bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imaging of human parafoveal area with large field of view in adaptive optics line scanning ophthalmoscope
Authors: Kong Wen , Chen Yiwei , Shi Guohua , He Yi 
Published: April 2024

The parafoveal area, with its high concentration of photoreceptors and fine retinal capillaries, is crucial for central vision and often exhibits early signs of pathological changes. The current adaptive optics scanning laser ophthalmoscope (AOSLO) provides an excellent tool to acquire accurate and detailed information about the parafoveal area with cellular resolution. However, limited by the scanning speed of two-dimensional scanning, the field of view (FOV) in the AOSLO system was usually less than or equal to 2∘, and the stitching for the parafoveal area required dozens of images, which was time-consuming and laborious. Unfortunately, almost half of patients are unable to obtain stitched images because of their poor fixation. To solve this problem, we integrate AO technology with the line-scan imaging method to build an adaptive optics line scanning ophthalmoscope (AOLSO) system with a larger FOV. In the AOLSO, afocal spherical mirrors in pairs are nonplanar arranged and the distance and angle between optical elements are optimized to minimize the aberrations, two cylinder lenses are orthogonally placed before the imaging sensor to stretch the point spread function (PSF) for sufficiently digitizing light energy. Captured human retinal images show the whole parafoveal area with [Formula: see text] FOV, 60[Formula: see text]Hz frame rate and cellular resolutions. Take advantage of the 5∘ FOV of the AOLSO, only 9 frames of the retina are captured with several minutes to stitch a montage image with an FOV of [Formula: see text], in which photoreceptor counting is performed within approximately 5∘ eccentricity. The AOLSO system not only provides cellular resolution but also has the capability to capture the parafoveal region in a single frame, which offers great potential for noninvasive studying of the parafoveal area.
In Vivo and In Silico Molecular Modeling Studies of Newly Synthesized Pyrazoles for Their Anti-Inflammatory and Analgesic Properties
Authors: Yadav Mithlesh , Hareen Shiv K. , Dinkar Ritu , Kumar Vijay , Sharma Shikha , Kumar Nitin , Mali Suraj N. 
Published: April 2024

Background: Pyrazole derivatives have gained attention as potential leads for developing anti-inflammatory and analgesic drugs. Chemical modifications of pyrazole structures offer a strategy to enhance their therapeutic properties, while minimizing undesirable effects. Objective: This study aimed to synthesize novel pyrazole derivatives through chemical modifications and assess their anti-inflammatory and analgesic activities. Methods: A series of pyrazole variants were synthesized by reacting various acetophenone derivatives and diethyl oxalate in basic conditions, followed by treatment with glacial acetic acid and hydrazine hydrate. The resulting compounds were further methylated and acetylated. The synthesized compounds were characterized using elemental analysis, 1H NMR, IR, and MASS spectroscopy. The anti-inflammatory activity was evaluated using the rat paw edema technique induced by carrageenan, while the analgesic activity was assessed using the writhing reflux method. Results: Among the newly synthesized pyrazole derivatives, compounds 3b, 3e and 3g′ demonstrated significant anti- inflammatory activity with reduced ulcerogenic potential. Compounds 3d, 3b′ and 3d′ exhibited notable analgesic activity compared to the standard drug. The chemical modifications introduced in these derivatives were confirmed through spectroscopic analyses. Conclusion: The findings of this study highlight the potential of pyrazole derivatives as promising candidates for anti- inflammatory and analgesic drug development. The structural modifications performed in this research improved the therapeutic activities of the compounds, while addressing safety concerns. Further investigations are warranted to elucidate the underlying mechanisms of action and optimize the pharmacological profiles of these novel pyrazole derivatives.
Psychometric properties of learning environment diagnostics instrument
Authors: Setiawan Risky , Hadi Samsul , Aman Aman 
Published: April 2024

The rise and growing prevalence of juvenile delinquency is a matter of concern for many parties. The objective of this study is to establish a research instrument in the form of a questionnaire that can be deployed to assess the learning environment perceived by high school students. This research endeavor constitutes a developmental study, wherein the outcomes are a single survey instrument encompassing six variables, nineteen indicators, and forty questions. The data-collecting process involved the utilization of a Google Form across five schools situated in five districts, encompassing a total of 1615 participants. The analysis of data provided by experts was conducted utilizing V. Aiken and field trials employing CFA Second Order. The findings of this study indicate that the diagnostic survey instrument used to assess the learning environment's impact on the mental health of high school students demonstrated validity, as evidenced by loading factor values exceeding the established minimal threshold. The reliability of the instrument remains insufficient. This survey can be utilized to detect adolescent persistent tendencies carried out by students or other school members that interfere with mental health.The emergence and significantly raising of juvenile delinquency.
GLI1+ Cells Contribute to Vascular Remodeling in Pulmonary Hypertension
Authors: Chu Xuran , Kheirollahi Vahid , Lingampally Arun , Chelladurai Prakash , Valasarajan Chanil , Vazquez-Armendariz Ana Ivonne , Hadzic Stefan , Khadim Ali , Pak Oleg , Rivetti Stefano , Wilhelm Jochen , Bartkuhn Marek , Crnkovic Slaven , Moiseenko Alena , Heiner Monika , Kraut Simone , Atefi Leila Sotoodeh , Koepke Janine , Valente Guilherme , Ruppert Clemens , Braun Thomas , Samakovlis Christos , Alexopoulos Ioannis , Looso Mario , Chao Cho-Ming , Herold Susanne , Seeger Werner , Kwapiszewska Grazyna , Huang Xiaoying , Zhang Jin-San , Pullamsetti Soni Savai , Weissmann Norbert , Li Xiaokun , El Agha Elie , Bellusci Saverio 
Published: April 2024

BACKGROUND:
The precise origin of newly formed ACTA2+ (alpha smooth muscle actin-positive) cells appearing in nonmuscularized vessels in the context of pulmonary hypertension is still debatable although it is believed that they predominantly derive from preexisting vascular smooth muscle cells (VSMCs).

METHODS:

Gli1

Cre-ERT2

; tdTomato

flox

mice were used to lineage trace GLI1+ (glioma-associated oncogene homolog 1-positive) cells in the context of pulmonary hypertension using 2 independent models of vascular remodeling and reverse remodeling: hypoxia and cigarette smoke exposure. Hemodynamic measurements, right ventricular hypertrophy assessment, flow cytometry, and histological analysis of thick lung sections followed by state-of-the-art 3-dimensional reconstruction and quantification using Imaris software were used to investigate the contribution of GLI1+ cells to neomuscularization of the pulmonary vasculature.

RESULTS:

The data show that GLI1+ cells are abundant around distal, nonmuscularized vessels during steady state, and this lineage contributes to around 50% of newly formed ACTA2+ cells around these normally nonmuscularized vessels. During reverse remodeling, cells derived from the GLI1+ lineage are largely cleared in parallel to the reversal of muscularization. Partial ablation of GLI1+ cells greatly prevented vascular remodeling in response to hypoxia and attenuated the increase in right ventricular systolic pressure and right heart hypertrophy. Single-cell RNA sequencing on sorted lineage-labeled GLI1+ cells revealed an
Acta2

high

fraction of cells with pathways in cancer and MAPK (mitogen-activated protein kinase) signaling as potential players in reprogramming these cells during vascular remodeling. Analysis of human lung-derived material suggests that GLI1 signaling is overactivated in both group 1 and group 3 pulmonary hypertension and can promote proliferation and myogenic differentiation.

CONCLUSIONS:
Our data highlight GLI1+ cells as an alternative cellular source of VSMCs in pulmonary hypertension and suggest that these cells and the associated signaling pathways represent an important therapeutic target for further studies.
Trends of Antihypertensive Prescription Among US Adults From 2010 to 2019 and Changes Following Treatment Guidelines: Analysis of Multicenter Electronic Health Records
Authors: Lin Pi‐I Debby , Rifas‐Shiman Sheryl , Merriman John , Petimar Joshua , Yu Han , Daley Matthew F. , Janicke David M. , Heerman William J. , Bailey L. Charles , Maeztu Carlos , Young Jessica , Block Jason P. 
Published: April 2024

Background
Guidelines for the use of antihypertensives changed in 2014 and 2017. To understand the effect of these guidelines, we examined trends in antihypertensive prescriptions in the United States from 2010 to 2019 using a repeated cross‐sectional design.

Methods and Results
Using electronic health records from 15 health care institutions for adults (20–85 years old) who had ≥1 antihypertensive prescription, we assessed whether (1) prescriptions of beta blockers decreased after the 2014 Eighth Joint National Committee (JNC 8) report discouraged use for first‐line treatment, (2) prescriptions for calcium channel blockers and thiazide diuretics increased among Black patients after the JNC 8 report encouraged use as first‐line therapy, and (3) prescriptions for dual therapy and fixed‐dose combination among patients with blood pressure ≥140/90 mm Hg increased after recommendations in the 2017 Hypertension Clinical Practice Guidelines. The study included 1 074 314 patients with 2 133 158 prescription episodes. After publication of the JNC 8 report, prescriptions for beta blockers decreased (3% lower in 2018–2019 compared to 2010–2014), and calcium channel blockers increased among Black patients (20% higher in 2015–2017 and 41% higher in 2018–2019, compared to 2010–2014), in accordance with guideline recommendations. However, contrary to guidelines, dual therapy and fixed‐dose combination decreased after publication of the 2017 Hypertension Clinical Practice Guidelines (9% and 11% decrease in 2018–2019 for dual therapy and fixed‐dose combination, respectively, compared to 2015–2017), and thiazide diuretics decreased among Black patients after the JNC 8 report (6% lower in 2018–2019 compared to 2010–2014).

Conclusions
Adherence to guidelines on prescribing antihypertensive medication was inconsistent, presenting an opportunity for interventions to achieve better blood pressure control in the US population.
Identification of

Prostaglandin I
2
Synthase

Rare Variants in Patients With Williams Syndrome and Severe Peripheral Pulmonary Stenosis
Authors: Chida‐Nagai Ayako , Akagawa Hiroyuki , Sawai Saori , Ma Yue‐Jiao , Yakuwa Satoshi , Muneuchi Jun , Yasuda Kazushi , Yamazawa Hirokuni , Yamamoto Toshiyuki , Takakuwa Emi , Tomaru Utano , Furutani Yoshiyuki , Kato Tatsuya , Harada Gen , Inai Kei , Nakanishi Toshio , Manabe Atsushi , Takeda Atsuhito , Jing Zhi‐Cheng 
Published: April 2024

Background
Peripheral pulmonary stenosis (PPS) is a condition characterized by the narrowing of the pulmonary arteries, which impairs blood flow to the lung. The mechanisms underlying PPS pathogenesis remain unclear. Thus, the aim of this study was to investigate the genetic background of patients with severe PPS to elucidate the pathogenesis of this condition.

Methods and Results

We performed genetic testing and functional analyses on a pediatric patient with PPS and Williams syndrome (WS), followed by genetic testing on 12 patients with WS and mild‐to‐severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole‐exome sequencing identified a rare
PTGIS
nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I
2
synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the
PTGIS
p.E314X variant‐encoding construct when compared with that in cells transfected with the wild‐type
PTGIS
‐encoding construct. p.E314X reduced the tube formation ability in human pulmonary artery endothelial cells and caspase 3/7 activity in both human pulmonary artery endothelial cells and human pulmonary artery smooth muscle cells. Compared with healthy controls, patients with PPS exhibited downregulated pulmonary artery endothelial prostaglandin I
2
synthase levels and urinary prostaglandin I metabolite levels. We identified another
PTGIS
rare splice‐site variant (c.1358+2T>C) in another pediatric patient with WS and severe PPS.

Conclusions

In total, 2 rare nonsense/splice‐site
PTGIS
variants were identified in 2 pediatric patients with WS and severe PPS.
PTGIS
variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.
Design, Rationale and Initial Findings From HERA‐FIB on 10 222 Patients With Atrial Fibrillation Presenting to an Emergency Department Over An 11‐Year Period
Authors: Salbach Christian , Yildirim Mustafa , Hund Hauke , Biener Moritz , Müller‐Hennessen Matthias , Frey Norbert , Katus Hugo A. , Giannitsis Evangelos , Milles Barbara Ruth 
Published: April 2024

Background
For the majority of patients with atrial fibrillation (AF), disease management has improved in recent years. However, there are still populations underrepresented or excluded in current registries and randomized controlled trials. HERA‐FIB (Heidelberg Registry of Atrial Fibrillation) was planned to assess real‐world evidence for the prevalence, demographic characteristics and management of patients with the diagnosis of AF presenting consecutively to a chest pain unit.

Methods and Results
HERA‐FIB is a retrospective, observational, single‐center study on patients with a diagnosis of AF presenting to a chest pain unit from June 2009 until March 2020. This article describes the structure, governance, outcome assessment, quality and data collection processes of the registry. Additionally, characteristics of populations of special interest are described. The study consecutively enrolled 10 222 patients presenting with AF to the chest pain unit of the University Hospital of Heidelberg. Clinical parameters and patient characteristics were assessed retrospectively. Outcome parameters included rates for all‐cause death, stroke, myocardial infarction and major bleedings. We were able to investigate patient cohorts of special interest such as advanced chronic kidney disease, octogenarians, and those with acute coronary syndrome who are often underrepresented in current studies and randomized controlled trials.

Conclusions
HERA‐FIB is one of the largest real‐world single‐center retrospective registries on patients with AF, which captures the era of transition from vitamin K antagonists to non–vitamin K oral anticoagulation regimens in clinical practice and offers the possibility to investigate patient populations usually underrepresented or excluded in current available randomized controlled trials and registries.

Registration

URL:
https://www.clinicaltrials.gov
; unique identifier: NCT05995561.
Plasma Metabolome Predicts Aortic Stiffness and Future Risk of Coronary Artery Disease and Mortality After 23 Years of Follow‐Up in the General Population
Authors: Ottosson Filip , Engström Gunnar , Orho‐Melander Marju , Melander Olle , Nilsson Peter M. , Johansson Madeleine 
Published: April 2024

Background
Increased aortic stiffness (arteriosclerosis) is associated with early vascular aging independent of age and sex. The underlying mechanisms of early vascular aging remain largely unexplored in the general population. We aimed to investigate the plasma metabolomic profile in aortic stiffness (vascular aging) and associated risk of incident cardiovascular disease and mortality.

Methods and Results

We included 6865 individuals from 2 Swedish population‐based cohorts. Untargeted plasma metabolomics was performed by liquid‐chromatography mass spectrometry. Aortic stiffness was assessed directly by carotid‐femoral pulse wave velocity (PWV) and indirectly by augmentation index (AIx@75). A least absolute shrinkage and selection operator (LASSO) regression model was created on plasma metabolites in order to predict aortic stiffness. Associations between metabolite‐predicted aortic stiffness and risk of new‐onset cardiovascular disease, cardiovascular mortality, and all‐cause mortality were calculated. Metabolite‐predicted aortic stiffness (PWV and AIx@75) was positively associated particularly with acylcarnitines, dimethylguanidino valeric acid, glutamate, and cystine. The plasma metabolome predicted aortic stiffness (PWV and AIx@75) with good accuracy (R
2
=0.27 and R
2
=0.39, respectively). Metabolite‐predicted aortic stiffness (PWV and AIx@75) was significantly correlated with age, sex, systolic blood pressure, body mass index, and low‐density lipoprotein. After 23 years of follow‐up, metabolite‐predicted aortic stiffness (PWV and AIx@75) was significantly associated with increased risk of new‐onset coronary artery disease, cardiovascular mortality, and all‐cause mortality.

Conclusions
Aortic stiffness is associated particularly with altered metabolism of acylcarnitines, cystine, and dimethylguanidino valeric acid. These metabolic disturbances predict increased risk of new‐onset coronary artery disease, cardiovascular mortality, and all‐cause mortality after more than 23 years of follow‐up in the general population.
DANSPOT: A Multicenter Stepped‐Wedge Cluster‐Randomized Trial of the Reclassification of Acute Myocardial Infarction: Rationale and Study Design
Authors: Strandkjær Nina , Jørgensen Nicoline , Hasselbalch Rasmus Bo , Kristensen Jonas , Knudsen Marie Sophie Sander , Kock Thilde Olivia , Lange Theis , Lindholm Matias Greve , Bruun Niels Eske , Holmvang Lene , Terkelsen Christian Juhl , Pedersen Claus Kjær , Christensen Martin Kirk , Lassen Jens Flensted , Hilsted Linda , Ladefoged Søren , Nybo Mads , Bor Mustafa Vakur , Dahl Morten , Hansen Annebirthe Bo , Kamstrup Pia Rørbæk , Bundgaard Henning , Torp‐Pedersen Christian , Iversen Kasper Karmark 
Published: April 2024

Background
Cardiac troponins are the preferred biomarkers for the diagnosis of acute myocardial infarction. Although sex‐specific 99th percentile thresholds of troponins are recommended in international guidelines, the clinical effect of their use is poorly investigated. The DANSPOT Study (The Danish Study of Sex‐ and Population‐Specific 99th percentile upper reference limits of Troponin) aims to evaluate the clinical effect of a prospective implementation of population‐ and sex‐specific diagnostic thresholds of troponins into clinical practice.

Methods
This study is a nationwide, multicenter, stepped‐wedge cluster‐randomized trial of the implementation of population‐ and sex‐specific thresholds of troponins in 22 of 23 clinical centers in Denmark. We established sex‐specific thresholds for 5 different troponin assays based on troponin levels in a healthy Danish reference population. Centers will sequentially cross over from current uniform manufacturer‐derived thresholds to the new population‐ and sex‐specific thresholds. The primary cohort is defined as patients with symptoms suggestive of acute coronary syndrome having at least 1 troponin measurement performed within 24 hours of arrival with a peak troponin value between the current uniform threshold and the new sex‐specific female and male thresholds. The study will compare the occurrence of the primary outcome, defined as a composite of nonfatal myocardial infarction, unplanned revascularization, and all‐cause mortality within 1 year, separately for men and women before and after the implementation of the new sex‐specific thresholds.

Conclusions
The DANSPOT Study is expected to show the clinical effects on diagnostics, treatment, and clinical outcomes in patients with myocardial infarction of implementing sex‐specific diagnostic thresholds for troponin based on a national Danish reference population.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT05336435.
Aortic Stenosis and Renal Function: A Bidirectional Mendelian Randomization Analysis
Authors: Ciofani Jonathan L. , Han Daniel , Allahwala Usaid K. , Bhindi Ravinay 
Published: April 2024

Background
Large observational studies have demonstrated a clear inverse association between renal function and risk of aortic stenosis (AS). Whether this represents a causal, reverse causal or correlative relationship remains unclear. We investigated this using a bidirectional 2‐sample Mendelian randomization approach.

Methods and Results

We collected summary statistics for the primary analysis of chronic kidney disease (CKD) and AS from genome‐wide association study meta‐analyses including 480 698 and 653 867 participants, respectively. We collected further genome‐wide association study summary statistics from up to 1 004 040 participants for sensitivity analyses involving estimated glomerular filtration rate (eGFR) derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. Inverse‐variance weighted was the primary analysis method, with weighted‐median, weighted‐mode, Mendelian randomization‐Egger, and Mendelian randomization‐Pleiotropy Residual Sum and Outlier as sensitivity analyses. We did not find evidence of a causal relationship between genetically predicted CKD liability as the exposure and AS as the outcome (odds ratio [OR], 0.94 per unit increase in log odds of genetic liability to CKD [95% CI, 0.85–1.04],
P
=0.26) nor robust evidence of AS liability as the exposure and CKD as the outcome (OR, 1.04 per unit increase in log odds of genetic liability to AS [95% CI, 0.97–1.12],
P
=0.30). The sensitivity analyses were neutral overall, as were the analyses using eGFR derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. All positive controls demonstrated strong significant associations.

Conclusions
The present study did not find evidence of a substantial effect of genetically predicted renal impairment on risk of AS. This has important implications for research efforts that attempt to identify prevention and treatment targets for both CKD and AS.
A Global Pela
Authors: Mudzakkir Amin , Mulyasari Prima Nurahmi , Ferza Ray 
Published: April 2024

Abstract
This research delves into the activities of the SSVA, a Moluccan diaspora organisation based in Vlissingen, the Netherlands, explicitly focusing on its pivotal role in establishing a sister-city relationship with the ancestral homeland, Ambon. Moving beyond a conventional development initiative, we posit that the Vlissingen-Ambon sister-city programme is rooted in a Moluccan traditional bond known as pela, which extends its influence globally, leading us to coin the term ‘global pela’. Employing a qualitative approach, we conducted in-depth interviews in May 2022 with key stakeholders and comprehensively analysed primary documents. Our findings revealed that the Moluccan diaspora community in Vlissingen has effectively addressed the psychological trauma experienced upon their initial migration to the Netherlands. Moreover, they have developed a unique diasporic community that transcends traditional notions of nationalism and formal citizenship. This research highlights the lasting importance of cultural bonds in fostering transnational relationships and healing historical wounds.