bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined effect of ozone and household air pollution on COPD in people aged less than 50 years old
Authors: Xing Zhenzhen , Yang Ting , Shi Su , Meng Xia , Chai Di , Liu WeiMing , Tong Yaqi , Wang Yuxia , Ma Yali , Pan MingMing , Cui Jia , Long Huanyu , Sun Tieying , Chen Renjie , Guo YanFei 
Published: October 2023

ObjectivesAir pollution has been suggested as an important risk factor for chronic obstructive pulmonary disease (COPD); however, evidence of interactive effects on COPD between different factors was sparse, especially for young adults. We aimed to assess the combined effects of ambient ozone (O3) and household air pollution on COPD in young individuals.MethodsWe conducted a population-based study of residents aged 15–50 years in the low-income and middle-income regions of western China. We used multivariable logistic regression models to examine the associations between long-term ozone exposure and COPD in young individuals.ResultsA total of 6537 young cases were identified among the participants, with a COPD prevalence rate of 7.8 (95% CI 7.2% to 8.5%), and most young COPD individuals were asymptomatic. Exposure to household air pollution was associated with COPD in young patients after adjustment for other confounding factors (OR 1.82, 95% CI 1.41 to 2.37). We also found positive associations of COPD with O3per IQR increase of 20 ppb (OR 1.92, 95% CI 1.59 to 2.32). The individual effects of household air pollution and O3were 1.68 (95% CI 1.18 to 2.46) and 1.55 (95% CI 0.99 to 2.43), respectively, while their joint effect was 3.28 (95% CI 2.35 to 4.69) with the relative excess risk due to interaction of 1.05 (95% CI 0.33 to 1.78).ConclusionsThis study concludes that exposure to ambient O3and household air pollution might be important risk factors for COPD among young adults, and simultaneous exposure to high levels of the two pollutants may intensify their individual effects.
Unveiling the antibacterial and antioxidant potential of Hedera helix leaf extracts: recent findings
Authors: Qabaha Khaled , Abbadi Jehad , Yaghmour Reem , Hijawi Thameen , Naser Saleh A. , Al-Rimawi Fuad 
Published: October 2023

Hedera helix L., a member of the Araliaceae family, is a commonly known decorative plant with recognized medicinal activities. In this study, the ethanolic extract from H. helix leaves was investigated for its total polyphenolic and flavonoid contents, as well as its antioxidant and antibacterial properties. The aim was to evaluate its potential for controlling certain infections by screening its antibacterial activity against selected pathogenic bacteria. The total phenolic and flavonoid contents of the extract were determined using colorimetric methods. The antioxidant activity was assessed through two assay methods: the 1, 1-diphenyl-2-picryl hydrazyl (DPPH) free radical scavenging activity and the reducing power ferric reducing/antioxidant power (FRAP). The antibacterial activity against different pathogenic bacteria, including Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa, was evaluated using the well diffusion method. The total phenolic and flavonoid contents of the H. helix extract were found to be 134.3 ± 4.9 mg gallic acid/g and 42.4 ± 3.6 mg catechin/g, respectively. The extract exhibited antioxidant activity, with a reducing power represented by an FRAP value of 9.5 ± 0.9 mmol Fe+2/g DW and a percentage inhibition of DPPH of 64.7 ± 3.8 at 80 µg/mL. The extract demonstrated antibacterial activity, inhibiting the growth of K. pneumoniae and S. aureus with zone of inhibition values of 18.5 and 23.2 mm, respectively, using 25 mg/well. However, E. coli and P. aeruginosa exhibited resistance to the extract. The findings of this study highlight the antibacterial and antioxidant properties of the ethanolic extract from H. helix leaves. The extract exhibited significant phenolic and flavonoid contents, as well as antioxidant activity. It also demonstrated antibacterial activity against selected pathogenic bacteria, suggesting its potential for controlling certain infections. Further research is warranted to identify the active compounds responsible for these activities and to explore their mechanisms of action.
Spontaneous CP violation and $$\mu -\tau $$ symmetry in two-Higgs-doublet models with flavour conservation
Authors: Alves João M. , Botella Francisco J. , Miró Carlos , Nebot Miguel 
Published: October 2023

AbstractIn multi-Higgs-doublet models, requiring simultaneously that (i) CP violation only arises spontaneously, (ii) tree level scalar flavour changing couplings are absent and (iii) the fermion mixing matrix is CP violating, can only be achieved in a very specific manner. A general approach with new clarifying insights on the question is presented. Considering the quark sector, that peculiar possibility is not viable on phenomenological grounds. We show that, considering the lepton sector, it is highly interesting and leads to viable models with$$\mu -\tau $$μ-τsymmetric PMNS matrices. Phenomenological implications of the models, both for Dirac and Majorana (in a type I seesaw scenario) neutrinos, are analysed.
Destroying the event horizon of a rotating black-bounce black hole
Authors: Zhao Lai , Xu Zhaoyi 
Published: October 2023

AbstractFor a rotating black hole to be nonsingular, it means that there are no spacetime singularities at its center. The destruction of the event horizon of such a rotating black hole is not constrained by the weak cosmic censorship conjecture, which may provide possibilities to understand the internal structure of black hole event horizons. In this paper, we employ test particles with large angular momentum and a scalar field with large angular momentum to investigate the potential of destroying the event horizon of rotating black-bounce black holes. Additionally, we investigate the possibility of destroying the event horizon of a rotating black-bounce black hole by considering test particles with large angular momentum and scalar fields with large angular momentum, covering the entire range of the rotating black-bounce black hole. We analyze the influence of the parameter m on the possibility of destroying the event horizon in this spacetime. Our analysis reveals that under extreme or near-extreme conditions, the event horizon of this spacetime can potentially be destroyed after the absorption of particles energy and angular momentum, as well as the scattering of scalar fields. Additionally, we find that as the parameter m increases, the event horizon of this spacetime model becomes more susceptible to destruction after the injection of test particles or the scattering of scalar fields.
A New Minimax Theorem for Randomized Algorithms
Authors: Ben-David Shalev , Blais Eric 
Published: October 2023

The celebrated minimax principle of Yao says that for any Boolean-valued function
f
with finite domain, there is a distribution μ over the domain of
f
such that computing
f
to error ε against inputs from μ is just as hard as computing
f
to error ε on worst-case inputs. Notably, however, the distribution μ depends on the target error level ε: the hard distribution which is tight for bounded error might be trivial to solve to small bias, and the hard distribution which is tight for a small bias level might be far from tight for bounded error levels.

In this work, we introduce a new type of minimax theorem which can provide a hard distribution μ that works for all bias levels at once. We show that this works for randomized query complexity, randomized communication complexity, some randomized circuit models, quantum query and communication complexities, approximate polynomial degree, and approximate logrank. We also prove an improved version of Impagliazzo’s hardcore lemma.
Our proofs rely on two innovations over the classical approach of using Von Neumann’s minimax theorem or linear programming duality. First, we use Sion’s minimax theorem to prove a minimax theorem for ratios of bilinear functions representing the cost and score of algorithms.
Second, we introduce a new way to analyze low-bias randomized algorithms by viewing them as “forecasting algorithms” evaluated by a certain proper scoring rule. The expected score of the forecasting version of a randomized algorithm appears to be a more fine-grained way of analyzing the bias of the algorithm. We show that such expected scores have many elegant mathematical properties—for example, they can be amplified linearly instead of quadratically. We anticipate forecasting algorithms will find use in future work in which a fine-grained analysis of small-bias algorithms is required.
KRT17high/CXCL8+ Tumor Cells Display Both Classical and Basal Features and Regulate Myeloid Infiltration in the Pancreatic Cancer Microenvironment
Authors: Carpenter Eileen S. , Kadiyala Padma , Elhossiny Ahmed M. , Kemp Samantha B. , Li Jay , Steele Nina G. , Nicolle Rémy , Nwosu Zeribe C. , Freeman Julia , Dai Henry , Paglia Daniel , Du Wenting , Donahue Katelyn , Morales Jacqueline , Medina-Cabrera Paola I. , Bonilla Monica E. , Harris Lindsey , The Stephanie , Gunchick Valerie , Peterson Nicole , Brown Kristee , Mattea Michael , Espinoza Carlos E. , McGue Jake , Kabala Sarah M. , Baliira Rachel K. , Renollet Nur M. , Mooney Ayden G. , Liu Jianhua , Bhalla Sean , Farida Jeremy P. , Ko Christopher , Machicado Jorge D. , Kwon Richard S. , Wamsteker Erik-Jan , Schulman Allison , Anderson Michelle A. , Law Ryan , Prabhu Anoop , Coulombe Pierre A. , Rao Arvind , Frankel Timothy L. , Bednar Filip , Shi Jiaqi , Sahai Vaibhav , Pasca Di Magliano Marina 
Published: October 2023

Abstract

Purpose:
Pancreatic ductal adenocarcinoma (PDAC) is generally divided in two subtypes, classical and basal. Recently, single-cell RNA sequencing has uncovered the coexistence of basal and classical cancer cells, as well as intermediary cancer cells, in individual tumors. The latter remains poorly understood; here, we sought to characterize them using a multimodal approach.

Experimental Design:
We performed subtyping on a single-cell RNA sequencing dataset containing 18 human PDAC samples to identify multiple intermediary subtypes. We generated patient-derived PDAC organoids for functional studies. We compared single-cell profiling of matched blood and tumor samples to measure changes in the local and systemic immune microenvironment. We then leveraged longitudinally patient-matched blood to follow individual patients over the course of chemotherapy.

Results:
We identified a cluster of KRT17-high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines. The proportion of KRT17high/CXCL8+ cells in patient tumors correlated with intratumoral myeloid abundance, and, interestingly, high protumor peripheral blood granulocytes, implicating local and systemic roles. Patient-derived organoids maintained KRT17high/CXCL8+ cells and induced myeloid cell migration in a CXCL8-dependent manner. In our longitudinal studies, plasma CXCL8 decreased following chemotherapy in responsive patients, while CXCL8 persistence portended worse prognosis.

Conclusions:
Through single-cell analysis of PDAC samples, we identified KRT17high/CXCL8+ cancer cells as an intermediary subtype, marked by a unique cytokine profile and capable of influencing myeloid cells in the tumor microenvironment and systemically. The abundance of this cell population should be considered for patient stratification in precision immunotherapy.
See related commentary by Faraoni and McAllister, p. 2297
Decreased Basophil Activation against House Dust Mite after Japanese Cedar Pollen Subcutaneous Immunotherapy: A Retrospective Study
Authors: Inuo Chisato , Ando Hitoshi , Tanaka Kenichi , Nakajima Yoichi , Tsuge Ikuya , Urisu Atsuo , Kondo Yasuto 
Published: October 2023

<b><i>Background:</i></b> Allergen-specific immunotherapy (AIT), an established treatment for allergic diseases, prevents the development of other allergic manifestations. Although the mechanisms remain unclear, AIT has been shown to reduce basophil activation (BA) against nontarget allergens. <b><i>Objectives:</i></b> The aim of this study was to assess immunological changes in <i>Dermatophagoides farinae</i> (<i>Der f</i>) after Japanese cedar pollen (JCP)-based subcutaneous immunotherapy (SCIT) monotherapy. <b><i>Method:</i></b> The data of 16 patients (age: 6–37 years) with JCP-induced allergic rhinitis who were sensitive to <i>Der f</i> (serum <i>Der f</i>-specific immunoglobulin E [IgE] level &gt;0.34 kU<sub>A</sub>/L) and received JCP-based SCIT for 5 years were reviewed retrospectively. BA by <i>Der f</i> and JCP extracts and serum-specific IgE and immunoglobulin G4 (IgG4) levels against these allergens were evaluated before and after completing 5 years of JCP-based SCIT monotherapy. <b><i>Results:</i></b> The areas under the dose-response curves of BA by <i>Der f</i> and JCP extracts were significantly reduced (<i>p</i> = 0.02 and <i>p</i> = 0.002, respectively). JCP-specific IgE levels decreased and JCP-specific IgG4 levels increased significantly (<i>p</i> &lt; 0.001 for both), whereas <i>Der f-</i>specific IgE and IgG4 levels did not change significantly. <b><i>Conclusions:</i></b> JCP-based SCIT monotherapy reduced <i>Der f</i>-specific BA. These findings suggest that JCP-based SCIT has the potential to modulate immune response toward nontarget allergens.
Cellular Heterogeneity of Activated Primary Human Macrophages and Associated Drug–Gene Networks: From Biology to Precision Therapeutics
Authors: Decano Julius L. , Maiorino Enrico , Matamalas Joan T. , Chelvanambi Sarvesh , Tiemeijer Bart M. , Yanagihara Yoshihiro , Mukai Shin , Jha Prabhash Kumar , Pestana Diego V.S. , D’Souza Edwin , Whelan Mary , Ge Rile , Asano Takaharu , Sharma Amitabh , Libby Peter , Singh Sasha A. , Aikawa Elena , Aikawa Masanori 
Published: October 2023

BACKGROUND:
Interferon-γ (IFNγ) signaling plays a complex role in atherogenesis. IFNγ stimulation of macrophages permits in vitro exploration of proinflammatory mechanisms and the development of novel immune therapies. We hypothesized that the study of macrophage subpopulations could lead to anti-inflammatory interventions.

METHODS:
Primary human macrophages activated by IFNγ (M(IFNγ)) underwent analyses by single-cell RNA sequencing, time-course cell-cluster proteomics, metabolite consumption, immunoassays, and functional tests (phagocytic, efferocytotic, and chemotactic). RNA-sequencing data were analyzed in LINCS (Library of Integrated Network-Based Cellular Signatures) to identify compounds targeting M(IFNγ) subpopulations. The effect of compound BI-2536 was tested in human macrophages in vitro and in a murine model of atherosclerosis.

RESULTS:

Single-cell RNA sequencing identified 2 major clusters in M(IFNγ): inflammatory (M(IFNγ)

i

) and phagocytic (M(IFNγ)

p

). M(IFNγ)

i

had elevated expression of inflammatory chemokines and higher amino acid consumption compared with M(IFNγ)

p

. M(IFNγ)

p

were more phagocytotic and chemotactic with higher Krebs cycle activity and less glycolysis than M(IFNγ)

i

. Human carotid atherosclerotic plaques contained 2 such macrophage clusters. Bioinformatic LINCS analysis using our RNA-sequencing data identified BI-2536 as a potential compound to decrease the M(IFNγ)

i

subpopulation. BI-2536 in vitro decreased inflammatory chemokine expression and secretion in M(IFNγ) by shrinking the M(IFNγ)

i

subpopulation while expanding the M(IFNγ)

p

subpopulation. BI-2536 in vivo shifted the phenotype of macrophages, modulated inflammation, and decreased atherosclerosis and calcification.

CONCLUSIONS:
We characterized 2 clusters of macrophages in atherosclerosis and combined our cellular data with a cell-signature drug library to identify a novel compound that targets a subset of macrophages in atherosclerosis. Our approach is a precision medicine strategy to identify new drugs that target atherosclerosis and other inflammatory diseases.
Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non–β-Blocking R-Enantiomer Carvedilol
Authors: Seo Kinya , Yamamoto Yuta , Kirillova Anna , Kawana Masataka , Yadav Sunil , Huang Yong , Wang Qianru , Lane Kerry V. , Pruitt Beth L. , Perez Marco V. , Bernstein Daniel , Wu Joseph C. , Wheeler Matthew T. , Parikh Victoria N. , Ashley Euan A. 
Published: October 2023

BACKGROUND:
Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor antagonists (β-blockers) are the first-line therapy for HCM. However, β-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown.

METHODS:

We screened 21 β-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure–volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM (
Myh6
R403Q
/+
and induced pluripotent stem cell (iPSC)-derived cardiomyocytes from patients with HCM (
MYH7
R403Q/+
).

RESULTS:

We identified that carvedilol, a β-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a β
1
-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α
1
-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of β-blocking effect, retains the ability to inhibit both α
1
-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In
Myh6
R403Q/+
mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in
MYH7
R403Q/+
iPSC-derived cardiomyocytes.

CONCLUSIONS:

R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α
1
-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.
Early Left Ventricular Unloading or Conventional Approach After Venoarterial Extracorporeal Membrane Oxygenation: The EARLY-UNLOAD Randomized Clinical Trial
Authors: Kim Min Chul , Lim Yongwhan , Lee Seung Hun , Shin Yoonmin , Ahn Joon Ho , Hyun Dae Young , Cho Kyung Hoon , Sim Doo Sun , Hong Young Joon , Kim Ju Han , Jeong Myung Ho , Jung Yong Hun , Jeong In-Seok , Ahn Youngkeun 
Published: October 2023

BACKGROUND:
Although venoarterial extracorporeal membrane oxygenation (VA-ECMO) is beneficial for the treatment of profound cardiogenic shock, peripheral VA-ECMO cannulation can increase left ventricular afterload, thus compromising myocardial recovery. We investigated whether early routine left ventricular unloading can reduce 30-day mortality compared with the conventional approach in patients with cardiogenic shock undergoing VA-ECMO.

METHODS:
This randomized clinical trial involved 116 patients with cardiogenic shock undergoing VA-ECMO from March 2021 to September 2022 at Chonnam National University Hospital, Gwangju, South Korea. The patients were randomly assigned to undergo either early routine left ventricular unloading with transseptal left atrial cannulation within 12 hours after randomization (n=58) or the conventional approach, which permitted rescue transseptal left atrial cannulation in case of an increased left ventricular afterload (n=58). The primary outcome was all-cause mortality within 30 days.

RESULTS:

All 116 randomized patients (mean age, 67.6±13.5 years; 34 [29.3%] women) completed the trial. At 30 days, all-cause death had occurred in 27 (46.6%) patients in the early group and 26 (44.8%) patients in the conventional group (hazard ratio, 1.02 [95% CI, 0.59–1.74];
P
=0.942). Crossover to rescue transseptal left atrial cannulation occurred in 29 patients (50%) in the conventional group according to a clear indication. Time to rescue transseptal cannulation in the conventional group was a median of 21.8 (interquartile range, 12.4–52.2) hours after randomization. There were no significant differences in other secondary outcomes between the 2 groups except for a shorter time to disappearance of pulmonary congestion in the early group (median, 3 [interquartile range, 2–6] versus 5 [interquartile range, 3–7] days;
P
=0.027).

CONCLUSIONS:
Among patients with cardiogenic shock undergoing VA-ECMO, early routine left ventricular unloading with transseptal left atrial cannulation did not reduce 30-day mortality compared with the conventional strategy, which permitted rescue transseptal left atrial cannulation. These findings should be cautiously interpreted until the results of multicenter trials using other unloading modalities become available.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04775472.
Real‐World Effectiveness of PCSK9 Inhibitors in Reducing LDL‐C in Patients With Familial Hypercholesterolemia in Italy: A Retrospective Cohort Study Based on the AIFA Monitoring Registries
Authors: Arca Marcello , Celant Simone , Olimpieri Pier Paolo , Colatrella Antonietta , Tomassini Luca , D'Erasmo Laura , Averna Maurizio , Zambon Alberto , Catapano Alberico Luigi , Russo Pierluigi 
Published: October 2023

Background
Information on the real‐world use of proprotein convertase subtilisin kexin 9 inhibitors (PCKS9is) in familial hypercholesterolemia are limited. We evaluated the pattern of prescription and the long‐term efficacy of alirocumab and evolocumab in Italian patients with familial hypercholesterolemia in clinical practice.

Methods and Results
The data set for analysis was extracted from the PCKS9i Italian Medicines Agency (AIFA) registry and included 2484 patients with heterozygous familial hypercholesterolemia (HeFH) and 62 patients with homozygous familial hypercholesterolemia (HoFH) who were prescribed PCKS9is from February 2017 to December 2021. As the follow‐up schedules were not prespecified and could vary, persistence and adherence as well as low‐density lipoprotein cholesterol (LDL‐C) changes during 2 years of treatment were analyzed in a final cohort of 1299 patients with familial hypercholesterolemia. At baseline, 53.8% of patients with HeFH and 69.4% of patients with HoFH were receiving maximally tolerated lipid‐lowering therapies, while 45.9% of patients with HeFH and 30.7% of patients with HoFH reported statin intolerance; mean LDL‐C was 197.7±52.3 mg/dL in HeFH and 252.0±106.2 mg/dL in HoFH. The 6‐month persistence and adherence to therapy were >85%, and LDL‐C reduction reached 58.6% (to 79.7 mg/dL) in HeFH and 57.6% (to 95.1 mg/dL) in HoFH after 24 months of treatment. The European Atherosclerosis Society/European Society of Cardiology LDL‐C goals were achieved in 43.3% of patients with HeFH and 37.5% of patients with HoFH.

Conclusions
PCKS9i prescribed to patients with familial hypercholesterolemia in clinical practice showed LDL‐C–lowering efficacy similar to that observed in controlled trials. However, 2 of 5 HeFH cases and 2 of 6 HoFH cases achieved the recommended LDL‐C goals. The full achievement of European Atherosclerosis Society/European Society of Cardiology LDL‐C goals should require a lower threshold for PCKS9i initiation and a combination of multiple therapies.