bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysregulated carbohydrate and lipid metabolism and risk of atrial fibrillation in advanced old age
Authors: Pellegrini Cara N , Buzkova Petra , Oesterle Adam , Heckbert Susan R , Tracy Russell P , Siscovick David S , Mukamal Kenneth J , Djoussé Luc , Kizer Jorge R 
Published: December 2022

ObjectiveObesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Fasting and postload levels of glucose and non-esterified fatty acids (NEFAs) reflect different facets of metabolic regulation. We sought to study their respective contributions to AF risk concurrently.MethodsWe assessed levels of fasting and postload glucose and NEFA in the Cardiovascular Health Study to identify associations with AF incidence and, secondarily, with ECG parameters of AF risk available at baseline. Linear and Cox regressions were performed.ResultsThe study included 1876 participants (age 77.7±4.4). During the median follow-up of 11.4 years, 717 cases of incident AF occurred. After adjustment for potential confounders, postload glucose showed an association with incident AF (HR per SD increment of postload glucose=1.11, 95% CI 1.02 to 1.21, p=0.017). Both glucose measures, but not NEFA, were positively associated with higher P wave terminal force in V1 (PTFV1); the association remained significant only for postload glucose when the two measures were entered together (β per SD increment=138 μV·ms, 95% CI 15 to 260, p=0.028). Exploratory analyses showed significant interaction by sex for fasting NEFA (pinteraction=0.044) and postload glucose (pinteraction=0.015) relative to AF, with relationships stronger in women. For postload glucose, the association with incident AF was observed among women but not among men.ConclusionsAmong older adults, postload glucose was positively associated with incident AF, with consistent findings for PTFV1. In exploratory analyses, the relationship with AF appeared specific to women. These findings require further study but suggest that interventions to address postprandial dysglycaemia late in life might reduce AF.
TIGIT blockade repolarizes AML-associated TIGIT+M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis
Authors: Brauneck Franziska , Fischer Brit , Witt Marius , Muschhammer Jana , Oelrich Jennyfer , da Costa Avelar Pedro Henrique , Tsoka Sophia , Bullinger Lars , Seubert Elisa , Smit Daniel J , Bokemeyer Carsten , Ackermann Christin , Wellbrock Jasmin , Haag Friedrich , Fiedler Walter 
Published: December 2022

BackgroundLeukemia-associated macrophages (LAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype, function, and plasticity of these cells. The present study provides an extensive characterization of macrophages in patients with acute myeloid leukemia (AML).MethodsThe phenotype and expression of coregulatory markers were assessed on bone marrow (BM)-derived LAM populations, using multiparametric flow cytometry. BM and blood aspirates were obtained from patients with newly diagnosed acute myeloid leukemia (pAML, n=59), patients in long-term remission (lrAML, n=8), patients with relapsed acute myeloid leukemia (rAML, n=7) and monocyte-derived macrophages of the blood from healthy donors (HD, n=17). LAM subpopulations were correlated with clinical parameters. Using a blocking anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) antibody or mouse IgG2α isotype control, we investigated polarization, secretion of cytokines, and phagocytosis on LAMs and healthy monocyte-derived macrophages in vitro.ResultsIn pAML and rAML, M1 LAMs were reduced and the predominant macrophage population consisted of immunosuppressive M2 LAMs defined by expression of CD163, CD204, CD206, and CD86. M2 LAMs in active AML highly expressed inhibitory receptors such as TIGIT, T-cell immunoglobulin and mucin-domain containing-3 protein (TIM-3), and lymphocyte-activation gene 3 (LAG-3). High expression of CD163 was associated with a poor overall survival (OS). In addition, increased frequencies of TIGIT+M2 LAMs were associated with an intermediate or adverse risk according to the European Leukemia Network criteria and the FLT3 ITD mutation. In vitro blockade of TIGIT shifted the polarization of primary LAMs or peripheral blood-derived M2 macrophages toward the M1 phenotype and increased secretion of M1-associated cytokines and chemokines. Moreover, the blockade of TIGIT augmented the anti-CD47-mediated phagocytosis of AML cell lines and primary AML cells.ConclusionOur findings suggest that immunosuppressive TIGIT+M2 LAMs can be redirected into an efficient effector population that may be of direct clinical relevance in the near future.
Treat-to-target in rheumatoid arthritis: a real-world study of the application and impact of treat-to-target within the wider context of patient management, patient centricity and advanced therapy use in Europe
Authors: Taylor Peter C. , Fautrel Bruno , Piette Yves , Romero-Yuste Susana , Broen Jasper , Welcker Martin , Howell Oliver , Rottier Elke , Zignani Monia , Van Beneden Katrien , Caporali Roberto , Alten Rieke 
Published: December 2022

BackgroundWhile treat-to-target (T2T) is endorsed for the management of rheumatoid arthritis (RA), data on the degree of implementation in clinical practice are limited. This study investigated the use of T2T for RA in a real-world setting across Europe.MethodsThe Adelphi RA Disease-Specific Programme was a point-in-time survey of rheumatologists and their consulting patients with RA conducted between January and October 2020 in Belgium, France, Germany, Italy, Spain and the UK. Rheumatologists completed an attitudinal survey, and a record form for their next 10–12 consulting patients, who were invited to voluntarily complete a patient-reported questionnaire. Data collected included clinical characteristics, treatment patterns and attitudes towards T2T.ResultsOverall, 316 rheumatologists provided data for 3120 patients, of whom 1108 completed the questionnaire. While 86.1% of rheumatologists estimated using T2T principles in clinical practice, only 66.6% of patients were reported by their physician to be managed using a T2T approach. Achieving disease remission was the most commonly reported treatment goal identified by rheumatologists (79.7%), followed by symptom control (47.8%) and reducing impact on quality of life (44.5%). 40.8% of rheumatologists and their patients were in agreement that a treatment goal had been set. When there was agreement on treatment goals, we observed better patient satisfaction, engagement and treatment success.ConclusionsDespite recommendations, the T2T approach in RA appears to be suboptimally implemented in clinical practice. This highlights the importance of patient-centricity in the decision-making process to define meaningful targets and select appropriate treatments to improve disease outcomes.
A Geometrically Exact Beam Finite Element for Non-Prismatic Strip Beams: Linearized Lateral-Torsional Stability
Authors: Gonçalves Rodrigo 
Published: December 2022

This paper presents a new geometrically exact beam finite element able to perform, accurately and efficiently, linear stability analyses of curved and tapered elastic strip beams (beams with thin rectangular cross-section) susceptible to lateral-torsional bucking. This element constitutes a non-trivial extension, to the spatial (3D) case, of that previously reported by the author for the in-plane (2D) case in Gonçalves [R. Gonçalves, A geometrically exact beam finite element for non-prismatic strip beams: The 2D case, Int. J. Struct. Stab. Dyn. (2022) 2350037]. To allow capturing accurately torsion effects, a torsion-related warping function is derived and included as an additional cross-section degree-of-freedom (DOF). Since the element is developed using a geometrically exact framework, complex effects such as load height and out-of-plane flexural-torsional effects are straightforwardly included. For implementation purposes, all fundamental expressions are provided in simple vector/matrix forms. A set of numerical examples is presented and discussed, to show that the proposed element provides very accurate solutions with a small DOF number, even for heavily curved and tapered members.
Anemia, Thrombocytopenia, and Changes in Biochemical Parameters Occurring in Patients with Uncomplicated Plasmodium falciparum Malaria: Data Analysis from Antimalarial Efficacy-Randomized Trials in Dakar and Kaolack Regions, Senegal
Authors: Sylla Khadime , Tine Roger , Sow Doudou , Lelo Souleye , Abiola Annie , NDiaye Jean Louis , NDiaye Magatte , Folly Kuaku , NDiaye Léon Amath , Gaye Oumar , Faye Babacar 
Published: December 2022

Background. Artemisinin-based Combination Therapies (ACTs) are widely used in the treatment of uncomplicated malaria. Plasmodium falciparum infection is often accompanied by disturbances of hematological and biochemical parameters. The objective of this study was to evaluate the changes in biochemical and hematological parameters during uncomplicated malaria in patients treated with ACTs. Methods. Data from patient with uncomplicated Plasmodium falciparum malaria were pooled from different open-randomized trial evaluating the efficacy of Artesunate-Mefloquine (ASMQ), Artesunate-Amodiaquine (ASAQ), Artemether-Lumefantrine (AL), and Dihydro-artemisinin-Piperaquine (DHAPQ) combinations. Biochemical (transaminases, creatinine, and bilirubin) and hematological (hemoglobin and platelet levels) parameters were performed at baseline (D0) and at day 7 after treatment (D7). Data were analyzed as both continuous and categorical variables with 95% confidence interval. Risks and trends were calculated using multivariate logistic random effect models. Results. A total of 720 patients with completed biological data were included in the analysis (320 in the AL arm, 160 in the ASMQ arm, 120 in the DHAPQ arm, and 88 in the ASAQ arm). The mean age of the patients was

9.43
±
9.1

years. Male subjects represented 58.47% (sex ratio was 1.4 for males). The mean hemoglobin level at inclusion (D0) was 9.79 g/dl and anemia (

Hb
<
11

g
/
dl

) was 71.43% (

aOR
=
1.16

0.68
−
1.98

p
=
0.57

). At D7, hemoglobin level was 9.63 g/dl and anemia was significantly more frequent (78.29% [

p
=
0.002

]). The mean platelet count at day 0 was 154075.5 platelets/mm3 of blood and 339328.7 platelets/mm3 at day 7. Thrombocytopenia was about 53.61% and was associated with malaria (

aOR
=
3.4

2.18
−
5.3

p
<

10

−
3

). 19.58% of patients had abnormal ALT and 40.28% had abnormal AST at D0. 27.22% of patients had normal bilirubin at D0. Renal function was normal in all patients in the study. Normalization of transaminases was noted between D0 and D7. The percentage of subjects with normal bilirubin increased between D0 and D7. Renal function did not vary significantly between D0 and D7. Conclusion. Results from this analysis showed that subjects with high parasitaemia had a greater risk of anemia and thrombocytopenia. Artemisinin combinations were well-tolerated as no major biological disturbances were noted. The effects of ACTs on hematologic and biochemical parameters were not different.
Eradication of Heterogeneous Tumors by T Cells Targeted with Combination Bispecific Chemically Self-assembled Nanorings
Authors: Petersburg Jacob , Vallera Daniel A. , Wagner Carston R. 
Published: December 2022

AbstractCancer stem-like cells (CSCs) are often the root cause of refractive relapse due to their inherent resistance to most therapies and ability to rapidly self-propagate. Recently, the antigen CD133 has been identified as a CSC marker on several cancer types and αCD133 therapies have shown selective targeting against CSCs with minimal off-target toxicity. Theoretically, by selectively eliminating CSCs, the sensitivity to bulk tumor-targeting therapies should be enhanced. Previously, our laboratory has developed bispecific chemically self-assembled nanorings (CSANs) that successfully induced T-cell eradication of EpCAM-positive (EpCAM+) tumors. We reasoned that targeting both CSCs [CD133-positive (CD133+)] and the bulk tumor (EpCAM+) simultaneously using our CSAN platform should produce a synergistic effect. We evaluated αCD133/αCD3 CSANs as both a single agent and in combination with αEpCAM/αCD3 CSANs to treat triple-negative breast cancer (TNBC) cells, which express a subpopulation of CD133+ cancer stem cells and EpCAM+ bulk tumor cells. Furthermore, an orthotopic breast cancer model validated the ability of αCD133 and αEpCAM targeting to combine synergistically in the elimination of TNBC MDA-MB-231 cells. Complete tumor eradication only occurred when EpCAM and CD133 were targeted simultaneously and lead to full remission in 80% of the test mice. Importantly, the depletion and enrichment of CD133 TNBCs highlighted the role of CD133+ cancer cells in regulating tumor growth and progression. Collectively, our results demonstrate that dual targeting with bispecific CSANs can be effective against heterogenous tumor cell populations and that elimination of primary and CD133+ CSCs may be necessary for eradication of at least a subset of TNBC.
Inclusion of 4-1BB Costimulation Enhances Selectivity and Functionality of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells
Authors: Starr Renate , Aguilar Brenda , Gumber Diana , Maker Madeleine , Huard Stephanie , Wang Dongrui , Chang Wen-Chung , Brito Alfonso , Chiu Vivian , Ostberg Julie R. , Badie Benham , Forman Stephen J. , Alizadeh Darya , Wang Leo D. , Brown Christine E. 
Published: December 2022

Chimeric antigen receptor (CAR) T cell immunotherapy is emerging as a powerful strategy for cancer therapy; however, an important safety consideration is the potential for off-tumor recognition of normal tissue. This is particularly important as ligand-based CARs are optimized for clinical translation. Our group has developed and clinically translated an IL13(E12Y) ligand–based CAR targeting the cancer antigen IL13Rα2 for treatment of glioblastoma (GBM). There remains limited understanding of how IL13-ligand CAR design impacts the activity and selectivity for the intended tumor-associated target IL13Rα2 versus the more ubiquitous unintended target IL13Rα1. In this study, we functionally compared IL13(E12Y)-CARs incorporating different intracellular signaling domains, including first-generation CD3ζ-containing CARs (IL13ζ), second-generation 4-1BB (CD137)–containing or CD28-containing CARs (IL13-BBζ or IL13-28ζ), and third-generation CARs containing both 4-1BB and CD28 (IL13-28BBζ). In vitro coculture assays at high tumor burden establish that second-generation IL13-BBζ or IL13-28ζ outperform first-generation IL13ζ and third-generation IL13-28BBζ CAR designs, with IL13-BBζ providing superior CAR proliferation and in vivo antitumor potency in human xenograft mouse models. IL13-28ζ displayed a lower threshold for antigen recognition, resulting in higher off-target IL13Rα1 reactivity both in vitro and in vivo. Syngeneic mouse models of GBM also demonstrate safety and antitumor potency of murine IL13-BBζ CAR T cells delivered systemically after lymphodepletion. These findings support the use of IL13-BBζ CARs for greater selective recognition of IL13Rα2 over IL13Rα1, higher proliferative potential, and superior antitumor responsiveness. This study exemplifies the potential of modulating factors outside the antigen targeting domain of a CAR to improve selective tumor recognition.Significance:This study reveals how modulating CAR design outside the antigen targeting domain improves selective tumor recognition. Specifically, this work shows improved specificity, persistence, and efficacy of 4-1BB–based IL13-ligand CARs. Human clinical trials evaluating IL13-41BB-CAR T cells are ongoing, supporting the clinical significance of these findings.
Immature Platelet Fraction Predicts Adverse Events in Patients With Acute Coronary Syndrome: the ISAR-REACT 5 Reticulated Platelet Substudy
Authors: Bongiovanni Dario , Schreiner Nina , Gosetti Rosanna , Mayer Katharina , Angiolillo Dominick J. , Sibbing Dirk , Holdenrieder Stefan , Anetsberger Aida , von Scheidt Moritz , Schunkert Heribert , Laugwitz Karl-Ludwig , Schüpke Stefanie , Kastrati Adnan , Fegers-Wustrow Isabel , Bernlochner Isabell 
Published: December 2022

Background:

Immature or reticulated platelets are associated with impaired efficacy of antiplatelet drugs and adverse events in cardiovascular patients. Their role as a predictive biomarker in patients with acute coronary syndrome treated with potent P2Y
12
receptor inhibitors is not fully understood. We aimed to prospectively evaluate reticulated platelets as a predictor of the primary end point of the ISAR-REACT 5 trial consisting of death, myocardial infarction, or stroke at 1 year in patients with acute coronary syndrome randomized to prasugrel or ticagrelor.

Methods:

Immature platelet fraction (IPF) was assessed within 48 hours after randomization. Patients were divided based on the IPF median values: the IPF
high
group included patients with IPF>median and the IPF
low
group included patients with IPF≤median. Platelet aggregation was assessed using the Multiplate Analyzer and was correlated to IPF.

Results:

Five hundred seventy-seven patients were included in the study. IPF values in % (median [interquartile range]) within the first 48 hours did not differ between the two study groups: 3.6 (2.5–5.2)% in the prasugrel group and 3.6 (2.5–5.4)% in the ticagrelor group (
P
=0.882). The incidence of the primary end point was significantly higher in the IPF
high
(IPF>3.6%) group compared with the IPF
low
(IPF
≤
3.6%) group: 13.0% versus 7.2% (HR
adj
, 1.74 [1.02–3.00];
P
=0.044), independently from the assigned drug (
P
int
=0.159). No significant association between IPF and BARC 3 to 5 bleeding was observed. ADP-induced platelet aggregation correlated significantly with IPF in patients treated with prasugrel (
r
=0.22;
P
=0.005) while no correlation was detected in patients treated with ticagrelor (
r
=0.09;
P
=0.257).

Conclusions:
Independently from drug treatment, IPF was associated with the primary end point and therefore is a promising biomarker for the prediction of adverse cardiovascular events in patients with acute coronary syndrome treated with prasugrel or ticagrelor.

Registration:

https://www.clinicaltrials.gov
; Unique identifier: NCT01944800.
Distributional patterns of the South American species of Parastacidae (Decapoda, Astacidea)
Authors: De los Rios-Escalante Patricio R. , Jara-Seguel Pedro , Contreras Angel , Latsague Mirtha , Lara Gladys , Rudolph Erich , Crandall Keith A. 
Published: December 2022

Abstract
The distributional patterns of the species of the South American freshwater crayfishes of the family Parastacidae were analysed using panbiogeographical track analyses to identify targeted regions of crayfish biodiversity for understanding biogeographical patterns. Two generalized tracks were identified using the track analysis approach: (1) Uruguay and Brazil (Parastacus brasiliensis, P. brasiliensis promatensis, P. buckupi, P. caeruleodactylus, P. defossus, P. fluviatilis, P. gomesae, P. guapo, P. macanudo, P. pilimanus, P. pilicarpus, P. saffordi, P. tuerkayi, P. varicosus); and (2) Central-southern Chile (P. nicoleti, P. pugnax, Samastacus spinifrons, Virilastacus araucanius, V. jarai, V. retamali and V. rucapihuelensis). These areas were exclusive, with no overlap between them. The results indicate the presence of South American Parastacidae crayfish in Atlantic coastal sub-tropical and Pacific coastal temperate wet climate regions with biogeographic similarities to other South American inland water decapods.
Falling Out of Time, Relationships, and Mood: A Case Study of Post-Concussion Syndrome
Authors: Whitehead Patrick M. , Senecal Gary 
Published: December 2022

Abstract
In this article, the authors examine post-concussion syndrome (PCS) from an existential-phenomenological perspective, specifically as a Heideggerian analysis of Dasein (or Daseinsanalysis; Condrau, 1988). As a medical syndrome, PCS was once defined in terms of its pathophysiology. However, in the absence of reliable evidence of pathophysiology, PCS has been removed from the DSM-5. We have suspended the natural attitude, in this case the biomedical model, and have taken seriously the symptoms of PCS as indications that meaningful changes have occurred within the structure of the patient’s existence. Following the medical theories of Goldstein (1995) and Gadamer (1996), the authors describe the significance of PCS as it is lived by Tyrese, an NCAA Division II football player whose series of concussions left him permanently sidelined. Careful consideration is paid to the existential dimensions of the syndrome, specifically the backgrounds of temporality, sociality, and attunement. In conclusion, a new approach to rehabilitation is explored.
Concessions in International Law
Authors: Alvik Ivar 
Published: December 2022

Abstract
The article examines the extent to which concessionary rights are protected under three different branches of international law; traditional customary law, the case law of the European Court of Human Rights, and arbitral practice under investment treaties. It reveals clear similarities with respect to when such rights are considered protected. However, it simultaneously argues that case law under investment treaties tends to adopt a less nuanced approach to the nature of such rights, almost invariably assuming them to constitute a kind of property. This again entails that the investor/concessionaire is seen to have a right to performance, and in effect to protection of his expectation interest. The article shows how this stands in contrast with a more nuanced perspective under the property provision of the echr, which better reflects the complexities of the issue under municipal law. While a failure to sufficiently respect an investor’s legitimate expectations may entail liability for the state, it is not necessarily comparable to expropriation of property and will usually entail only that the investor has a right to recover his reliance loss. The article argues that this may be reflective of a more general tendency in international investment law and arbitration also pointed to by others, where the modality of protection under investment treaties threatens to distort important nuances and concerns and overprotect foreign investment compared to other private rights and interests under municipal law.
Integration (of Immigrants) in the European Union: A Controversial Concept
Authors: Bottero Matteo 
Published: December 2022

Abstract
Integration is one of the major challenges posed to the European Union by the immigration of third-country nationals. And it is even more so in view of the mass influx of displaced persons stemming from the Russian military invasion of Ukraine. This article discusses the controversial concept of (immigrant) integration underpinned by the current EU legal and policy framework. It argues that, on the one hand, the concept of integration resulting from instruments of primary and secondary EU legislation, soft law and policy is inspired by the respect for fundamental rights and prohibition of discrimination. On the other hand, it stresses that the EU action mainly aims at preserving Member States’ sovereignty over immigration. The resulting EU normative framework for integration, including the newly adopted EU Blue Card Directive and the extension of temporary protection for Ukrainian refugees, allows and encourages the strategic selection of the most socio-economically and culturally desirable immigrants.