criteria for inclusion and were divided into excessive and nonexcessive orderers. Distribution of telemetry use was bimodal. Among nonexcessive users, 24.4% of patient days were with telemetry compared with 51.6% among excessive users. On average, both excessive (6.1% reduction) and nonexcessive users (2.8% reduction) decreased telemetry use postimplementation, and these reductions were sustained over a 16‐month period. Sixteen interviews were conducted. Physicians believed that the tool was successful because it caused them to more closely consider if telemetry was indicated for each patient. Physicians also voiced frustration with interruptions to their workflow, and some noted that they commonly use telemetry outside of practice standards to monitor patients who were acutely but not critically ill.

Conclusions
Embedding telemetry practice standards into the electronic health record in the form of clinical decision support is effective at reducing excess telemetry use. Although the intervention was well received, there are persistent barriers, such as preexisting views on telemetry and existing workflow habits, that may inhibit higher adoption of standards.
Association of Renin‐Angiotensin‐Aldosterone System Inhibitors With Clinical Outcomes, Hemodynamics, and Myocardial Remodeling Among Patients With Advanced Heart Failure on Left Ventricular Assist Device Support
Authors: Gallone Guglielmo , Ibero Javier , Morley‐Smith Andrew , Monteagudo Vela Maria , Fiorelli Francesca , Konicoff Mailen , Edwards Gemma , Raj Binu , Shanmuganathan Mayooran , Pidello Stefano , Frea Simone , De Ferrari Gaetano Maria , Panoulas Vasileios , Stock Ulrich , Bowles Christopher , Dunning John , Riesgo Gil Fernando 
Published: April 2024

Background
We evaluated the potential benefits of renin‐angiotensin‐aldosterone system inhibitors (RAASi) in patients with left ventricular assist device support.

Methods and Results

A total of 165 consecutive patients undergoing left ventricular assist device implant and alive at 6‐month on support were studied. RAASi status after 6‐month visit along with clinical reasons for nonprescription/uptitration were retrospectively assessed. The primary outcome was a composite of heart failure hospitalization or cardiovascular death between 6 and 24 months after left ventricular assist device implant. Remodeling and hemodynamic outcomes were explored by studying the association of RAASi new prescription/uptitration versus unmodified therapy at 6‐month visit with the change in echocardiographic parameters and hemodynamics between 6 and 18 months. After the 6‐month visit, 76% of patients were on RAASi. Patients' characteristics among those receiving and not receiving RAASi were mostly similar. Of 85 (52%) patients without RAASi new prescription/uptitration at 6‐month visit, 62% had no apparent clinical reason. RAASi were independently associated with the primary outcome (adjusted hazard ratio, 0.31 [95% CI, 0.16–0.69]). The baseline rates of optimal echocardiographic profile (neutral interventricular septum, mitral regurgitation less than mild, and aortic valve opening) and hemodynamic profile (cardiac index ≥2.2 L/min per m
2
, wedge pressure <18 mm Hg, and right atrial pressure <12 mm Hg) were similar between groups. At 18 months, patients receiving RAASi new prescription/uptitration at 6 months had higher rates of optimal hemodynamic profile (57.5% versus 37.0%;
P
=0.032) and trends for higher rates of optimal echocardiographic profile (39.6% versus 22.9%;
P
=0.055) compared with patients with 6‐month unmodified therapy. Optimal 18‐month hemodynamic and echocardiographic profiles were associated with the primary outcome (log‐rank=0.022 and log‐rank=0.035, respectively).

Conclusions
RAASi are associated with improved outcomes and improved hemodynamics among mechanically unloaded patients.
Sex‐Associated Metabolites and Incident Stroke, Incident Coronary Heart Disease, Hypertension, and Chronic Kidney Disease in the REGARDS Cohort
Authors: Couch Catharine A. , Ament Zsuzsanna , Patki Amit , Kijpaisalratana Naruchorn , Bhave Varun , Jones Alana C. , Armstrong Nicole D. , Cushman Mary , Kimberly W. Taylor , Irvin M. Ryan 
Published: April 2024

Background
Sex disparities exist in cardiometabolic diseases. Metabolomic profiling offers insight into disease mechanisms, as the metabolome is influenced by environmental and genetic factors. We identified metabolites associated with sex and determined if sex‐associated metabolites are associated with incident stoke, incident coronary heart disease, prevalent hypertension, and prevalent chronic kidney disease.

Methods and Results
Targeted metabolomics was conducted for 357 metabolites in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) case‐cohort substudy for incident stroke. Weighted logistic regression models were used to identify metabolites associated with sex in REGARDS. Sex‐associated metabolites were replicated in the HyperGEN (Hypertension Genetic Epidemiology Network) and using the literature. Weighted Cox proportional hazard models were used to evaluate associations between metabolites and incident stroke. Cox proportional hazard models were used to evaluate associations between metabolites and incident coronary heart disease. Weighted logistic regression models were used to evaluate associations between metabolites and hypertension and chronic kidney disease. Fifty‐one replicated metabolites were associated with sex. Higher levels of 6 phosphatidylethanolamines were associated with incident stroke. No metabolites were associated with incident coronary heart disease. Higher levels of uric acid and leucine and lower levels of a lysophosphatidylcholine were associated with hypertension. Higher levels of indole‐3‐lactic acid, 7 phosphatidylethanolamines, and uric acid, and lower levels of betaine and bilirubin were associated with chronic kidney disease.

Conclusions
These findings suggest that the sexual dimorphism of the metabolome may contribute to sex differences in stroke, hypertension, and chronic kidney disease.
Moderate Endurance Exercise Increases Arrhythmia Susceptibility and Modulates Cardiac Structure and Function in a Sexually Dimorphic Manner
Authors: George Sharon A. , Trampel Katy Anne , Brunner Kelsey , Efimov Igor R. 
Published: April 2024

Background
Although moderate endurance exercise has been reported to improve cardiovascular health, its effects on cardiac structure and function are not fully characterized, especially with respect to sexual dimorphism. We aimed to assess the effects of moderate endurance exercise on cardiac physiology in male versus female mice.

Methods and Results
C57BL/6J mice of both sexes were run on a treadmill for 6 weeks. ECG and echocardiography were performed every 2 weeks. After 6 weeks of exercise, mice were euthanized, and triple parametric optical mapping was performed on Langendorff perfused hearts to assess cardiac electrophysiology. Arrhythmia inducibility was tested by programmed electrical stimulation. Left ventricular tissue was fixed, and RNA sequencing was performed to determine exercise‐induced transcriptional changes. Exercise‐induced left ventricular dilatation was observed in female mice alone, as evidenced by increased left ventricular diameter and reduced left ventricular wall thickness. Increased cardiac output was also observed in female exercised mice but not males. Optical mapping revealed further sexual dimorphism in exercise‐induced modulation of cardiac electrophysiology. In female mice, exercise prolonged action potential duration and reduced voltage‐calcium influx delay. In male mice, exercise reduced the calcium decay constant, suggesting faster calcium reuptake. Exercise increased arrhythmia inducibility in both male and female mice; however, arrhythmia duration was increased only in females. Lastly, exercise‐induced transcriptional changes were sex dependent: females and males exhibited the most significant changes in contractile versus metabolism‐related genes, respectively.

Conclusions
Our data suggest that moderate endurance exercise can significantly alter multiple aspects of cardiac physiology in a sex‐dependent manner. Although some of these effects are beneficial, like improved cardiac mechanical function, others are potentially proarrhythmic.
ALM/BMI: A Clinically Superior Index for Identifying Skeletal Muscle Dysfunction in Patients With Heart Failure
Authors: Tinggaard Andreas Bugge , Skou Maria Kreiberg , Jessen Niels , Nørrelund Helene , Wiggers Henrik 
Published: April 2024

Background
Skeletal muscle wasting is critical in patients with heart failure (HF). Whereas prior studies have employed appendicular lean mass (ALM) normalized by height squared to identify low skeletal muscle mass, the potential of ALM normalized to body mass index (ALM/BMI) remains unexplored in patients with HF. In this study, we compared the use of 2 skeletal muscle mass indices in patients with HF to examine their sex‐specific correlations with measures of physical capacity, quality of life, and daily physical activity.

Methods and Results

A total of 111 patients with HF underwent dual x‐ray absorptiometry, physical capacity tests, and accelerometry and answered a quality‐of‐life questionnaire. ALM normalized by height squared and ALM/BMI indices disagreed in classifying low muscle mass (Cohen's κ, −0.008 [95% CI, −0.094 to 0.177];
P
=0.93). ALM/BMI correlated well with 6‐minute walking distance in women and men (
R
=0.67 and 0.49;
P
<0.001), with maximal oxygen uptake in women and men (
R
=0.41 and 0.48;
P
<0.05), and with maximal muscle strength in women and men (
R
=0.54 and 0.43;
P
<0.01). Inversely, ALM normalized by height squared did not correlate significantly with 6‐minute walking distance or maximal oxygen uptake and correlated with maximal muscle strength only in men (
R
=0.43;
P
<0.001). Only ALM/BMI allowed for identification of a low‐muscle‐mass group characterized by poor quality of life (Minnesota Living With Heart Failure Questionnaire score of 33±21 versus 25±16;
P
=0.027) and less daily time spent in moderate to vigorous physical activity (8 [3–17] versus 15 [9–37] minutes;
P
<0.001).

Conclusions
ALM/BMI was superior for identifying clinically significant muscle dysfunction in both female and male patients with HF.
Impact of Coronary Microvascular Dysfunction on Functional Left Ventricular Remodeling and Diastolic Dysfunction
Authors: Aldujeli Ali , Tsai Tsung‐Ying , Haq Ayman , Tatarunas Vacis , Knokneris Aurimas , Briedis Kasparas , Unikas Ramunas , Onuma Yoshinobu , Brilakis Emmanouil S. , Serruys Patrick W. 
Published: April 2024

Background
Coronary microvascular dysfunction (CMD) is a common complication of ST‐segment–elevation myocardial infarction (STEMI) and can lead to adverse cardiovascular events. Whether CMD after STEMI is associated with functional left ventricular remodeling (FLVR) and diastolic dysfunction, has not been investigated.

Methods and Results

This is a nonrandomized, observational, prospective study of patients with STEMI with multivessel disease. Coronary flow reserve and index of microcirculatory resistance of the culprit vessel were measured at 3 months post‐STEMI. CMD was defined as index of microcirculatory resistance ≥25 or coronary flow reserve <2.0 with a normal fractional flow reserve. We examined the association between CMD, LV diastolic dysfunction, FLVR, and major adverse cardiac events at 12‐month follow‐up. A total of 210 patients were enrolled; 59.5% were men, with a median age of 65 (interquartile range, 58–76) years. At 3‐month follow‐up, 57 patients (27.14%) exhibited CMD. After 12 months, when compared with patients without CMD, patients with CMD had poorer LV systolic function recovery (−10.00% versus 8.00%;
P
<0.001), higher prevalence of grade 2 LV diastolic dysfunction (73.08% versus 1.32%;
P
<0.001), higher prevalence of group 3 or 4 FLVR (11.32% versus 7.28% and 22.64% versus 1.99%, respectively;
P
<0.001), and higher incidence of major adverse cardiac events (50.9% versus 9.8%;
P
<0.001). Index of microcirculatory resistance was independently associated with LV diastolic dysfunction and adverse FLVR.

Conclusions
CMD is present in ≈1 of 4 patients with STEMI during follow‐up. Patients with CMD have a higher prevalence of LV diastolic dysfunction, adverse FLVR, and major adverse cardiac events at 12 months compared with those without CMD.

Registration

URL:
https://www.clinicaltrials.gov
; Unique Identifier: NCT05406297.
Short‐Chain Fatty Acid Butyrate Is an Inotropic Agent With Vasorelaxant and Cardioprotective Properties
Authors: Seefeldt Jacob Marthinsen , Homilius Casper , Hansen Jakob , Lassen Thomas Ravn , Jespersen Nichlas Riise , Jensen Rebekka Vibjerg , Boedtkjer Ebbe , Bøtker Hans Erik , Nielsen Roni 
Published: April 2024

Background
The heart can metabolize the microbiota‐derived short‐chain fatty acid butyrate. Butyrate may have beneficial effects in heart failure, but the underlying mechanisms are unknown. We tested the hypothesis that butyrate elevates cardiac output by mechanisms involving direct stimulation of cardiac contractility and vasorelaxation in rats.

Methods and Results

We examined the effects of butyrate on (1) in vivo hemodynamics using parallel echocardiographic and invasive blood pressure measurements, (2) isolated perfused hearts in Langendorff systems under physiological conditions and after ischemia and reperfusion, and (3) isolated coronary arteries mounted in isometric wire myographs. We tested Na‐butyrate added to injection solutions or physiological buffers and compared its effects with equimolar doses of NaCl. Butyrate at plasma concentrations of 0.56 mM increased cardiac output by 48.8±14.9%, stroke volume by 38.5±12.1%, and left ventricular ejection fraction by 39.6±6.2%, and lowered systemic vascular resistance by 33.5±6.4% without affecting blood pressure or heart rate in vivo. In the range between 0.1 and 5 mM, butyrate increased left ventricular systolic pressure by up to 23.7±3.4% in isolated perfused hearts and by 9.4±2.9% following ischemia and reperfusion, while reducing myocardial infarct size by 81.7±16.9%. Butyrate relaxed isolated coronary septal arteries concentration dependently with an EC
50
=0.57 mM (95% CI, 0.23–1.44).

Conclusions
We conclude that butyrate elevates cardiac output through mechanisms involving increased cardiac contractility and vasorelaxation. This effect of butyrate was not associated with adverse myocardial injury in damaged hearts exposed to ischemia and reperfusion.
Robust discrimination of multiple naturalistic same-hand movements from MEG signals with convolutional neural networks
Authors: Zubarev Ivan , Nurminen Mila , Parkkonen Lauri 
Published: April 2024

Abstract
Discriminating patterns of brain activity corresponding to multiple hand movements are a challenging problem at the limit of the spatial resolution of magnetoencephalography (MEG). Here, we use the combination of MEG, a novel experimental paradigm, and a recently developed convolutional-neural-network-based classifier to demonstrate that four goal-directed real and imaginary movements—all performed by the same hand—can be detected from the MEG signal with high accuracy: &gt;70% for real movements and &gt;60% for imaginary movements. Additional experiments were used to control for possible confounds and to establish the empirical chance level. Investigation of the patterns informing the classification indicated the primary contribution of signals in the alpha (8–12 Hz) and beta (13–30 Hz) frequency range in the contralateral motor areas for the real movements, and more posterior parieto–occipital sources for the imagined movements. The obtained high accuracy can be exploited in practical applications, for example, in brain–computer interface-based motor rehabilitation.
Highly conserved bifidobacteria in the human gut: Bifidobacterium longum subsp. longum as a potential modulator of elderly innate immunity
Authors: Longhi G. , Lugli G.A. , Bianchi M.G. , Rizzo S.M. , Tarracchini C. , Mancabelli L. , Vergna L.M. , Alessandri G. , Fontana F. , Taurino G. , Chiu M. , Milani C. , van Sinderen D. , Bussolati O. , Ventura M. , Turroni F. 
Published: April 2024

Abstract
Aging is a physiological and immunological process involving the deterioration of human health, characterised by the progressive alteration of organs and their functions. The speed and extent of such decline are dependent on lifestyle, environment, and genetic factors. Moreover, with advancing age, humans become progressively more fragile and prone to acute and chronic diseases. Although the intestinal microbiota is predisposed to perturbations that accompany aging and frailty, it is generally accepted that the gut microbiota engages in multiple interactions that affect host health throughout the host life span. In the current study, an exhaustive in silico investigation of gut-associated bifidobacteria in healthy individuals from birth to old age revealed that Bifidobacterium longum subsp. longum is the most prevalent member, especially during infancy and in centenarians. Moreover, B. longum subsp. longum genome reconstruction and strain tracing among human gut microbiomes allowed the identification of prototypes of this taxon in the human gut microbiota of healthy elderly individuals. Such analyses guided culturomics attempts to isolate B. longum subsp. longum strains that matched the genomic content of B. longum subsp. longum prototypes from healthy elderly individuals. The molecular effects of selected B. longum subsp. longum strains on the human host were further investigated using in vitro microbe-host interactions, revealing differences in the host immune system transcriptome, with a reduction in gene expression of inflammation-related cytokines. These intriguing findings support the potential anti-aging effects of elderly associated prototypes of B. longum subsp. longum.
Reappraising Reprisals Against Enemy Civilians in Customary International Humanitarian Law
Authors: Moir Lindsay 
Published: April 2024

Abstract
Belligerent reprisals are a controversial and largely discredited mechanism for the enforcement of international humanitarian law. Additional Protocol i of 1977 prohibits a range of reprisal activity, including reprisals against enemy civilians. A (relatively small) number of States are not Parties to Additional Protocol i, whilst some States Parties have made declarations and/or reservations to the Protocol which could be seen as attempts to limit the operation of the prohibition. Its status as a rule of customary international law is therefore an important question. This article argues that opposition to the prohibition in customary law is neither as widespread nor consistent as has previously been suggested and that the weight of evidence points towards the existence (or development) of a customary prohibition. Consistent opposition by the UK and the US, however, makes it unlikely that the customary prohibition would be opposable to those particular States.