bluuebunny/crossref_metadata_2025_split huggingface dataset:
Food and Drug Administration Public Workshop Summary—Development Considerations of Antifungal Drugs to Address Unmet Medical Need
Authors: Yasinskaya Yuliya , Bala Shukal , Waack Ursula , Dixon Cheryl , Higgins Karen , Moore Jason N , Jjingo Caroline J , O'Shaughnessy Elizabeth , Colangelo Philip , Botgros Radu , Nambiar Sumathi , Angulo David , Dane Aaron , Chiller Tom , Hodges Michael R , Sandison Taylor , Hope William , Walsh Thomas J , Pappas Peter , Katragkou Aspasia , Kovanda Laura , Rex John H , Marr Kieren A , Ostrosky-Zeichner Luis , Sekine Shohko , Deshpande Monika , Shukla Sunita J , Farley John 
Published: April 2023

Abstract
Pressing challenges in the treatment of invasive fungal infections (IFIs) include emerging and rare pathogens, resistant/refractory infections, and antifungal armamentarium limited by toxicity, drug-drug interactions, and lack of oral formulations. Development of new antifungal drugs is hampered by the limitations of the available diagnostics, clinical trial endpoints, prolonged trial duration, difficulties in patient recruitment, including subpopulations (eg, pediatrics), and heterogeneity of the IFIs. On 4 August 2020, the US Food and Drug Administration convened a workshop that included IFI experts from academia, industry, and other government agencies to discuss the IFI landscape, unmet need, and potential strategies to facilitate the development of antifungal drugs for treatment and prophylaxis. This article summarizes the key topics presented and discussed during the workshop, such as incentives and research support for drug developers, nonclinical development, clinical trial design challenges, lessons learned from industry, and potential collaborations to facilitate antifungal drug development.
Rapid Rule-Out of Myocardial Infarction Using a Single High-Sensitivity Cardiac Troponin I Measurement Strategy at Presentation to the Emergency Department: The SAFETY Study
Authors: Fabre-Estremera Blanca , Smith Stephen W , Sandoval Yader , Schulz Karen , Okeson Brynn , Cullen Louise , Apple Fred S 
Published: April 2023

Abstract

Background
Our study addressed the diagnostic performance of the Atellica® IM High-Sensitivity Troponin I (hs-cTnI) assay for the rapid rule-out of myocardial infarction (MI) using a single hs-cTnI measurement at presentation in patients presenting to a US emergency department (ED).

Methods
This was a prospective, observational, cohort study of consecutive ED patients with suspected acute coronary syndrome, using 12-lead electrocardiogram and serial hs-cTnI measurements ordered on clinical indication (SAFETY, NCT04280926). ST-segment elevation MI patients were excluded. The optimal threshold required a sensitivity ≥99% and a negative predictive value (NPV) ≥99.5% for MI during index hospitalization as primary outcome. Type 1 MI (T1MI), myocardial injury, and 30-day adverse events were considered secondary outcomes. Event adjudications were established using the hs-cTnI assay used in clinical care.

Results
In 1171 patients, MI occurred in 97 patients (8.3%), 78.3% of which were type 2 MI. The optimal rule out hs-cTnI threshold was &lt;10 ng/L, which identified 519 (44.3%) patients as low risk at presentation, with sensitivity of 99.0% (95% CI, 94.4–100) and NPV of 99.8% (95% CI, 98.9–100). For T1MI, sensitivity was 100% (95% CI, 83.9–100) and NPV 100% (95% CI, 99.3–100). Regarding myocardial injury, the sensitivity and NPV were 99.5% (95% CI, 97.9–100) and 99.8% (95% CI, 98.9–100), respectively. For 30-day adverse events, sensitivity was 96.8% (95% CI, 94.3–98.4) and NPV 97.9% (95% CI, 96.2–98.9).

Conclusions
A single hs-cTnI measurement strategy enabled the rapid identification of patients at low risk of MI and 30-day adverse events, allowing potential discharge early after ED presentation.

Clinicaltrials.gov Registration number
NCT04280926.
Papillary muscle abnormality as an electrocardiographic mimicker of apical hypertrophic cardiomyopathy: a case report
Authors: Janjua Jamal , Burdowski Joseph , Tickoo Sumit , Galin Ira 
Published: April 2023

Abstract

Background
Apical hypertrophic cardiomyopathy (ApHCM) is often associated with characteristic giant T wave inversions (GNT) in precordial leads without septal Q waves and increased QRS voltage on 12-lead electrocardiograms (ECGs). However, these electrocardiographic findings are not specific to ApHCM and can be mimicked by papillary muscle abnormalities. Differentiation between the two is important as the disease course, treatment, and prognosis differ substantially.

Case summary
We report a case report of two such patients both of which presented with abnormal ECGs concerning for ApHCM. Echocardiogram did not show characteristic findings of ApHCM. Cardiac magnetic resonance imaging (MRI) showed apically displaced, hypertrophied papillary muscles responsible for electrocardiographic abnormalities.

Discussion
Papillary muscle abnormalities including hypertrophy and/or apical displacement can result in giant negative T wave and increased QRS voltage like those seen in ApHCM and should be considered especially in otherwise healthy individuals with normal or near-normal transthoracic echocardiograms. Role of cardiac MRI is critical in this context and is the imaging modality of choice for accurate diagnosis.
Use of machine learning algorithms to predict life-threatening ventricular arrhythmia in sepsis
Authors: Li Le , Zhang Zhuxin , Zhou Likun , Zhang Zhenhao , Xiong Yulong , Hu Zhao , Yao Yan 
Published: April 2023

Abstract

Aims
Life-threatening ventricular arrhythmias (LTVAs) are common manifestations of sepsis. The majority of sepsis patients with LTVA are unresponsive to initial standard treatment and thus have a poor prognosis. There are very limited studies focusing on the early identification of patients at high risk of LTVA in sepsis to perform optimal preventive treatment interventions. We aimed to develop a prediction model to predict LTVA in sepsis using machine learning (ML) approaches.

Methods and results
Six ML algorithms including CatBoost, LightGBM, and XGBoost were employed to perform the model fitting. The least absolute shrinkage and selection operator (LASSO) regression was used to identify key features. Methods of model evaluation involved in this study included area under the receiver operating characteristic curve (AUROC), for model discrimination, calibration curve, and Brier score, for model calibration. Finally, we validated the prediction model both internally and externally. A total of 27 139 patients with sepsis were identified in this study, 1136 (4.2%) suffered from LTVA during hospitalization. We screened out 10 key features from the initial 54 variables via LASSO regression to improve the practicability of the model. CatBoost showed the best prediction performance among the six ML algorithms, with excellent discrimination (AUROC = 0.874) and calibration (Brier score = 0.157). The remarkable performance of the model was presented in the external validation cohort (n = 9492), with an AUROC of 0.836, suggesting certain generalizability of the model. Finally, a nomogram with risk classification of LTVA was shown in this study.

Conclusion
We established and validated a machine leaning-based prediction model, which was conducive to early identification of high-risk LTVA patients in sepsis, thus appropriate methods could be conducted to improve outcomes.
Comparative ecosystem modelling of dynamics and stability of subtropical estuaries under external perturbations in the Gulf of Mexico
Authors: Li C , Liu H 
Published: April 2023

Abstract
Human intervention and climate change jointly influence the functions and dynamics of marine ecosystems. Studying the impacts of human and climate on ecosystem dynamics is challenging. Unlike experimental studies, research on natural systems is not amendable at the scale of time, space, and biology. With confounding factors well balanced for two adjacent subtropical estuaries except urbanized disturbances, we conducted ecosystem modelling using indirect reasoning by exclusion to quantify the relative impacts of human disruption on estuarine ecosystems under climate variability. One major finding of this study is that the human intervention tends to magnify species fluctuations, complicate the species interaction network, and enhance species interaction strength combined with disclosed downscaling climate effects (indexed as North Atlantic Oscillation and Atlantic Multi-decadal Oscillation) on estuarine hydrology and biological communities. In addition, functional groups appeared to respond more diversely to external forcing in company with human interventions. While human perturbation was shown to destabilize the estuarine ecosystems, making them vulnerable to environmental variability under climate change, buffering effects of species diversity and trophic interaction tend to underpin the ecosystem functions. The findings of this study contribute to the holistic assessment and strategic management of estuarine ecosystems subjected to human and natural disturbances in the face of climate change.
Correlations of Values of Random Diagonal Forms
Authors: Blomer Valentin , Li Junxian 
Published: April 2023

Abstract
We study the value distribution of diagonal forms in $k$ variables and degree $d$ with random real coefficients and positive integer variables, normalized so that the mean spacing is one. We show that the $\ell $-correlation of almost all such forms is Poissonian when $k$ is large enough depending on $\ell $ and $d$.
The Power of Specialization: NGO Advocacy in Global Conservation Governance
Authors: Shibaike Takumi 
Published: April 2023

AbstractOrganizational ecology has attracted growing interest in global governance research in recent years. As a structural theory, however, organizational ecology has overlooked how organizations may shape the organizational environment by their own choices. Bridging the insights of organizational ecology and the study of nongovernmental organizations (NGOs), I argue that the organizational choice of specialism (as opposed to generalism) increases the power of NGOs to influence an environmental condition—issue salience—by targeting a small but engaged segment of the public. Focusing on wildlife conservation governance, I collected new comprehensive data on NGOs and issue characteristics (2008–2015). My empirical analysis shows that specialist NGO density is strongly associated with issue salience. I further examined causal processes in the case of pangolin conservation advocacy, in which specialist NGOs first raised issue salience and generalist NGOs followed. The findings suggest a division of labor among NGOs and challenge a conventional view that the power of NGOs is concentrated in a small number of prominent organizations.
Comprehensive Pediatric Reference Limits for High-Sensitivity Cardiac Troponin I and NT-proBNP in the CALIPER Cohort
Authors: Bohn Mary Kathryn , Adeli Khosrow 
Published: April 2023

Abstract

Background
Cardiac biomarkers have increasing application in pediatric populations, including congenital heart disease, myocarditis, and heart failure. Clinical practice is limited by evidence gaps in pediatric reference limits to inform clinical decision-making. The current study aimed to establish comprehensive pediatric reference limits for N-terminal (NT)-pro hormone brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI) in the CALIPER cohort of healthy children and adolescents.

Methods
Analytical immunoassay performance was assessed through precision, linearity, and method comparison (Abbott Alinity ci system). Subsequently, approximately 200 serum samples collected from apparently healthy children (birth to 18 years) were analyzed for hs-cTnI and NT-proBNP. Reference limits (2.5th, 97.5th, and 99th percentiles) were established as per Clinical and Laboratory Standards Institute EP-28A3c guidelines with associated 90% confidence intervals.

Results
Of all pediatric serum samples analyzed, 46% had detectable hs-cTnI concentrations (limit of detection: 1.3 ng/L). Both hs-cTnI and NT-proBNP demonstrated markedly elevated neonatal concentrations with 99th percentiles of 55.8 and 1785 ng/L, respectively. No statistically significant age-specific differences were observed beyond 1 year of age across all cardiac biomarkers examined. No sex-specific association was observed between hs-cTnI and NT-proBNP concentration and adolescence.

Conclusions
We report age-specific reference limits for hs-cTnI and NT-proBNP in a healthy Canadian cohort of children and adolescents measured using Alinity immunoassays for the first time. These data support the need for pediatric-specific interpretation to reduce misinformed clinical decision-making and calls to action larger cohort studies such that reference limits can be more robustly defined.
The Investor-State Dispute Settlement Reform Process: Design, Dilemmas and Discontents
Authors: Arato Julian , Claussen Kathleen , Langford Malcolm 
Published: April 2023

Abstract
This Special Issue takes the pulse of the UN Commission on International Trade Law process on reforming investor-state dispute settlement (ISDS) at its midway point. It features contributions by members of the Academic Forum on ISDS, engaging with various topics on the negotiating table, as well as some that are off the table or hovering in-between. Together, these articles seek to address questions of design, dilemmas and discontent – especially how states negotiate the values and tradeoffs of reform, and engage (or not) with critics of the process. They do so from the perspectives of law, social science and public policy and they employ a range of methods, including computational approaches.
Elastic integrative analysis of randomised trial and real-world data for treatment heterogeneity estimation
Authors: Yang Shu , Gao Chenyin , Zeng Donglin , Wang Xiaofei 
Published: April 2023

Abstract
We propose a test-based elastic integrative analysis of the randomised trial and real-world data to estimate treatment effect heterogeneity with a vector of known effect modifiers. When the real-world data are not subject to bias, our approach combines the trial and real-world data for efficient estimation. Utilising the trial design, we construct a test to decide whether or not to use real-world data. We characterise the asymptotic distribution of the test-based estimator under local alternatives. We provide a data-adaptive procedure to select the test threshold that promises the smallest mean square error and an elastic confidence interval with a good finite-sample coverage property.
Dynamics of direct impact accretion in degenerate binary systems
Authors: Kramarev Nikita , Yudin Andrey 
Published: April 2023

ABSTRACTWe consider the gas dynamics in an accreting binary system of degenerate stars within the framework of the Newtonian approximation. In such a system, the accretion stream can impact the surface of a white dwarf (WD) or neutron star (NS) as a result of the very compact orbit. This causes a loss of angular momentum from the orbit and spin-up of the accretor. We construct an approximation for the specific angular momentum of the accreting matter, which goes to spin up the accretor and approximations for some other parameters of the system. It is shown that the obtained approximation of the specific momentum is qualitatively different from the widely used Keplerian formula. It should affect the boundary between scenarios of immediate tidal disruption and slow mass-loss of the donor in WD–WD and NS–NS binaries, as well as the time of stable mass transfer in the stripping scenario.
Cosmological simulations of two-component wave dark matter
Authors: Huang Hsinhao , Schive Hsi-Yu , Chiueh Tzihong 
Published: April 2023

ABSTRACT
Wave (fuzzy) dark matter ($\psi \rm {DM}$) consists of ultralight bosons, featuring a solitonic core within a granular halo. Here we extend $\psi \rm {DM}$ to two components, with distinct particle masses m and coupled only through gravity, and investigate the resulting soliton–halo structure via cosmological simulations. Specifically, we assume $\psi \rm {DM}$ contains 75 per cent major component and 25 per cent minor component, fix the major-component particle mass to $m_{\rm major}=1\times 10^{-22}\, \rm eV$, and explore two different minor-component particle masses with mmajor: mminor = 3: 1 and 1: 3, respectively. For mmajor: mminor = 3: 1, we find that (i) the major- and minor-component solitons coexist, have comparable masses, and are roughly concentric. (ii) The soliton peak density is significantly lower than the single-component counterpart, leading to a smoother soliton-to-halo transition and rotation curve. (iii) The combined soliton mass of both components follows the same single-component core–halo mass relation. In dramatic contrast, for mmajor: mminor = 1: 3, a minor-component soliton cannot form with the presence of a stable major-component soliton; the total density profile, for both halo and soliton, is thus dominated by the major component and closely follows the single-component case. To support this finding, we propose a toy model illustrating that it is difficult to form a soliton in a hot environment associated with a deep gravitational potential. The work demonstrates that the extra flexibility added to the multi-component $\psi \rm {DM}$ model can resolve observational tensions over the single-component model while retaining its key features.
WDR5 is required forDUX4expression and its pathological effects in FSHD muscular dystrophy
Authors: Mocciaro Emanuele , Giambruno Roberto , Micheloni Stefano , Cernilogar Filippo M , Andolfo Annapaola , Consonni Cristina , Pannese Maria , Ferri Giulia , Runfola Valeria , Schotta Gunnar , Gabellini Davide 
Published: April 2023

AbstractFacioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent neuromuscular disorders. The disease is linked to copy number reduction and/or epigenetic alterations of the D4Z4 macrosatellite on chromosome 4q35 and associated with aberrant gain of expression of the transcription factor DUX4, which triggers a pro-apoptotic transcriptional program leading to muscle wasting. As today, no cure or therapeutic option is available to FSHD patients. Given its centrality in FSHD, blocking DUX4 expression with small molecule drugs is an attractive option. We previously showed that the long non protein-coding RNA DBE-T is required for aberrant DUX4 expression in FSHD. Using affinity purification followed by proteomics, here we identified the chromatin remodeling protein WDR5 as a novel DBE-T interactor and a key player required for the biological activity of the lncRNA. We found that WDR5 is required for the expression of DUX4 and its targets in primary FSHD muscle cells. Moreover, targeting WDR5 rescues both cell viability and myogenic differentiation of FSHD patient cells. Notably, comparable results were obtained by pharmacological inhibition of WDR5. Importantly, WDR5 targeting was safe to healthy donor muscle cells. Our results support a pivotal role of WDR5 in the activation of DUX4 expression identifying a druggable target for an innovative therapeutic approach for FSHD.
Piecing together the puzzle of emotional consciousness
Authors: Engelen Tahnée , Mennella Rocco 
Published: April 2023

AbstractThe search for neural correlates of emotional consciousness has gained momentum in the last decades. Nonetheless, disagreements concerning the mechanisms that determine the experiential qualities of emotional consciousness—the “what is it like” to feel an emotion—as well as on their neural correlates have far-reaching consequences on how researchers study and measure emotion, sometimes leading to seemingly irresolvable impasses. The current paper lays out in a balanced way the viewpoint of both cognitive and precognitive approaches to emotional consciousness on the basis of commonalities and differences between the claims of some relevant theories of emotions. We examine the sufficiency of the existing evidence in support of the proposed theories of emotional consciousness by going through the methodological specificity of the study of emotional consciousness and its unique challenges and highlighting what can and cannot be imported by advances in research on perceptual consciousness. We propose that there are three key experimental contrasts that are each equally necessary in the search for the neural correlates of emotional consciousness and each contrast alone coming with its own limitations. We conclude by acknowledging some of the most promising avenues in the field, which may help go beyond the current limitations and collaboratively piece together the puzzle of emotional consciousness.
Ka-band cryogenic low-noise receiver of the Misasa 54 m antenna for deep-space communications and radio astronomy
Authors: Tsuboi Masato , Hasegawa Yutaka , Tabuchi Go , Murata Yasuhiro , Yuchi Koji , Toda Tomoaki , Uchimura Takashi , Kimura Kimihiro , Kasuga Takashi 
Published: April 2023

Abstract
We built a Ka-band dual-circular-polarization low-noise receiver for the Misasa 54 m parabola antenna in Misasa, Japan. The antenna is designed to be combined with a transmitter and receiver system at the X band (around 8 GHz) and simultaneously with a receiver system at the Ka band. The Ka band is the frequency band around 30 GHz, which is important for deep-space communications and radio astronomy. The receiver comprises some waveguide components including a feed horn, a circular polarizer, and low-noise amplifiers. The components are installed in a vacuum vessel and are cooled to 4 K with a Gifford–McMahon refrigerator, providing low-noise performance. The receiver is capable of simultaneously handling the left- and right-hand circular-polarization (LHCP and RHCP) channels. The receiver-noise temperature was measured to be TRX ≃ 14 K in both the LHCP and RHCP channels. The system-noise temperature, including the antenna loss and atmospheric attenuation at the zenith, was measured to be Tsys = 36–37 K in both the LHCP and RHCP channels on a clear day in September at Misasa. When the receiver is used with the X-band transmitter, the system-noise temperature is maintained at Tsys ≃ 42 K in the RHCP channel. The degradation in the system-noise temperature is attributed to a frequency-selective reflector, which divides the signals in the X and Ka bands. There is no contamination from the transmitter to damage the receiver. The receiver has already been in use for deep-space communications and radio-astronomy observations. Our team in the radio-astronomy laboratory of ISAS/JAXA is responsible for the development of the receiver and the measurements of its performance.
Cryoelectron microscopic structure of the nucleoprotein–RNA complex of the European filovirus, Lloviu virus
Authors: Hu Shangfan , Fujita-Fujiharu Yoko , Sugita Yukihiko , Wendt Lisa , Muramoto Yukiko , Nakano Masahiro , Hoenen Thomas , Noda Takeshi 
Published: April 2023

Abstract
Lloviu virus (LLOV) is a novel filovirus detected in Schreiber's bats in Europe. The isolation of the infectious LLOV from bats has raised public health concerns. However, the virological and molecular characteristics of LLOV remain largely unknown. The nucleoprotein (NP) of LLOV encapsidates the viral genomic RNA to form a helical NP-RNA complex, which acts as a scaffold for nucleocapsid formation and de novo viral RNA synthesis. In this study, using single-particle cryoelectron microscopy, we determined two structures of the LLOV NP–RNA helical complex, comprising a full-length and a C-terminally truncated NP. The two helical structures were identical, demonstrating that the N-terminal region determines the helical arrangement of the NP. The LLOV NP–RNA protomers displayed a structure similar to that in the Ebola and Marburg virus, but the spatial arrangements in the helix differed. Structure-based mutational analysis identified amino acids involved in the helical assembly and viral RNA synthesis. These structures advance our understanding of the filovirus nucleocapsid formation and provide a structural basis for the development of antifiloviral therapeutics.