bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of programmed death ligand 1 expression by interferon‐γ and tumour necrosis factor‐α in canine tumour cell lines
Authors: Owaki Ryo , Deguchi Tatsuya , Konnai Satoru , Maekawa Naoya , Okagawa Tomohiro , Hosoya Kenji , Kim Sangho , Sunaga Takafumi , Okumura Masahiro
Published: February 2023

Expression of programmed death ligand 1 (PD‐L1) on tumour cells provides an immune evasion mechanism by inducing suppression of cytotoxic T cells. Various regulatory mechanisms of PD‐L1 expression have been described in human tumours, however, little is known in canine tumours. To investigate whether inflammatory signalling is involved in PD‐L1 regulation in canine tumours, the effects of interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α treatment were examined in canine malignant melanoma cell lines (CMeC and LMeC) and an osteosarcoma cell line (HMPOS). The protein level of PD‐L1 expression was upregulated by IFN‐γ and TNF‐α stimulation. Upon IFN‐γ stimulation, all cell lines showed an increase in expression of PD‐L1, signal transducer and activator of transcription (STAT)1, STAT3 and genes regulated by STAT activation. Upregulated expression of these genes was suppressed by the addition of a JAK inhibitor, oclacitinib. Contrastingly, upon TNF‐α stimulation, all cell lines exhibited higher gene expression of the nuclear factor kappa B (NF‐κB) gene RELA and genes regulated by NF‐κB activation, whereas expression of PD‐L1 was upregulated in LMeC only. Upregulated expression of these genes was suppressed by the addition of an NF‐κB inhibitor, BAY 11‐7082. The expression level of cell surface PD‐L1 induced by IFN‐γ and TNF‐α treatment was reduced by oclacitinib and BAY 11‐7082, respectively, indicating that upregulation of PD‐L1 expression by IFN‐γ and TNF‐α stimulation is regulated via the JAK‐STAT and NF‐κB signalling pathways, respectively. These results provide insights into the role of inflammatory signalling in PD‐L1 regulation in canine tumours.
A retrospective study of canine oral extramedullary plasmacytoma over a 15‐year period (July 2004–July 2019): Treatment, histologic parameters and clinical outcomes
Authors: Evenhuis Janny V. , Oates Andrew , Hoyer Naomi , Vilander Allison C. , Thamm Douglass H. , Worley Deanna R.
Published: February 2023

A total of 45 cases of canine oral extramedullary plasmacytomas (EMPs) presented to a tertiary referral institution over a 15‐year period were examined. Histologic sections of 33 of these cases were examined for histopathologic prognostic indicators. Patients underwent variable treatment including surgical intervention, chemotherapy and/or radiation therapy. Long term survival was observed in the majority of dogs with a median survival time of 973 days (2–4315 days). However, almost 1/3 of dogs had progression of plasma cell disease, including two cases with myeloma‐like progression. Histologic characterization of these tumours did not reveal criteria to predict tumour malignancy. However, cases without tumour progression did not exceed 28 mitotic figures in ten 400× fields (2.37 mm2). All cases with tumour related death showed at least moderate nuclear atypia. Oral EMPs may represent a local manifestation of systemic plasma cell disease or singular focal neoplasia.
Nonstationary Stochastic Response of Hysteretic Systems Endowed With Fractional Derivative Elements
Authors: Zhang Wei , Spanos Pol D. , Di Matteo Alberto
Published: February 2023

In this paper, a computationally efficient approach is proposed for the determination of the nonstationary response statistics of hysteretic oscillators endowed with fractional derivative elements. This problem is of particular practical significance since many important engineering systems exhibit hysteretic/inelastic behavior optimally captured only through the concept of fractional derivative, and many natural excitations as seismic waves and atmospheric turbulence are both stochastic and nonstationary in time. Specifically, the approach is based on a statistical linearization scheme involving an equivalent system of augmented dimension. First, relying on a transformation scheme, the fractional derivative term is represented by a set of coupled linear ordinary differential equations. Next, the evolution of the system response statistics is captured by incorporating the statistical linearization technique in a nonstationary sense. This involves integrating in time a set of ordinary differential equations. Several numerical applications pertaining to classical hysteretic oscillators are considered, and the versatility of the proposed method is assessed via comparison with pertinent Monte Carlo simulations.
Multiple superconducting transitions in α-Sn/β-Sn mixed films grown by molecular beam epitaxy
Authors: Ding Yuanfeng , Li Bingxin , Yao Jinshan , Song Huanhuan , Wei Lian , Lu Yang , Huang Junwei , Yuan Hongtao , Lu Hong , Chen Yan-Feng
Published: February 2023

We have tried to grow α-Sn films on two different substrates with different sample structures by molecular beam epitaxy. The mixture of an α phase with a β phase in the Sn film has been confirmed. The electrical transport properties have been measured and multiple superconducting transitions have been observed in these α-Sn/β-Sn mixed films. Enhanced critical temperatures and critical fields as well as shorter coherence lengths are observed, as compared to bulk β-Sn. The two-dimensional nature is demonstrated by angle-dependent measurements and a type-II superconductor is indicated by the magnetization measurements. We attribute the multiple superconducting transitions to the β-Sn islands formed within the film.
On the limitations of thermal atomic layer deposition of InN using ammonia
Authors: Rönnby Karl , Pedersen Henrik , Ojamäe Lars
Published: February 2023

Chemical vapor deposition of indium nitride (InN) is severely limited by the low thermal stability of the material, and, thus, low-temperature deposition processes such as atomic layer deposition (ALD) are needed to deposit InN films. The two chemically and structurally closely related materials—aluminum nitride and gallium nitride (GaN)—can be deposited by both plasma and thermal ALD, with ammonia (NH3) as a nitrogen precursor in thermal processes. InN, however, can only be deposited using plasma ALD, indicating that there might be a limitation to thermal ALD with NH3 for InN. We use quantum-chemical density functional theory calculations to compare the adsorption process of NH3 on GaN and InN to investigate if differences in the process could account for the lack of thermal ALD of InN. Our findings show a similar reactive adsorption mechanism on both materials, in which NH3 could adsorb onto a vacant site left by a desorbing methyl group from the surfaces. The difference in energy barrier for this adsorption indicates that the process is many magnitudes slower on InN compared to GaN. Slow kinetics would hinder NH3 from reactively adsorbing onto InN in the timeframe of the ALD growth process and, thus, limit the availability of a thermal ALD process.
Phase-modulated Rice model for statistical distributions of complex signals
Authors: Wilson D. Keith , Ostashev Vladimir E. , Krackow Max E.
Published: February 2023

The basic Rice model is commonly used to describe complex signal statistics from randomly scattered waves. It correctly describes weak (Born) scattering, as well as fully saturated scattering, and smoothly interpolates between these extremes. However, the basic Rice model is unsuitable for situations involving scattering by random inhomogeneities spanning a broad range of spatial scales, as commonly occurs for sound scattering by turbulence in the atmospheric boundary layer and other scenarios. In such scenarios, the phase variations are often considerably stronger than those predicted by the basic Rice model. Therefore, the basic Rice model is extended to include a random modulation in the signal phase, which is attributable to the influence of the largest, most energetic inhomogeneities in the propagation medium. Various joint and marginal distributions for the complex signal statistics are derived to incorporate the phase-modulation effect. Approximations of the phase-modulated Rice model involving the Nakagami distribution for amplitude, and the wrapped normal and von Mises distributions for phase, are also developed and analyzed. The phase-modulated Rice model and various approximations are shown to greatly improve agreement with simulated data for sound propagation in the near-ground atmosphere.
A computational study of trailing edge noise suppression with embedded structural compliance
Authors: Arif Irsalan , Leung Randolph C. K. , Naseer Muhammad Rehan
Published: February 2023

A unique concept for suppression of trailing edge noise scattering from a splitter plate in a low Reynolds number flow is proposed. The key idea of the concept is the adoption of a structural compliance system embedded with a finite number of elastic panels. Specific compliance system designs are devised for promotion of panel structural resonance that effectively absorbs broadband flow/acoustic fluctuation energy responsible for noise scattering. The concept is examined using high-fidelity direct aeroacoustic simulation together with spatiotemporal aeroacoustic-structural interaction analysis. The concept is confirmed feasible and outperforms many similar trailing edge noise reduction approaches reported in the literature.
Learnable spectral dimension compression mapping for full-band speech enhancement
Authors: Hu Qinwen , Hou Zhongshu , Chen Kai , Lu Jing
Published: February 2023

The highly imbalanced power spectral density of full-band speech signals poses a significant challenge to full-band speech enhancement, and the commonly used spectral features that mimic the behavior of the human auditory system are not an optimal choice for full-band speech enhancement. In this paper, a learnable spectral dimension compression mapping is proposed to effectively compress the spectral feature along frequency, preserving high resolution in low frequencies while compressing information in high frequencies in a more flexible manner. Experimental results verify that the proposed method can be easily combined with different full-band speech enhancement models and achieve better performance.
Microscopic activated dynamics theory of the shear rheology and stress overshoot in ultradense glass-forming fluids and colloidal suspensions
Authors: Ghosh Ashesh , Schweizer Kenneth S.
Published: February 2023

We formulate a particle and force level, activated dynamics-based statistical mechanical theory for the continuous startup nonlinear shear rheology of ultradense glass-forming hard sphere fluids and colloidal suspensions in the context of the elastically collective nonlinear Langevin equation approach and a generalized Maxwell model constitutive equation. Activated structural relaxation is described as a coupled local-nonlocal event involving caging and longer range collective elasticity which controls the characteristic stress relaxation time. Theoretical predictions for the deformation-induced enhancement of mobility, the onset of relaxation acceleration at remarkably low values of stress, strain, or shear rate, apparent power law thinning of the steady-state structural relaxation time and viscosity, a nonvanishing activation barrier in the shear thinning regime, an apparent Herschel–Buckley form of the shear rate dependence of the steady-state shear stress, exponential growth of different measures of a yield or flow stress with packing fraction, and reduced fragility and dynamic heterogeneity under deformation were previously shown to be in good agreement with experiments. The central new question we address here is the defining feature of the transient response—the stress overshoot. In contrast to the steady-state flow regime, understanding the transient response requires an explicit treatment of the coupled nonequilibrium evolution of structure, elastic modulus, and stress relaxation time. We formulate a new quantitative model for this aspect in a physically motivated and computationally tractable manner. Theoretical predictions for the stress overshoot are shown to be in good agreement with experimental observations in the metastable ultradense regime of hard sphere colloidal suspensions as a function of shear rate and packing fraction, and accounting for deformation-assisted activated motion appears to be crucial for both the transient and steady-state responses.
Chronic Statin Treatment Does Not Impair Exercise Lipolysis or Fat Oxidation in Exercise-Trained Individuals With Obesity and Dyslipidemia
Authors: Alvarez-Jimenez Laura , Moreno-Cabañas Alfonso , Morales-Palomo Felix , Ortega Juan F. , Mora-Rodriguez Ricardo
Published: February 2023

Objective: To determine whether statin medication in individuals with obesity, dyslipidemia, and metabolic syndrome affects their capacity to mobilize and oxidize fat during exercise. Methods: Twelve individuals with metabolic syndrome pedaled during 75 min at 54 ± 13% (5.7 ± 0.5 metabolic equivalents) while taking statins (STATs) or after 96-hr statin withdrawal (PLAC) in a randomized double-blind fashion. Results: At rest, PLAC increased low-density lipoprotein cholesterol (i.e., STAT 2.55 ± 0.96 vs. PLAC 3.16 ± 0.76 mmol/L; p = .004) and total cholesterol blood levels (i.e., STAT 4.39 ± 1.16 vs. PLAC 4.98 ± 0.97 mmol/L; p = .008). At rest, fat oxidation (0.99 ± 0.34 vs. 0.76 ± 0.37 μmol·kg−1·min−1 for STAT vs. PLAC; p = .068) and the rates of plasma appearance of glucose and glycerol (i.e., Ra glucose–glycerol) were not affected by PLAC. After 70 min of exercise, fat oxidation was similar between trials (2.94 ± 1.56 vs. 3.06 ± 1.94 μmol·kg−1·min−1, STA vs. PLAC; p = .875). PLAC did not alter the rates of disappearance of glucose in plasma during exercise (i.e., 23.9 ± 6.9 vs. 24.5 ± 8.2 μmol·kg−1·min−1 for STAT vs. PLAC; p = .611) or the rate of plasma appearance of glycerol (i.e., 8.5 ± 1.9 vs. 7.9 ± 1.8 μmol·kg−1·min−1 for STAT vs. PLAC; p = .262). Conclusions: In patients with obesity, dyslipidemia, and metabolic syndrome, statins do not compromise their ability to mobilize and oxidize fat at rest or during prolonged, moderately intense exercise (i.e., equivalent to brisk walking). In these patients, the combination of statins and exercise could help to better manage their dyslipidemia.
Disruptions in endocytic traffic contribute to the activation of the NLRP3 inflammasome
Authors: Lee Bali , Hoyle Christopher , Wellens Rose , Green Jack P. , Martin-Sanchez Fatima , Williams Daniel M. , Matchett Billie J. , Seoane Paula I. , Bennett Hayley , Adamson Antony , Lopez-Castejon Gloria , Lowe Martin , Brough David
Published: February 2023

Inflammation driven by the NLRP3 inflammasome is coordinated through multiple signaling pathways and is regulated by subcellular organelles. Here, we tested the hypothesis that NLRP3 senses disrupted endosome trafficking to trigger inflammasome formation and inflammatory cytokine secretion. NLRP3-activating stimuli disrupted endosome trafficking and triggered localization of NLRP3 to vesicles positive for endolysosomal markers and for the inositol lipid PI4P. Chemical disruption of endosome trafficking sensitized macrophages to the NLRP3 activator imiquimod, driving enhanced inflammasome activation and cytokine secretion. Together, these data suggest that NLRP3 can sense disruptions in the trafficking of endosomal cargoes, which may explain in part the spatial activation of the NLRP3 inflammasome. These data highlight mechanisms that could be exploited in the therapeutic targeting of NLRP3.
Ecological Stability Emerges at the Level of Strains in the Human Gut Microbiome
Authors: Wolff Richard , Shoemaker William , Garud Nandita
Published: February 2023

To date, there has been an intense focus on the ecological dynamics of the human gut microbiome at the species level. However, there is considerable genetic diversity within species at the strain level, and these intraspecific differences can have important phenotypic effects on the host, impacting the ability to digest certain foods and metabolize drugs.
Aryl Hydrocarbon Receptor Activation Ameliorates Acute Respiratory Distress Syndrome through Regulation of Th17 and Th22 Cells in the Lungs
Authors: Holloman Bryan Latrell , Cannon Alkeiver , Wilson Kiesha , Nagarkatti Prakash , Nagarkatti Mitzi
Published: February 2023

Acute respiratory distress syndrome (ARDS) is a type of respiratory failure that is triggered by a variety of bacterial and viral infections, including the coronavirus SARS-CoV2. ARDS is associated with a hyperimmune response in the lungs that which is challenging to treat.
Cell-Cell Signaling Proteobacterial LuxR Solos: a Treasure Trove of Subgroups Having Different Origins, Ligands, and Ecological Roles
Authors: Bez Cristina , Geller Alexander Martin , Levy Asaf , Venturi Vittorio
Published: February 2023

Many proteobacteria possess LuxR solos which are quorum sensing LuxR-type regulators that are not paired with a cognate LuxI-type synthase. LuxR solos have been implicated in intraspecies, interspecies, and interkingdom communication by sensing endogenous and exogenous acyl-homoserine lactones (AHLs) as well as non-AHL signals.
Antimicrobial Susceptibility Testing Using the MYCO Test System and MIC Distribution of 8 Drugs against Clinical Isolates of Nontuberculous Mycobacteria from Shanghai
Authors: Ying Ruoyan , Yang Jinghui , Wu Xiaocui , Yu Fangyou , Sha Wei
Published: February 2023

We designed customized panel that contains 8 repurposed drugs, including vancomycin (VAN), bedaquiline (BDQ), delamanid (DLM), faropenem (FAR), meropenem (MEM), clofazimine (CLO), cefoperazone-avibactam (CFP-AVI), and cefoxitin (FOX) from the MYCO test system. To better understand the efficacy of these 8 drugs against different NTM species, we determined the MICs of 241 NTM isolates collected in Shanghai, China.
Maternal Rumen Bacteriota Shapes the Offspring Rumen Bacteriota, Affecting the Development of Young Ruminants
Authors: Jin Shuwen , Zhang Zhe , Zhang Gonghai , He Bo , Qin Yilang , Yang Bin , Yu Zhongtang , Wang Jiakun
Published: February 2023

Using a study design that enabled direct comparison of the rumen microbiota between sheep dams and their lambs, between littermates, and between sheep dams and lambs from other mothers, we identified the heritable subsets of rumen bacteriota in Hu sheep, some of which may play important roles in affecting the growth traits of young lambs. Some maternal rumen bacteria could help predict the growth traits of the young offspring, and they may assist in breeding of and selection for high-performance sheep.
Study of Microbial Sulfur Metabolism in a Near Real-Time Pathway through Confocal Raman Quantitative 3D Imaging
Authors: He Wanying , Cai Ruining , Xi Shichuan , Yin Ziyu , Du Zengfeng , Luan Zhendong , Sun Chaomin , Zhang Xin
Published: February 2023

Microorganisms contribute significantly to the formation of deep-sea elemental sulfur, so studies on their growth and dynamic sulfur metabolism are important to understand the deep-sea sulfur cycle. However, near real-time
in situ
nondestructive metabolic studies of microorganisms remain a great challenge due to the limitations of existing methods.
Epidemiology and Genetic Characteristics of Carbapenem-Resistant Escherichia coli in Chinese Intensive Care Unit Analyzed by Whole-Genome Sequencing: a Prospective Observational Study
Authors: Ding Ying , Zhuang Hemu , Zhou Junxin , Xu Lijie , Yang Yi , He Jintao , Liang Min , Jia Shicheng , Guo Xiuliu , Han Xinhong , Liu Haiyang , Zhang Linghong , Jiang Yan , Yu Yunsong
Published: February 2023

CREC represents a public health threat worldwide, and its colonization precedes or occurs simultaneously with infection; once the colonization rate increases, the infection rate rises sharply. In our hospital, the colonization rate of CREC remained low, and almost all of the CREC isolates detected were ICU acquired.
Plasma Gelsolin Enhances Phagocytosis of Candida auris by Human Neutrophils through Scavenger Receptor Class B
Authors: Suprewicz Łukasz , Skłodowski Karol , Walewska Alicja , Deptuła Piotr , Sadzyńska Alicja , Eljaszewicz Andrzej , Moniuszko Marcin , Janmey Paul A. , Bucki Robert
Published: February 2023

The incidence of life-threatening multidrug-resistant
Candida auris
infections is rapidly growing, causing substantial economic costs due to outbreaks in hospital wards. Primary and secondary immunodeficiencies in susceptible individuals, such as those with leukemia, solid organ transplants, diabetes, and ongoing chemotherapy, often correlate with decreased plasma gelsolin concentration (hypogelsolinemia) and impairment of innate immune responses due to severe leukopenia.
Efficacy of clozapine compared with other second-generation antipsychotic drugs in patients with treatment-resistant schizophrenia: protocol for a systematic review and individual patient data meta-analysis of randomised controlled trials
Authors: Siafis Spyridon , Schneider-Thoma Johannes , Hamza Tasnim , Bighelli Irene , Dong Shimeng , Hansen Wulf-Peter , Davis John M , Salanti Georgia , Leucht Stefan
Published: February 2023

Introduction

Guidelines recommend clozapine for treatment-resistant schizophrenia. However, meta-analysis of aggregate data (AD) did not demonstrate higher efficacy of clozapine compared with other second-generation antipsychotics but found substantial heterogeneity between trials and variation between participants in treatment effects. Therefore, we will conduct an individual participant data (IPD) meta-analysis to estimate the efficacy of clozapine compared with other second-generation antipsychotics while accounting for potentially important effect modifiers.

Methods and analysis

In a systematic review, two reviewers will independently search Cochrane Schizophrenia Group’s trial register (without restrictions in date, language or state of publication) and related reviews. We will include randomised controlled trials (RCTs) in participants with treatment-resistant schizophrenia comparing clozapine with other second-generation antipsychotics for at least 6 weeks. We will apply no restrictions in age, gender, origin, ethnicity or setting, but exclude open-label studies, studies from China, experimental studies and phase II of cross-over trials. IPD will be requested from trial authors and cross-check against published results. AD will be extracted in duplicate. Risk of bias will be assessed using Cochrane’s Risk of Bias 2 tool.

The primary outcome will be overall symptoms of schizophrenia.

We will synthesise results using random-effects meta-analysis and meta-regression methods in a 3-level Bayesian model. The model combines IPD with AD when IPD is not available for all studies, and include participant, intervention and study design characteristics as potential effect modifiers. The effect size measures will be mean difference (or standardised mean difference when different scales were used). Confidence in the evidence will be assessed using GRADE.

Ethics and dissemination

This project has been approved by the ethics commission of the Technical University of Munich (#612/21 S-NP). The results will be published open-access in a peer-review journal and a plain-language version of the results will be disseminated.

If we need to amend this protocol, we will describe the change and give the rationale in a specific section in the resulting publication ‘Changes with respect to the protocol’.

Systematic review registration

PROSPERO (#CRD42021254986)
Double-blind, randomised placebo-controlled clinical trial of metformin as an adjunct to a sleep–wake, activity and metabolically focused behavioural intervention to improve cardiometabolic outcomes and mood symptoms in youth with major mood syndromes: study protocol
Authors: Wilson Chloe , Carpenter Joanne Sarah , Nichles Alissa , Zmicerevska Natalia , Song Yun Ju Christine , McHugh Catherine , Hamilton Blake , Hockey Samuel , Crouse Jacob , Koethe Dagmar , Scott Elizabeth M , Hickie Ian B
Published: February 2023

Introduction

Metformin is a medication likely to improve measures of cardiometabolic disturbance in young people with mental illness. Evidence also suggests metformin may improve depressive symptoms. This 52-week double-blind randomised control trial (RCT) aims to investigate the efficacy of metformin pharmacotherapy as an adjunct to a healthy lifestyle behavioural intervention in improving cardiometabolic outcomes, and depressive, anxiety and psychotic symptoms in youth with clinically diagnosed major mood syndromes.

Methods and analysis

At least 266 young people aged 16–25 presenting for mental healthcare for major mood syndromes who are also at risk for poor cardiometabolic outcomes will be invited to participate in this study. All participants will engage in a 12-week sleep–wake, activity and metabolically focused behavioural intervention programme. As an adjunctive intervention, participants will receive either metformin (500–1000 mg) or placebo pharmacotherapy for 52 weeks.

Participants will undergo a series of assessments including: (1) self-report and clinician-administered assessments; (2) blood tests; (3) anthropometric assessments (height, weight, waist circumference and blood pressure); and (4) actigraphy. Univariate and multivariate tests (generalised mixed-effects models) will be used to examine changes in primary and secondary outcomes (and associations with predetermined predictor variables).

Ethics and dissemination

This study has been approved by the Sydney Local Health District Research Ethics and Governance Office (X22-0017). The results of this double-blind RCT will be disseminated into the scientific and broader community through peer-reviewed journals, conference presentations, social media and university websites.

Trial registration number

Australian New Zealand Clinical Trials Registry (ANZCTR) Number: ACTRN12619001559101p, 12 November 2019.
Antimicrobial Stewardship for Ventilator Associated Pneumonia in Intensive Care (the ASPIC trial): study protocol for a randomised controlled trial
Authors: Foucrier Arnaud , Roquilly Antoine , Bachelet Delphine , Martin-Loeches Ignacio , Bougle Adrien , Timsit Jean-François , Montravers Philippe , Zahar Jean-Ralph , Eloy Philippine , Weiss Emmanuel
Published: February 2023

Introduction

Ventilator-associated pneumonia (VAP) remains the leading cause of infections treated in the intensive care units (ICU). In a personalised care approach, we hypothesise that the duration of treatment of VAP can be reduced in function of the response to treatment.

Methods and analysis

The Antimicrobial Stewardship for Ventilator-Associated Pneumonia in Intensive Care (ASPIC) trial is a pragmatic national multicentre, phase III, non-inferiority, comparative randomised (1:1) single-blinded clinical trial. Five hundred and ninety adult patients hospitalised in 24 French ICU with a microbiologically confirmed first episode of VAP that received appropriate empirical antibiotic therapy will be included. They will be randomly allocated to standard management with duration of appropriate antibiotic fixed for 7 days according to international guidelines or antimicrobial stewardship based on daily clinical assessment of clinical cure. The assessment of clinical cure will be repeated daily until at least three criteria of clinical cure are met, allowing the discontinuation of antibiotic therapy in experimental group. The primary endpoint is a composite endpoint combining of all-cause mortality measured at day 28, treatment failure or new episode of microbiologically confirmed VAP until day 28.

The aim of the study is to demonstrate that a strategy to reduce the duration of antibiotic therapy for VAP based on clinical assessment is safe could lead to changes in practice as part of a personalised therapeutic approach, by reducing exposure to antibiotics and their side effects.

Ethics and dissemination

The ASPIC trial has been approved by the French regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM; EUDRACT number 2021-002197-78, 19 August 2021) and an independent ethics committee the Comité de Protection des Personnes Ile-de-France III (CNRIPH : 21.03.25.60729, 10 October 2021) for the study protocol (version ASPIC−1.3; 03 September 2021) for all study centres. Participant recruitment is scheduled to begin in 2022. Results will be published in international peer-reviewed medical journals.

Trial registration number

NCT05124977.
Association between frailty, chronic conditions and socioeconomic status in community-dwelling older adults attending primary care: a cross-sectional study using practice-based research network data
Authors: Mangin Dee , Lawson Jennifer , Risdon Cathy , Siu Henry Yu-Hin , Packer Tamar , Wong Sabrina T , Howard Michelle
Published: February 2023

Objectives

Frailty is a multidimensional syndrome of loss of reserves in energy, physical ability, cognition and general health. Primary care is key in preventing and managing frailty, mindful of the social dimensions that contribute to its risk, prognosis and appropriate patient support. We studied associations between frailty levels and both chronic conditions and socioeconomic status (SES).

Design

Cross-sectional cohort study

Setting

A practice-based research network (PBRN) in Ontario, Canada, providing primary care to 38 000 patients. The PBRN hosts a regularly updated database containing deidentified, longitudinal, primary care practice data.

Participants

Patients aged 65 years or older, with a recent encounter, rostered to family physicians at the PBRN.

Intervention

Physicians assigned a frailty score to patients using the 9-point Clinical Frailty Scale. We linked frailty scores to chronic conditions and neighbourhood-level SES to examine associations between these three domains.

Results

Among 2043 patients assessed, the prevalence of low (scoring 1–3), medium (scoring 4–6) and high (scoring 7–9) frailty was 55.8%, 40.3%, and 3.8%, respectively. The prevalence of five or more chronic diseases was 11% among low-frailty, 26% among medium-frailty and 44% among high-frailty groups (χ2=137.92, df 2, p<0.001). More disabling conditions appeared in the top 50% of conditions in the highest-frailty group compared with the low and medium groups. Increasing frailty was significantly associated with lower neighbourhood income (χ2=61.42, df 8, p<0.001) and higher neighbourhood material deprivation (χ2=55.24, df 8, p<0.001).

Conclusion

This study demonstrates the triple disadvantage of frailty, disease burden and socioeconomic disadvantage. Frailty care needs a health equity approach: we demonstrate the utility and feasibility of collecting patient-level data within primary care. Such data can relate social risk factors, frailty and chronic disease towards flagging patients with the greatest need and creating targeted interventions.
Please wear a mask: a systematic case for mask wearing mandates
Authors: Fumagalli Roberto
Published: February 2023

This paper combines considerations from ethics, medicine and public health policy to articulate and defend a systematic case for mask wearing mandates (MWM). The paper argues for two main claims of general interest in favour of MWM. First, MWM provide a more effective, just and fair way to tackle the ongoing COVID-19 pandemic than policy alternatives such as laissez-faire approaches, mask wearing recommendations and physical distancing measures. And second, the proffered objections against MWM may justify some exemptions for specific categories of individuals, but do not cast doubt on the justifiability of these mandates. Hence, unless some novel decisive objections are put forward against MWM, governments should adopt MWM.
Diagnostic value of intereye difference metrics for optic neuritis in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders
Authors: Oertel Frederike Cosima , Zimmermann Hanna G , Motamedi Seyedamirhosein , Chien Claudia , Aktas Orhan , Albrecht Philipp , Ringelstein Marius , Dcunha Anitha , Pandit Lekha , Martinez-Lapiscina Elena H , Sanchez-Dalmau Bernardo , Villoslada Pablo , Palace Jacqueline , Roca-Fernández Adriana , Leite Maria Isabel , Sharma Srilakshmi M , Leocani Letizia , Pisa Marco , Radaelli Marta , Lana-Peixoto Marco Aurélio , Fontenelle Mariana Andrade , Havla Joachim , Ashtari Fereshteh , Kafieh Rahele , Dehghani Alireza , Pourazizi Mohsen , Marignier Romain , Cobo-Calvo Alvaro , Asgari Nasrin , Jacob Anu , Huda Saif , Mao-Draayer Yang , Green Ari J , Kenney Rachel , Yeaman Michael R , Smith Terry J , Cook Lawrence , Brandt Alexander U , Paul Friedemann , Petzold Axel
Published: February 2023

Background

The novel optic neuritis (ON) diagnostic criteria include intereye differences (IED) of optical coherence tomography (OCT) parameters. IED has proven valuable for ON diagnosis in multiple sclerosis but has not been evaluated in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4+NMOSD). We evaluated the diagnostic accuracy of intereye absolute (IEAD) and percentage difference (IEPD) in AQP4+NMOSD after unilateral ON >6 months before OCT as compared with healthy controls (HC).

Methods

Twenty-eight AQP4+NMOSD after unilateral ON (NMOSD-ON), 62 HC and 45 AQP4+NMOSD without ON history (NMOSD-NON) were recruited by 13 centres as part of the international Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica study. Mean thickness of peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) were quantified by Spectralis spectral domain OCT. Threshold values of the ON diagnostic criteria (pRNFL: IEAD 5 µm, IEPD 5%; GCIPL: IEAD: 4 µm, IEPD: 4%) were evaluated using receiver operating characteristics and area under the curve (AUC) metrics.

Results

The discriminative power was high for NMOSD-ON versus HC for IEAD (pRNFL: AUC 0.95, specificity 82%, sensitivity 86%; GCIPL: AUC 0.93, specificity 98%, sensitivity 75%) and IEPD (pRNFL: AUC 0.96, specificity 87%, sensitivity 89%; GCIPL: AUC 0.94, specificity 96%, sensitivity 82%). The discriminative power was high/moderate for NMOSD-ON versus NMOSD-NON for IEAD (pRNFL: AUC 0.92, specificity 77%, sensitivity 86%; GCIP: AUC 0.87, specificity 85%, sensitivity 75%) and for IEPD (pRNFL: AUC 0.94, specificity 82%, sensitivity 89%; GCIP: AUC 0.88, specificity 82%, sensitivity 82%).

Conclusions

Results support the validation of the IED metrics as OCT parameters of the novel diagnostic ON criteria in AQP4+NMOSD.
Anti-Argonaute antibodies as a potential biomarker in NMOSD
Authors: Carta Sara , Le Duy Do , Rogemond Veronique , Derache Nathalie , Chaumont Hugo , Fromont Agnès , Cabasson Sebastien , Boudot de la Motte Marine , Honnorat Jerome , Marignier Romain
Published: February 2023

Background and objectives

Neuromyelitis optica spectrum disorders (NMOSDs) are a group of diseases mainly characterised by recurrent optic neuritis and/or myelitis. Most cases are associated with a pathogenic antibody against aquaporin-4 (AQP4-Ab), while some patients display autoantibodies targeting the myelin oligodendrocyte glycoprotein (myelin oligodendrocyte glycoprotein antibodies (MOG-Abs)). Anti-Argonaute antibodies (Ago-Abs) were first described in patients with rheumatological conditions and were recently reported as a potential biomarker in patients with neurological disorders. The aims of the study were to investigate if Ago-Abs can be detected in NMOSD and to evaluate its clinical usefulness.

Methods

Sera from patients prospectively referred to our centre with suspected NMOSD were tested for AQP4-Abs, MOG-Abs and Ago-Abs with cell-based assays.

Results

The cohort included 104 prospective patients: 43 AQP4-Abs-positive cases, 34 MOG-Abs positive cases and 27 double-negative patients. Ago-Abs were detected in 7 of 104 patients (6.7%). Clinical data were available for six of seven patients. The median age at onset of patients with Ago-Abs was 37.5 [IQR 28.8–50.8]; five of six patients tested positive also for AQP4-Abs. Clinical presentation at onset was transverse myelitis in five patients, while one presented with diencephalic syndrome and experienced a transverse myelitis during follow-up. One case presented a concomitant polyradiculopathy. Median EDSS score at onset was 7.5 [IQR 4.8–8.4]; median follow-up was 40.3 months [IQR 8.3–64.7], and median EDSS score at last evaluation was 4.25 [IQR 1.9–5.5].

Conclusion

Ago-Abs are present in a subset of patients with NMOSD and, in some cases, represent the only biomarker of an autoimmune process. Their presence is associated with a myelitis phenotype and a severe disease course.
A rare side effect of methotrexate therapy: drug-induced osteopathy with multiple fractures of the lower limb
Authors: Singh Delila , Hesse Nina , Skapenko Alla , Schulze-Koops Hendrik
Published: February 2023

Methotrexate is associated with bone lesions that are rare and, although presenting with a typical localisation to the lower extremities and appearing with a characteristic radiologic morphology, largely unknown and often misdiagnosed as osteoporotic insufficiency fractures. The correct and early diagnosis, however, is key for treatment and prevention of further osteopathology. Here, we present a patient with rheumatoid arthritis who developed multiple painful insufficiency fractures in the left foot (processus anterior calcanei, tuber calcanei) and in the right lower leg and foot (anterior and dorsal calcaneus and at the cuboid and distal tibia) during therapy with methotrexate, which were all misdiagnosed as osteoporotic. The fractures occurred between 8 months and 35 months after starting methotrexate. Discontinuation of methotrexate resulted in rapid pain relief and no further fractures have occurred. This case powerfully demonstrates the importance of raising awareness of methotrexate osteopathy in order to take appropriate therapeutic measures, including and perniciously discontinuing methotrexate.
Folic acid protects against age-associated apoptosis and telomere attrition of neural stem cells in senescence-accelerated mouse prone 8
Authors: Li Zhenshu , Cai Ke , Sun Yue , Zhou Dezheng , Yan Jing , Luo Suhui , Huang Guowei , Gao Yuxia , Li Wen
Published: February 2023

Folic acid (FA) could improve cognitive performance and attenuate brain cell injury in the aging brain; FA supplementation is also associated with inhibiting neural stem cell (NSC) apoptosis. However, its role in age-associated telomere attrition remains unclear. We hypothesized that FA supplementation attenuates age-associated apoptosis of NSCs in mice via alleviating telomere attrition in senescence-accelerated mouse prone 8 (SAMP8). In this study, 4-month-old male SAMP8 mice were assigned equal numbers to four different diet groups ( n = 15). Fifteen age-matched senescence-accelerated mouse resistant 1 mice, fed with the FA-normal diet, were used as the standard aging control group. After FA treatment for 6 months, all mice were sacrificed. NSC apoptosis, proliferation, oxidative damage, and telomere length were evaluated by immunofluorescence and Q-fluorescent in situ hybridization. The results showed that FA supplementation inhibited age-associated NSC apoptosis and prevented telomere attrition in the cerebral cortex of SAMP8 mice. Importantly, this effect might be explained by the decreased levels of oxidative damage. In conclusion, we demonstrate it may be one of the mechanisms by which FA inhibits age-associated NSC apoptosis by alleviating telomere length shortening.
ERCC6 plays a promoting role in the progression of non-small cell lung cancer
Authors: Luo Hui , Xiao Zhehao , Huang Cheng , Wu Wei , Xie Qingbin
Published: February 2023

Although excision repair cross-complementing group 6 (ERCC6) has been reported to be associated with lung cancer risk, the specific roles of ERCC6 in non-small cell lung cancer (NSCLC) progression are inadequately studied. Thus, this study aimed to examine the potential functions of ERCC6 in NSCLC. The expression of ERCC6 in NSCLC was analyzed by immunohistochemical staining and quantitative PCR. Celigo cell count, colony formation, flow cytometry, wound-healing, and transwell assays were used to evaluate the effects of ERCC6 knockdown on the proliferation, apoptosis, and migration of NSCLC cells. The effect of ERCC6 knockdown on tumor-forming ability of NSCLC cells was estimated by establishing xenograft model. ERCC6 was highly expressed in NSCLC tumor tissues and cell lines, and high ERCC6 expression was significantly associated with poor overall survival. Additionally, ERCC6 knockdown significantly suppressed cell proliferation, colony formation and migration, while accelerated cell apoptosis of NSCLC cells in vitro. Moreover, ERCC6 knockdown inhibited tumor growth in vivo. Further studies verified that ERCC6 knockdown attenuated the expression levels of Bcl-w, CCND1, and c-Myc. Altogether, these data unveil a major role of ERCC6 in the progression of NSCLC, and ERCC6 is expected to become a novel therapeutic target for NSCLC treatment.
Feasibility of the observation of a heavy scalar through the fully hadronic final state at the LHeC
Authors: Malwa Elias , Kumar Mukesh , Mellado Bruce , Ruan Xifeng
Published: February 2023

The proposed future Large Hadron electron collider provides sufficient center of mass energies, $$\sqrt{s}$$

s

, to probe heavy particles decaying into $$W^\pm (Z)-$$

W
±

(
Z
)

-

boson of mass $$>2m_W$$

>
2

m
W

$$(2m_Z)$$

(
2

m
Z

)

. In this work we present a study to produce one such heavy CP even scalar H of mass $$2m_h< m_H < 2 m_t$$

2

m
h

<

m
H

<
2

m
t

through charged-current production mode where $$H \rightarrow W^+W^-$$

H
→

W
+

W
-

, where hadronic decay of $$W^\pm -$$

W
±

-

boson is considered to reconstruct $$m_H$$

m
H

. Due to the presence of missing energy and forward jet in this channel, it is challenging to reconstruct $$m_H$$

m
H

with above final state and thus we employed three different reconstruction methods and discuss the significance of each one. For this analysis we consider a benchmark value of $$m_H = 270$$

m
H

=
270

GeV and $$\sqrt{s} \approx 1.3$$

s

≈
1.3

TeV with an assumed luminosity of 1 ab$$^{-1}$$

-
1

.
$$AdS_5$$ vacua and holographic RG flows from 5D $$N=4$$ gauged supergravity
Authors: Karndumri Parinya
Published: February 2023

We study five-dimensional $$N=4$$

N
=
4

gauged supergravity coupled to five vector multiplets with $$SO(2)_D\times SO(3)\times SO(3)$$

S
O

(
2
)

D

×
S
O

(
3
)

×
S
O

(
3
)

gauge group. There are four supersymmetric $$AdS_5$$

A
d

S
5

vacua in the truncation to $$SO(2)_{\text {diag}}$$

S
O

(
2
)

diag

invariant scalars. Two of these vacua preserve the full $$N=4$$

N
=
4

supersymmetry with $$SO(2)_D\times SO(3)\times SO(3)$$

S
O

(
2
)

D

×
S
O

(
3
)

×
S
O

(
3
)

and $$SO(2)_D\times SO(3)_{\text {diag}}$$

S
O

(
2
)

D

×
S
O

(
3
)

diag

symmetries. These have an analogue in $$N=4$$

N
=
4

gauged supergravity with $$SO(2)\times SO(3)\times SO(3)$$

S
O
(
2
)
×
S
O
(
3
)
×
S
O
(
3
)

gauge group. The other two $$AdS_5$$

A
d

S
5

vacua preserve only $$N=2$$

N
=
2

supersymmetry with $$SO(2)_{\text {diag}}\times SO(3)$$

S
O

(
2
)

diag

×
S
O

(
3
)

and $$SO(2)_{\text {diag}}$$

S
O

(
2
)

diag

symmetry. The former has an analogue in the previous study of $$SO(2)_D\times SO(3)$$

S
O

(
2
)

D

×
S
O

(
3
)

gauge group while the latter is a genuinely new $$N=2$$

N
=
2

$$AdS_5$$

A
d

S
5

vacuum. These vacua should be dual to $$N=2$$

N
=
2

and $$N=1$$

N
=
1

superconformal field theories (SCFTs) in four dimensions with different flavour symmetries. We give the full scalar mass spectra at all of the $$AdS_5$$

A
d

S
5

critical points which provide information on conformal dimensions of the dual operators. Finally, we study holographic RG flows interpolating between these $$AdS_5$$

A
d

S
5

vacua and find a new class of solutions. In addition to the RG flows from the trivial $$SO(2)_D\times SO(3)\times SO(3)$$

S
O

(
2
)

D

×
S
O

(
3
)

×
S
O

(
3
)

$$N=4$$

N
=
4

critical point, at the origin of the scalar manifold, to all the other critical points, there is a family of RG flows from the trivial $$N=4$$

N
=
4

critical point to the new $$SO(2)_{\text {diag}}$$

S
O

(
2
)

diag

$$N=2$$

N
=
2

critical point that pass arbitrarily close to the $$SO(2)_D\times SO(3)_{\text {diag}}$$

S
O

(
2
)

D

×
S
O

(
3
)

diag

$$N=4$$

N
=
4

critical point.
Analytical expressions for pulse profile of neutron stars in plasma environments
Authors: Briozzo Gastón , Gallo Emanuel
Published: February 2023

We present an analytical study of light curves of slowly rotating radio pulsars with emphasis on the chromatic effects derived from the presence of a plasma environment; analyzing the effects of the compactness, the metric model, and the electronic plasma density profile. After doing a numerical integration of the trajectories and luminosity curves of pulsars for different spherically symmetric metrics representing the exterior region of the pulsar, we generalize the approximate Beloborodov formula in order to include plasma corrections, obtaining simple analytical expressions for the trajectories and the observed flux and significantly simplifying the calculation of the pulse profiles by a drastic reduction of their computational cost. We study the errors committed by our approximation, comparing the numerical and analytical procedures. We also show how to use the new formalism to model the flux coming from different emission caps, not necessarily circular or antipodal and including the case of ring-shaped hot spots. Finally, we extend the classification introduced by Beloborodov to the case of two distinguishable, non-antipodal, finite size emission caps, showing the respective classification maps and some of the characteristic pulse profiles.
The Relationship of Patient Characteristics and Prolonged Pain after Treatment of Carpometacarpal Joint Arthritis of the Thumb
Authors: ARASEGAWA Yoshito , MURAMATSU Keiichi , INOUE Kiyotaka , UEDA Takeshi , JYOUICHI Kouhei , KINOSHITA Daisuke
Published: February 2023

Background: The carpometacarpal (CMC) joint of the thumb is the second most common site of osteoarthritis in the hand. Clinical severity stage of CMC joint arthritis has not been correlated with the pain level of the patient. Recently, the association of joint pain with patient psychological factor, such as depression or case-specific personality, has been investigated. This study was designed to determine the impact of psychological factors to residual pain after treatment of CMC joint arthritis, using pain catastrophizing scale (PCS) and the Yatabe–Guilford (YG) personality test.

Methods: Twenty-six patients (7 males and 19 females) with 26 hands were included. Thirteen patients classified as Eaton stage 3 underwent suspension arthroplasty and 13 patients as Eaton stage 2 underwent conservative treatment using a custom fitted orthosis. Clinical evaluation was assessed using Visual Analogue Scale (VAS) and the quick Disabilities of the Arm, Shoulder and Hand Questionnaire Score (QuickDASH) at initial evaluation, at 1 month and at 3 months after treatment. We compared both groups using the PCS and YG test.

Results: The PCS showed significant difference in the VAS scores only at initial evaluation in both surgical and conservative treatment. There was a significant difference in VAS at 3 months between the two groups in both surgical and conservative treatment and in QuickDASH at 3 months in conservative treatment.

Conclusions: The YG test has been used mainly in psychiatry. Although this test has not yet been used worldwide, its usefulness has been recognised and applied clinically, especially in Asia. Patient characteristics are strongly associated with residual pain of the CMC joint arthritis of the thumb. The YG test is a useful tool to analyse pain-related patient characteristics and can be utilised to determine the therapeutic modalities and most effective rehabilitation programme for pain control.

Level of Evidence: Level III (Therapeutic)