bluuebunny/crossref_metadata_2025_split huggingface dataset:
6 PBPK model-informed dosing guidelines in pediatric clinical care – initiation and drug prioritization
Authors: Freriksen Jolien , de Hoop-Sommen Marika , van der Heijden Joyce , Greupink Rick , de Wildt Saskia 
Published: May 2023

IntroductionWith approximately 50% of the drugs being prescribed off-label, the pediatric population is in need for an innovative approach to establish harmonized, best evidence-based dosing guidelines. Physiologically-based pharmacokinetic (PBPK) modelling is a valuable approach to predict drug pharmacokinetics (PK) and to support dosing. As a first step to implement PBPK-informed dosing in pediatric clinical care, we aimed to identify drugs suitable to verify the PBPK approach and prioritize drugs in need of model-informed dosing.MethodsTo select a drug, it required to be listed on: 1. the Model List of Essential Medicines for Children (EMLc) of the WHO and on 2. the Dutch Pediatric Formulary (DPF). Also, a Simcyp® PBPK compound model had to be available. The level of evidence of the dosing recommendations in the DPF, the availability of pediatric pharmacokinetic data, and the opinion of clinicians on the relevance of the drug were reviewed for further prioritization.ResultsOf all drugs on the EMLc, 199 are listed in the DPF. For 76 of them, a Simcyp® compound model is available, either directly in the software, its repository, or from scientific literature. Eleven drugs have sufficient PK data to verify the PBPK modeling approach. For 48 drugs, we identify a moderate to high priority for a model-informed dose.ConclusionsThis work now provides input for the next steps which include verification of PBPK model performance in pediatrics and subsequent PBPK modelling to establish dosing guidelines. A joint effort and an internationally accessible platform are needed to share information on pediatric PBPK modelling to eventually implement model-informed doses in clinical practice.This abstract is based on research funded by the Bill & Melinda Gates Foundation
Women and non-white people among Lasker Award recipients from 1946 to 2022: cross sectional study
Authors: Jacobs Jeremy W , Bibb Lorin A , Allen Elizabeth S , Ward Dawn C , Booth Garrett S , Silver Julie K , Adkins Brian D 
Published: May 2023

Abstract

Objective
To determine whether gender and racial inequities exist among Lasker Award recipients.

Design
Observational, cross sectional analysis.

Setting
Population based study.

Participants
Recipients of four Lasker Awards from 1946 to 2022.

Main outcome measures

Gender and race (non-white categorized as racialized
v
white categorized as non-racialized) of all Lasker Award recipients. Personal characteristics of award recipients were categorized by four independent authors using previously established methods and consistency of categorization among authors was analyzed. Women and non-white people were thought to be underrepresented among Lasker Award recipients compared with professional degree recipients overall.

Results

Among 397 Lasker Award recipients since 1946, 92.2% (366/397) were men. Most award recipients were identified as white (95.7%, 380/397). One non-white woman was identified as having received a Lasker Award over the course of seven decades. The proportion of women among award recipients in the most recent decade (2013-22) is similar to the first decade of awards (1946-55; 15.6%, 7/45
v
12.9%, 8/62). The median timeframe from terminal degree receipt to Lasker Award conferral for all award recipients is 30 years. The proportion of women who received a Lasker Award between 2019 and 2022 (7.1%) was less than would be expected based on the proportion of life science doctorates awarded to women

in 1989 (30 years previously; 38.1%).

Conclusions
The number of women and non-white people in academic medicine and biomedical research continues to increase, yet the proportion of women among Lasker Award recipients has not changed in more than 70 years. Additionally, time from terminal degree receipt to Lasker Award conferral does not appear to fully account for the observed inequities. These findings establish the need for further investigation of possible factors that could hinder women and non-white people from entering the pool of eligible award recipients, potentially limiting the diversification of the science and academic biomedical workforce.
Evaluation of emergency care education and triage implementation: an observational study at a hospital in rural Liberia
Authors: Towns Kathleen , Dolo Isaac , Pickering Ashley E , Ludmer Nicholas , Karanja Viola , Marsh Regan H , Horace Minnie , Dweh Denny , Dalieh Tresa , Myers Sharon , Bukhman Alice , Gashi Jason , Sonenthal Paul , Ulysse Patrick , Cook Rebecca , Rouhani Shada A 
Published: May 2023

IntroductionIn Liberia, emergency care is still in its early development. In 2019, two emergency care and triage education sessions were done at J. J. Dossen Hospital in Southeastern Liberia. The observational study objectives evaluated key process outcomes before and after the educational interventions.MethodsEmergency department paper records from 1 February 2019 to 31 December 2019 were retrospectively reviewed. Simple descriptive statistics were used to describe patient demographics and χ2analyses were used to test for significance. ORs were calculated for key predetermined process measures.ResultsThere were 8222 patient visits recorded that were included in our analysis. Patients in the post-intervention 1 group had higher odds of having a documented full set of vital signs compared with the baseline group (16% vs 3.5%, OR: 5.4 (95% CI: 4.3 to 6.7)). After triage implementation, patients who were triaged were 16 times more likely to have a full set of vitals compared with those who were not triaged. Similarly, compared with the baseline group, patients in the post-intervention 1 group had higher odds of having a glucose documented if they presented with altered mental status or a neurologic complaint (37% vs 30%, OR: 1.7 (95% CI: 1.3 to 2.2)), documented antibiotic administration if they had a presumed bacterial infection (87% vs 35%, OR: 12.8 (95% CI: 8.8 to 17.1)), documented malaria test if presenting with fever (76% vs 61%, OR: 2.05 (95% CI: 1.37 to 3.08)) or documented repeat set of vitals if presenting with shock (25% vs 6.6%, OR: 8.85 (95% CI: 1.67 to 14.06)). There was no significant difference in the above process outcomes between the education interventions.ConclusionThis study showed improvement in most process measures between the baseline and post-intervention 1 groups, benefits that persisted post-intervention 2, thus supporting the importance of short-course education interventions to durably improve facility-based care.
Balloon Angioplasty for Symptomatic Intracranial Artery Stenosis (BASIS): protocol of a prospective, multicentre, randomised, controlled trial
Authors: Sun Xuan , Yang Ming , Sun Dapeng , Peng Guangge , Deng Yiming , Zhao Xingquan , Liu Liping , Ma Ning , Gao Feng , Mo Dapeng , Yu Wengui , Wang Yongjun , Wang Yilong , Miao Zhongrong 
Published: May 2023

BackgroundThe superiority of balloon angioplasty plus aggressive medical management (AMM) to AMM alone for symptomatic intracranial artery stenosis (sICAS) on efficacy and safety profiles still lacks evidence from randomised controlled trials (RCTs).AimTo demonstrate the design of an RCT on balloon angioplasty plus AMM for sICAS.DesignBalloon Angioplasty for Symptomatic Intracranial Artery Stenosis (BASIS) trial is a multicentre, prospective, randomised, open-label, blinded end-point trial to investigate whether balloon angioplasty plus AMM could improve clinical outcome compared with AMM alone in patients with sICAS. Patients eligible in BASIS were 35–80 years old, with a recent transient ischaemic attack within the past 90 days or ischaemic stroke between 14 days and 90 days prior to enrolment due to severe atherosclerotic stenosis (70%–99%) of a major intracranial artery. The eligible patients were randomly assigned to receive balloon angioplasty plus AMM or AMM alone at a 1:1 ratio. Both groups will receive identical AMM, including standard dual antiplatelet therapy for 90 days followed by long-term single antiplatelet therapy, intensive risk factor management and life-style modification. All participants will be followed up for 3 years.Study outcomesStroke or death in the next 30 days after enrolment or after balloon angioplasty procedure of the qualifying lesion during follow-up, or any ischaemic stroke or revascularisation from the qualifying artery after 30 days but before 12 months of enrolment, is the primary outcome.DiscussionBASIS trail is the first RCT to compare the efficacy and safety of balloon angioplasty plus AMM to AMM alone in sICAS patients, which may provide an alternative perspective for treating sICAS.Trial registration numberNCT03703635;https://www.clinicaltrials.gov.
The S- and P-wave fully charmed tetraquark states and their radial excitations
Authors: Yu Guo-Liang , Li Zhen-Yu , Wang Zhi-Gang , Jie Lu , Meng Yan 
Published: May 2023

AbstractInspired by recent progresses in observations of the fully charmed tetraquark states by LHCb, CMS, and ATLAS collaborations, we perform a systematic study of the ground states and the first radial excitations of the S- and P-wave $$\textrm{cc}\bar{\textrm{c}}\bar{\textrm{c}}$$

cc

c

¯

c

¯

system. Their mass spectra, root mean square (r.m.s.) radii and radial density distributions are studied with the relativized quark model. The calculations show that there is no stable bound states for the fully charmed tetraquark states, and the r.m.s. radii of these tetraquark states are smaller than 1 fm. Our results support assigning X(6600) structure, M$$_{X(6600)}=6552\pm 10\pm 12$$

X
(
6600
)

=
6552
±
10
±
12

MeV, as one of the $$0^{++}$$

0

+
+

(1S) and $$2^{++}$$

2

+
+

(1S) states or their mixtures. Another structure also named as X(6600) by CMS Collaboration, M$$_{X(6600)}=6.62\pm 0.03^{+0.02}_{-0.01}$$

X
(
6600
)

=
6.62
±
0
.

03

-
0.01

+
0.02

GeV, may arise from the lowest 1P states with $$J^{PC}=0^{-+}$$

J

PC

=

0

-
+

, $$1^{-+}$$

1

-
+

, and $$2^{-+}$$

2

-
+

. The possible assignments for X(6900) include the $$0^{++}$$

0

+
+

(2S), $$2^{++}$$

2

+
+

(2S) states, and the highest 1P state with $$J^{PC}=0^{-+}$$

J

PC

=

0

-
+

. As for X(7200), it can be interpreted as one of the highest 2P states with $$J^{PC}=0^{-+}$$

J

PC

=

0

-
+

, $$1^{-+}$$

1

-
+

, and $$2^{-+}$$

2

-
+

, and the 3S states can not be completely excluded from the candidates.
Model-independent analysis of $$\varvec{b \rightarrow d}$$ processes
Authors: Bause Rigo , Gisbert Hector , Golz Marcel , Hiller Gudrun 
Published: May 2023

AbstractWe perform a model-independent analysis of $$|\Delta b|=|\Delta d|=1$$

|
Δ
b
|
=
|
Δ
d
|
=
1

processes to test the standard model and probe flavor patterns of new physics. Constraints on Wilson coefficients are obtained from global fits to $$B^+ \rightarrow \pi ^+ \,\mu ^+\mu ^-$$

B
+

→

π
+

μ
+

μ
-

, $$B^0_s\rightarrow \bar{K}^{*0}\, \mu ^+\mu ^-$$

B
s
0

→

K

¯

∗
0

μ
+

μ
-

, $$B^0\rightarrow \mu ^+\mu ^-$$

B
0

→

μ
+

μ
-

, and radiative $$B \rightarrow X_d \,\gamma $$

B
→

X
d

γ

decays data. The fits are consistent with the standard model but leave sizable room for new physics. Besides higher-statistics measurements and more data in theory-friendly bins of the dilepton mass, further complementary observables such as angular distributions of $$B_s^0 \rightarrow \bar{K}^{*0}\,\ell ^+ \ell ^-$$

B
s
0

→

K

¯

∗
0

ℓ
+

ℓ
-

, $$B \rightarrow \rho \,\ell ^+ \ell ^-$$

B
→
ρ

ℓ
+

ℓ
-

or the baryonic modes $$\Xi _b \rightarrow \Sigma \,\ell ^+ \ell ^-$$

Ξ
b

→
Σ

ℓ
+

ℓ
-

, $$\Omega _b^- \rightarrow \Xi ^- \, \ell ^+ \ell ^-$$

Ω
b
-

→

Ξ
-

ℓ
+

ℓ
-

are necessary to resolve the significant degeneracy in the fit for the semileptonic four-fermion operators. Assuming minimal quark flavor violation, the $$b \rightarrow s$$

b
→
s

global fit implies tight constraints on the $$b \rightarrow d$$

b
→
d

couplings, and hence allows to test this paradigm with improved data. Another benefit from $$|\Delta b|=|\Delta d|=1$$

|
Δ
b
|
=
|
Δ
d
|
=
1

processes is to shed light on the B-anomalies in $$|\Delta b|=|\Delta s|=1$$

|
Δ
b
|
=
|
Δ
s
|
=
1

modes from a new angle. Specifically, studies of lepton flavor-specific and dineutrino modes are informative on the lepton flavor structure. Rare $$b \rightarrow d \, \ell \ell , \nu \bar{\nu }$$

b
→
d

ℓ
ℓ
,
ν

ν

¯

decays can be studied at high luminosity flavor facilities LHCb, Belle II, and a future Z-factory.
Nonlinear Weighting Ensemble Learning Model to Diagnose Parkinson’s Disease Using Multimodal Data
Authors: Castillo-Barnes D. , Martinez-Murcia F. J. , Jimenez-Mesa C. , Arco J. E. , Salas-Gonzalez D. , Ramírez J. , Górriz J. M. 
Published: May 2023

Parkinson’s Disease (PD) is the second most prevalent neurodegenerative disorder among adults. Although its triggers are still not clear, they may be due to a combination of different types of biomarkers measured through medical imaging, metabolomics, proteomics or genetics, among others. In this context, we have proposed a Computer-Aided Diagnosis (CAD) system that combines structural and functional imaging data from subjects in Parkinson’s Progression Markers Initiative dataset by means of an Ensemble Learning methodology trained to identify and penalize input sources with low classification rates and/ or high-variability. This proposal improves results published in recent years and provides an accurate solution not only from the point of view of image preprocessing (including a comparison between different intensity preservation techniques), but also in terms of dimensionality reduction methods (Isomap). In addition, we have also introduced a bagging classification schema for scenarios with unbalanced data. As shown by our results, the CAD proposal is able to detect PD with [Formula: see text] of balanced accuracy, and opens up the possibility of combining any number of input data sources relevant for PD.
Quantum invariants of links and 3-manifolds with boundary defined via virtual links
Authors: Kauffman Louis H. , Ogasa Eiji 
Published: May 2023

We introduce new topological quantum invariants, surface link quantum invariants, of compact oriented 3-manifolds with boundary where the boundary is a disjoint union of two identical surfaces. The invariants are constructed by using virtual knots and links. These invariants are new, nontrivial, and calculable examples of quantum invariants of 3-manifolds with non-vacuous boundary. Our new invariants, surface link quantum invariants, give new invariants of classical knots and links, i.e., knots and links in the 3-sphere. That is, virtual knot theory induces a new, classical knot invariant.
Reconsidering Electroluminescence Cooling of a Heated Diode
Authors: Kirk Alexander P. 
Published: May 2023

Electroluminescence cooling of a heated infrared-emitting diode has been claimed [P. Santhanam, D. J. Gray, Jr. and R. J. Ram, Thermoelectrically pumped light-emitting diodes operating above unity efficiency, Phys. Rev. Lett. 108 (2012) 097403]. After analyzing the operating characteristics of this diode, it is evident that electroluminescence cooling was not demonstrated.
The Prognostic Value and Potential Mechanism of Tumor-Nutrition-Inflammation Index and Genes in Patients with Advanced Lung Cancer
Authors: Wang Huan , Shi Yuting , Shi Yueli , Cao Mengqing , Zhang Long , Wu Yuan , Xu Yun , Wang Kai , Weng Xianwu 
Published: May 2023

Background. Lung cancer (LC) has the highest mortality rate all over the world. It is necessary to search for novel potential biomarkers that are easily accessible and inexpensive in identifying patients with LC at early stage. Methods. A total of 195 patients with advanced LC who have received first-line chemotherapy were involved in this study. The optimized cut-off values of AGR and SIRI (AGR = albumin/globulin; SIRI = neutrophil

∗

monocyte/lymphocyte) were determined by survival function analysis based on R software. COX regression analysis was performed to obtain the independent factors for establishing the nomogram model. A nomogram model comprising these independent prognostic parameters was built for the TNI (tumor-nutrition-inflammation index) score calculation. The predictive accuracy was demonstrated through ROC curve and calibration curves after index concordance. Results. The optimized cut-off values of AGR and SIRI were 1.22 and 1.60, respectively. It was revealed that liver metastasis, SCC, AGR, and SIRI were independent prognostic factors in advanced lung cancer by Cox analysis. Afterwards, the nomogram model comprised of these independent prognostic parameters was built for TNI scores calculation. Based on the TNI quartile values, patients were divided into four groups. And it was indicated that higher TNI had worse OS (

P
<
0.05

) via Kaplan–Meier analysis and log-rank test. Moreover, the C-index and 1-year AUC area were 0.756 (0.723–0.788) and 75.62, respectively. There was high consistency shown in the calibration curves between predicted and actual survival proportions in the TNI model. In addition, tumor-nutrition-inflammation index and genes play an important role in LC development that might affect some pathways related to tumor development including cell cycle, homologous recombination, and P53 signaling pathway from a molecular level. Conclusion. TNI might be an analytical tool which was practical and precise for survival prediction of patients with advanced LC. Tumor-nutrition-inflammation index and genes play an important role in LC development. A preprint has previously been published [1].
HLA Class II Loss and JAK1/2 Deficiency Coevolve in Melanoma Leading to CD4 T-cell and IFNγ Cross-Resistance
Authors: Stupia Simone , Heeke Christina , Brüggemann Alicia , Zaremba Anne , Thier Beatrice , Kretz Julia , Sucker Antje , Philip Manuel , Zelinskyy Gennadiy , Ferrone Soldano , Roesch Alexander , Horn Susanne , Hadaschik Eva , Schadendorf Dirk , Trilling Mirko , Dittmer Ulf , Griewank Klaus , Zhao Fang , Paschen Annette 
Published: May 2023

Abstract

Purpose:
Recent studies have demonstrated HLA class II (HLA-II)–dependent killing of melanoma cells by cytotoxic CD4 T cells. We investigated evolution of HLA-II–loss tumors that escape cytotoxic CD4 T-cell activity and contribute to immunotherapy resistance.

Experimental Design:
Melanoma cells from longitudinal metastases were studied for constitutive and IFN-inducible HLA-II expression, sensitivity towards autologous CD4 T cells, and immune evasion by HLA-II loss. Clinical significance of HLA-II–low tumors was determined by analysis of transcriptomic data sets from patients with immune checkpoint blockade (ICB).

Results:
Analysis of longitudinal samples revealed strong intermetastatic heterogeneity in melanoma cell–intrinsic HLA-II expression and subclonal HLA-II loss. Tumor cells from early lesions either constitutively expressed HLA-II, sensitizing to cytotoxic CD4 T cells, or induced HLA-II and gained CD4 T-cell sensitivity in the presence of IFNγ. In contrast, late outgrowing subclones displayed a stable CD4 T-cell–resistant HLA-II–loss phenotype. These cells lacked not only constitutive but also IFNγ-inducible HLA-II due to JAK1/2-STAT1 pathway inactivation. Coevolution of JAK1/2 deficiency and HLA-II loss established melanoma cross-resistance to IFNγ and CD4 T cells, as detected in distinct stage IV metastases. In line with their immune-evasive phenotype, HLA-II–low melanomas showed reduced CD4 T-cell infiltrates and correlated with disease progression under ICB.

Conclusions:
Our study links melanoma resistance to CD4 T cells, IFNγ, and ICB at the level of HLA-II, highlighting the significance of tumor cell–intrinsic HLA-II antigen presentation in disease control and calling for strategies to overcome its downregulation for improvement of patient outcome.
ROR2/PCP a New Pathway Controlling Endothelial Cell Polarity Under Flow Conditions
Authors: Bougaran Pauline , Bats Marie Lise , Delobel Valentin , Rubin Sébastien , Vaurs Juliette , Couffinhal Thierry , Duplàa Cécile , Dufourcq Pascale 
Published: May 2023

Background:
Endothelial cells (ECs) are sensitive to physical forces created by blood flow, especially to laminar shear stress. Among the cell responses to laminar flow, EC polarization against the flow direction emerges as a key event, particularly during the development and remodeling of the vascular network. EC adopt an elongated planar cell shape with an asymmetrical distribution of intracellular organelles along the axis of blood flow. This study aimed to investigate the involvement of planar cell polarity via the receptor ROR2 (receptor tyrosine kinase-like orphan receptor 2) in endothelial responses to laminar shear stress.

Methods:

We generated a genetic mouse model with EC-specific deletion of
Ror2
, in combination with in vitro approaches involving loss- and gain-of-function experiments.

Results:

During the first 2 weeks of life, the endothelium of the mouse aorta undergoes a rapid remodeling associated with a loss of EC polarization against the flow direction. Notably, we found a correlation between ROR2 expression and endothelial polarization levels. Our findings demonstrate that deletion of
Ror2
in murine ECs impaired their polarization during the postnatal development of the aorta. In vitro experiments further validated the essential role of ROR2 in both EC collective polarization and directed migration under laminar flow conditions. Exposure to laminar shear stress triggered the relocalization of ROR2 to cell-cell junctions where it formed a complex with VE-Cadherin and β-catenin, thereby regulating adherens junctions remodeling at the rear and front poles of ECs. Finally, we showed that adherens junctions remodeling and cell polarity induced by ROR2 were dependent on the activation of the small GTPase Cdc42.

Conclusions:
This study identified ROR2/planar cell polarity pathway as a new mechanism controlling and coordinating collective polarity patterns of EC during shear stress response.