bluuebunny/crossref_metadata_2025 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

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.
Autoridad policial, socialización legal y justicia procedimental: percepciones en adolescentes de Guadalajara
Authors: Grijalva-Eternod Áurea Esther
Published: April 2024

(analytical)Police is one of the worst evaluated institutions in Mexico and its relationship with youth is fragile. This paper seeks to identify which variables influence police legitimacy among adolescents, operationalized as the perception of the duty to obey. For this purpose, data from 1011 surveys applied to high school students in the Guadalajara Metropolitan Area, as part of the International Self-Reported Delinquency Study, are used. The results indicated that, in order to enhance authority, it is necessary to serve the citizens diligently, but apply procedural justice strategies. Likewise, gender-related differences between men and women were found, which are discussed in terms of their implications for the authorities involved in the processes of legal socialization adolescents.
Acesso à saúde por mulheres migrantes internacionais e refugiadas no município de São Paulo no contexto da pandemia de Covid-19
Authors: Cespedes Beatriz , Macedo Renata Mourão , Silveira Cássio , Coviello Denise Martin
Published: April 2024

The present study is a narrative literature review aimed at understanding the specificities of access to healthcare for international migrants and refugees, with a focus on migrant women, and reflecting on the impact of the Covid-19 pandemic on this population. Articles were searched in databases in the Virtual Health Library, refining by sources from the Latin American and Caribbean Literature in Health Sciences (LILACS), MEDLINE, PubMed Central (PMC), and the Scientific Electronic Library (Scielo). From the articles found, after reading the abstracts, 35 met the inclusion criteria and were analyzed according to the principles of thematic analysis. The literature shows that access to healthcare for international migrants and refugees has specificities that can contribute to a situation of health vulnerability, potentially exacerbated by the Covid-19 pandemic. Due to social inequalities, sociocultural differences, the burden of domestic work, and different forms of violence accentuated during the pandemic, migrant women constitute a severely affected group by the setbacks of the socio-sanitary crisis caused by Covid-19. The scarcity of focused public policies makes it difficult to confront this challenge, which, to be solved, must take into account the socio-economic, cultural, symbolic, and linguistic barriers existing between them and the service, as well as the central role they play in family care, acting as a bridge between the migrant community and the healthcare system
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

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: >70% for real movements and >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

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

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.
Implementation of Emergency Preparedness and Response-Rapid Team Program in Niger
Authors: Sani Kadri , Moustapha Mahamadou , Mohamed Garba , Adamou Bagouari , Habibatou Ide , Aboubacar Issiaka , Karim Mohamed , Tassiou Elhadji , Yayé Hanki , Mamadou Kourouma , Alkassoum Ibrahim
Published: April 2024

Introduction: The WHO’s prompt declaration of a Public Health Emergency of International Concern (PHEIC) shepherded an effective coordinated response to contain the epidemic. Objective: The aim of this study is to describe the experiences, challenges, and lessons learned during the Implementation of Emergency Preparedness and Response-Rapid Response Team (EPR-RRT) program. Method: The study used mixed methods approach quantitative and qualitative data from a literature review of WHO AFRO coordination mechanisms and the Niger Public Health Emergency Operational Centre (PHEOC). The study was conducted in the National Public Health Emergency Operational Centre (PHEOC) of Niger during 12 months from September 2022 to September 2023. Results: The implementation of this program began with the evaluation of Niger's capacities and capacity building of teams to prepare, detect and respond to public health emergencies within 24 hours of an alert. The team of multi-disciplinary and multi-sector experts was identified and selected and trained on series of modules training. The team is composed of a total of 50 experts from 6 ONE HEALTH sectoral ministries. The average age is 49.94 (±5.9) years with extremes ranging from 33 to 56 years. The sex ratio is 0.35. The team have acquired the experience of being deployed in 4 regions of the country, 6 districts as part of the response to 6 public health events. Conclusion: The rapid response team has made it possible not only to acquire the technical and operational skills, financial, human and logistical capacities to respond rapidly when a public health emergency occurs.
Part I: Improving Wildfire Occurrence Prediction for CONUS Using Deep Learning and Fire Weather Variables
Authors: Earnest Bethany L. , McGovern Amy , Karstens Christopher , Jirak Israel
Published: April 2024

The purpose of this research is to build an operational model for predicting wildfire occurrence for the contiguous United States (CONUS) in the 1–10-day range using the U-Net 3+ machine learning model. This paper illustrates the range of model performance resulting from choices made in the modeling process, such as how labels are defined for the model and how input variables are codified for the model. By combining the capabilities of the U-Net 3+ model with a neighborhood loss function, fractions skill score (FSS), we can quantify model success by predictions made both in and around the location of the original fire occurrence label. The model is trained on weather, weather-derived fuel, and topography observational inputs and labels representing fire occurrence. Observational weather, weather-derived fuel, and topography data are sourced from the gridded surface meteorological (gridMET) dataset, a daily, CONUS-wide, high-spatial-resolution dataset of surface meteorological variables. Fire occurrence labels are sourced from the U.S. Department of Agriculture’s Fire Program Analysis Fire-Occurrence Database (FPA-FOD), which contains spatial wildfire occurrence data for CONUS, combining data sourced from the reporting systems of federal, state, and local organizations. By exploring the many aspects of the modeling process with the added context of model performance, this work builds understanding around the use of deep learning to predict fire occurrence in CONUS.

Significance Statement

Our work seeks to explore the limits to which deep learning can predict wildfire occurrence in CONUS with the ultimate goal of providing decision support to those allocating fire resources during high fire seasons. By exploring with what accuracy and lead time we can provide insights to these persons, we hope to reduce loss of life, reduce damage to property, and improve future event preparedness. We compare two models, one trained on all fires in the continental United States and the other on only large lightning fires. We found that a model trained on all fires produced a higher probability of fire.
Part II: Lessons Learned from Predicting Wildfire Occurrence for CONUS Using Deep Learning and Fire Weather Variables
Authors: Earnest Bethany L. , McGovern Amy , Karstens Christopher , Jirak Israel
Published: April 2024

This paper illustrates the lessons learned as we applied the U-Net3+ deep learning model to the task of building an operational model for predicting wildfire occurrence for the contiguous United States (CONUS) in the 1–10-day range. Through the lens of model performance, we explore the reasons for performance improvements made possible by the model. Lessons include the importance of labeling, the impact of information loss in input variables, and the role of operational considerations in the modeling process. This work offers lessons learned for other interdisciplinary researchers working at the intersection of deep learning and fire occurrence prediction with an eye toward operationalization.
Aristotelian perplexity and well-being, then and now
Authors: Jardine Nicholas
Published: April 2024

The term ‘ aporia’ (perplexity, impasse, obstacle, doubt, puzzle) is frequent throughout Aristotle's works. This essay summarises Aristotle's explicit accounts of aporia, then explores the various roles it plays in his inquiries into nature. There follow some suggestions about ways in which study of current establishment and pursuit of scientific agendas might profit from reflection on the diverse modes and functions of perplexity. The final section reflects on the Aristotelian link between perplexity and eudaimonia (wellbeing, self-fulfilment, blessedness).
Restorative justice in healthcare settings: Better outcomes for patients and medical professionals
Authors: Nickson Ray , Neikirk Alice
Published: April 2024

Current responses to medical negligence insufficiently consider the broader needs of affected stakeholders. We argue that responses to medical negligence should adopt a restorative justice frame. This article recounts the experience of our daughter’s avoidable suffering and subsequent death in the healthcare system. Our experience as victims of medical negligence, and the broader literature on restorative justice, responsive regulation and health care, suggest that non-adversarial alternatives will better address the needs of victims and encourage a restoration in healthcare relationships.
High-fat diet enhances cell proliferation and compromises intestinal permeability in a translational canine intestinal organoid model
Authors: Nagao Itsuma , Ambrosini Yoko M.
Published: April 2024

Background

Emerging evidence underscores the responsiveness of the mammalian intestine to dietary cues, notably through the involvement of LGR5 + intestinal stem cells in orchestrating responses to diet-driven signals. However, the effects of high-fat diet (HFD) on these cellular dynamics and their impact on gut integrity remain insufficiently understood. Our study aims to assess the multifaceted interactions between palmitic acid (PA), cell proliferation, and the intestinal epithelial barrier using a canine colonoid model. Canine models, due to their relevance in simulating human intestinal diseases, offer a unique platform to explore the molecular mechanisms underlying HFD derived intestinal dysfunction.

Results

Canine colonoids were subjected to PA exposure, a surrogate for the effects of HFD. This intervention revealed a remarkable augmentation of cell proliferative activity. Furthermore, we observed a parallel reduction in transepithelial electrical resistance (TEER), indicating altered epithelium barrier integrity. While E-cadherin exhibited consistency, ZO-1 displayed a noteworthy reduction in fluorescence intensity within the PA-exposed group.

Conclusions

By employing canine intestinal organoid systems, we provide compelling insights into the impact of PA on intestinal physiology. These findings underscore the importance of considering both cell proliferative activity and epithelial integrity in comprehending the repercussions of HFDs on intestinal health. Our study contributes to a deeper understanding of the consequences of HFD on intestinal homeostasis, utilizing valuable translational in vitro models derived from dogs.
Physician engagement in reproductive health advocacy: findings from a mixed methods evaluation of a leadership and advocacy program
Authors: Jones Heidi E. , Manze Meredith , Brakman Anita , Kwan Amy , Davies MiQuel , Romero Diana
Published: April 2024

Background

Medical curricula include advocacy competencies, but how much physicians engage in advocacy and what enables this engagement is not well characterized. The authors assessed facilitators and barriers to advocacy identified by physician alumni of a reproductive health advocacy training program.

Methods

The authors present secondary results from a mixed methods program evaluation from 2018 to 2020, using alumni data from a cross-sectional survey (n = 231) and in-depth interviews (IDIs, n = 36). The survey measured engagement in policy, media, professional organization, and medical education advocacy and the value placed on the community fostered by the program (eight questions, Cronbach’s alpha = 0.81). The authors estimated the association of community value score with advocacy engagement using multivariable Poisson regression to estimate prevalence ratios and analyzed IDI data inductively.

Results

Over one third of alumni were highly engaged in legislative policy (n = 90, 39%), professional organizations (n = 98, 42%), or medical education (n = 89, 39%), with fewer highly active in media-based advocacy (n = 54, 23%) in the year prior to the survey. Survey and IDI data demonstrated that passion, sense of urgency, confidence in skills, and the program’s emphasis on different forms of advocacy facilitated engagement in advocacy, while insufficient time, safety concerns, and sense of effort redundancies were barriers. The program community was also an important facilitator, especially for “out loud” efforts and for those working in environments perceived as hostile to abortion care (e.g., alumni in hostile environments with high community value scores were 1.8 times [95% CI 1.3, 2.6] as likely to report medium/high levels of media advocacy compared to those with low scores after adjusting for age, gender, and clinical specialty).

Conclusion

Physician advocacy training curricula should include both skills- and community-building and identify a full range of forms of advocacy. Community-building is especially important for physician advocacy for reproductive health services such as abortion care.
Exploring new frontiers: cell surface vimentin as an emerging marker for circulating tumor cells and a promising therapeutic target in advanced gastric Cancer
Authors: Li Heming , Zhu Yang-Zhuangzhuang , Xu Lu , Han Tao , Luan Jiasi , Li Xin , Liu Yuting , Wang Zhi , Liu Qiuge , Kong Xiangyu , Zou Chunpu , Su Lin , Hou Yifei , Chen Xiao , Chen Lujun , Wang Ruoyu , Xu Zihang , Zhao Mingfang
Published: April 2024

Background

Circulating tumor cells (CTCs) hold immense promise in guiding treatment strategies for advanced gastric cancer (GC). However, their clinical impact has been limited due to challenges in identifying epithelial-mesenchymal transition (EMT)-CTCs using conventional methods.

Methods

To bridge this knowledge gap, we established a detection platform for CTCs based on the distinctive biomarker cell surface vimentin (CSV). A prospective study involving 127 GC patients was conducted, comparing CTCs enumeration using both EpCAM and CSV. This approach enabled the detection of both regular and EMT-CTCs, providing a comprehensive analysis. Spiking assays and WES were employed to verify the reliability of this marker and technique. To explore the potential inducer of CSV+CTCs formation, a combination of Tandem Mass Tag (TMT) quantitative proteomics, m6A RNA immunoprecipitation–qPCR (MeRIP–qPCR), single-base elongation- and ligation-based qPCR amplification method (SELECT) and RNA sequencing (RNA-seq) were utilized to screen and confirm the potential target gene. Both in vitro and in vivo experiments were performed to explore the molecular mechanism of CSV expression regulation and its role in GC metastasis.

Results

Our findings revealed the potential of CSV in predicting therapeutic responses and long-term prognosis for advanced GC patients. Additionally, compared to the conventional EpCAM-based CTCs detection method, the CSV-specific positive selection CTCs assay was significantly better for evaluating the therapeutic response and prognosis in advanced GC patients and successfully predicted disease progression 14.25 months earlier than radiology evaluation. Apart from its excellent role as a detection marker, CSV emerges as a promising therapeutic target for attenuating GC metastasis. It was found that fat mass and obesity associated protein (FTO) could act as a potential catalyst for CSV+CTCs formation, and its impact on the insulin-like growth factor-I receptor (IGF-IR) mRNA decay through m6A modification. The activation of IGF-I/IGF-IR signaling enhanced the translocation of vimentin from the cytoplasm to the cell surface through phosphorylation of vimentin at serine 39 (S39). In a GC mouse model, the simultaneous inhibition of CSV and blockade of the IGF-IR pathway yielded promising outcomes.

Conclusion

In summary, leveraging CSV as a universal CTCs marker represents a significant breakthrough in advancing personalized medicine for patients with advanced GC. This research not only paves the way for tailored therapeutic strategies but also underscores the pivotal role of CSV in enhancing GC management, opening new frontiers for precision medicine.
Lower extremity movement quality in professional team sport athletes: Inter-rater agreement and relationships with quantitative results from the corresponding pattern
Authors: Keller Matthias , Niederer Daniel , Schwesig René , Kurz Eduard
Published: April 2024

Background

Adequate movement control and quality can be prerequisite functions for performance of the lower extremity. The purposes of our work were 1) to explore the agreement of an efficient test battery assessing qualitative movement execution and 2) to determine its consistency with quantitative performance tests from the corresponding movement pattern.

Methods

The participants were professional male association football players competing in the first German Bundesliga. They performed four movement quality tests (Single-limb balance squat, Balance forward hop, Balance side hop, Balance 90° rotation hop) and the corresponding performance tests (Y-balance test, Forward hop for distance, Side hop test, Square hop test). Qualitative tests were judged by two experienced raters; the ratings were compared to determine inter-rater agreement using Kappa statistics. The relationship with the quantitative tests was determined using Spearman’s rank correlations.

Results

Thirty participants (19 to 33 years old) were included in this study. We found an at least substantial level of agreement (Cohen’s Kappa, 0.64-0.84) with an excellent percentage of exact (83-93%) agreement between the two raters for the movement quality tests. Our findings revealed that the quantitative test results are only slightly related to the movement quality outcomes (ρ(27) <|0.3| and P > 0.2).

Conclusions

Consequently, the qualitative test results provide unique information and complement corresponding quantitative performance tests in professional football athletes. Their observational judgement of foot position, lower limb alignment and upper body control in sagittal, frontal, and transverse planes is agreeable.
Alzheimer’s and neurodegenerative disease biomarkers in blood predict brain atrophy and cognitive decline
Authors: Dark Heather E. , An Yang , Duggan Michael R. , Joynes Cassandra , Davatzikos Christos , Erus Guray , Lewis Alexandria , Moghekar Abhay R. , Resnick Susan M. , Walker Keenan A.
Published: April 2024

Background

Although blood-based biomarkers have been identified as cost-effective and scalable alternatives to PET and CSF markers of neurodegenerative disease, little is known about how these biomarkers predict future brain atrophy and cognitive decline in cognitively unimpaired individuals. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of Alzheimer’s disease (AD) pathology (amyloid-β [Aβ42/40], phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Additionally, we determined whether sex, APOEε4 status, and plasma amyloid-β status modified these associations.

Methods

Plasma biomarkers were measured using Quanterix SIMOA assays. Regional brain volumes were measured by 3T MRI, and a battery of neuropsychological tests assessed five cognitive domains. Linear mixed effects models adjusted for demographic factors, kidney function, and intracranial volume (MRI analyses) were completed to relate baseline plasma biomarkers to baseline and longitudinal brain volume and cognitive performance.

Results

Brain volume analyses included 622 participants (mean age ± SD: 70.9 ± 10.2) with an average of 3.3 MRI scans over 4.7 years. Cognitive performance analyses included 674 participants (mean age ± SD: 71.2 ± 10.0) with an average of 3.9 cognitive assessments over 5.7 years. Higher baseline pTau-181 was associated with steeper declines in total gray matter volume and steeper regional declines in several medial temporal regions, whereas higher baseline GFAP was associated with greater longitudinal increases in ventricular volume. Baseline Aβ42/40 and NfL levels were not associated with changes in brain volume. Lower baseline Aβ42/40 (higher Aβ burden) was associated with a faster decline in verbal memory and visuospatial performance, whereas higher baseline GFAP was associated with a faster decline in verbal fluency. Results were generally consistent across sex and APOEε4 status. However, the associations of higher pTau-181 with increasing ventricular volume and memory declines were significantly stronger among individuals with higher Aβ burden, as was the association of higher GFAP with memory decline.

Conclusions

Among cognitively unimpaired older adults, plasma biomarkers of AD pathology (pTau-181) and astrogliosis (GFAP), but not neuronal injury (NfL), serve as markers of future brain atrophy and cognitive decline.
A retrospective case series of the surgical management of thirty-one penile fibropapilloma cases presented to University College Dublin Veterinary Hospital (UCDVH) between 2017 and 2023
Authors: Thomson Eilidh Elizabeth , Kelly Emmet Thomas , Beltman Marijke Eileen , Ryan Eoin Gerard
Published: April 2024

Background

Penile fibropapilloma is a condition caused by bovine papilloma virus and is frequently encountered in young bulls. Penile fibropapillomatosis is thought to be spread through homosexual mounting behaviour. Fibropapillomas of the penis are painful, often bleed and can impede normal intromission. Treatment may range from allowing time for slow, spontaneous regression to surgical resection but recurrence following surgery is reported by some authors.

Case Presentation

Thirty one bulls that were presented to University College Dublin Veterinary Hospital from March 2017 to March 2023 for surgical resection of penile fibropapillomas were included in this retrospective case series. Twenty-seven of the 31 bulls (87%) were under two years of age. The majority (42%) of bulls presented were Hereford, but Angus, Charolais, Holstein-Friesian and Limousin breeds were also seen. Following examination and diagnosis of penile fibropapilloma, regional anaesthesia (xylazine-procaine epidural and internal pudendal nerve block) and standing surgical intervention (resection and cautery) was performed in each case. Phone call follow-up was performed by one author (EET) in all 31 cases and 2 cases out of the 28 that were contactable showed post-surgical recurrence of penile fibropapillomatosis (i.e., 7.1% recurrence rate).

Conclusion

This case series summarises the history and presenting findings of 31 bovine penile fibropapilloma cases and describes a regional anaesthetic and standing surgical approach for successful case management.
Parametrized multiplicative integral inequalities
Authors: Frioui Assia , Meftah Badreddine , Shokri Ali , Lakhdari Abdelghani , Mukalazi Herbert
Published: April 2024

In this paper, we introduce a biparametrized multiplicative integral identity and employ it to establish a collection of inequalities for multiplicatively convex mappings. These inequalities encompass several novel findings and refinements of established results. To enhance readers’ comprehension, we offer illustrative examples that highlight appropriate choices of multiplicatively convex mappings along with graphical representations. Finally, we demonstrate the applicability of our results to special means of real numbers within the realm of multiplicative calculus.