bluuebunny/crossref_metadata_2025 huggingface dataset:
Exoproducts of the Most Common
Achromobacter
Species in Cystic Fibrosis Evoke Similar Inflammatory Responses
In Vitro
Authors: Sahl Cecilia , Baumgarten Maria , Shannon Oonagh , Påhlman Lisa I.
Published: June 2023

Achromobacter xylosoxidans
is an emerging pathogen among people with cystic fibrosis (CF). Current routine diagnostic methods are often unable to distinguish
A. xylosoxidans
from other
Achromobacter
species, and the clinical relevance of different species is still unknown.
Increased Production of Pathogenic, Airborne Fungal Spores upon Exposure of a Soil Mycobiota to Chlorinated Aromatic Hydrocarbon Pollutants
Authors: Martins Celso , Piontkivska Daryna , Mil-Homens Dalila , Guedes Paula , Jorge João M. P. , Brinco João , Bárria Cátia , Santos Ariana C. F. , Barras Ricardo , Arraiano Cecília , Fialho Arsénio , Goldman Gustavo H. , Silva Pereira Cristina
Published: June 2023

Fungi colonizing soil and organic pollutants often meet. The consequences of this encounter constitute an outstanding question.
Fifteen-minute consultation: Approach to the infant with stridor and suspected laryngomalacia
Authors: Whittaker Rachel , Nieto Hannah , Stephenson Kate
Published: June 2023

Stridor in an infant is a significant clinical sign; the primary objectives are to ensure that the airway is safe and to arrange timely, appropriate management. A structured history, examination and targeted investigations will determine the cause and guide care.

Laryngomalacia is the most common cause of stridor in an infant. The stridor tends to start shortly after birth, classically presenting as a positional stridor in the first month, which gradually resolves before 12–18 months of age in mild cases. There is a wide spectrum of severity; few require surgical intervention. This article will outline how the infant is appropriately assessed and managed.
Incidence of infant Gram-negative invasive bacterial infections in England, 2011–2019: an observational study using population-wide surveillance data
Authors: Hallmaier-Wacker Luisa K , Andrews Amelia , Hope Russell , Demirjian Alicia , Lamagni Theresa L , Collin Simon M
Published: June 2023

Objective

Invasive bacterial infections account for an estimated 15% of infant deaths worldwide. We aimed to estimate the incidence and trends in invasive bacterial infections in infants caused by Gram-negative pathogens in England during 2011–2019.

Methods

Laboratory-confirmed invasive bacterial infections in infants (<1 year old) were identified in the UK Health Security Agency national laboratory surveillance data from April 2011 to March 2019. Polymicrobial infections were defined as two or more bacterial species from the same normally sterile sample site. Early-onset infections were defined as <7 days from birth and late-onset as ≥7 days (neonates 7–28 days; infants ≥29 days). Trend analyses were carried out using Poisson (for episodes/incidence) and beta (for proportions) regression.

Results

The annual incidence of invasive bacterial infections increased by 35.9%, from 189.8 to 258.0 cases per 100 000 live births (p<0.001). Late-onset infections in both neonates and infants increased substantially over the study period (p<0.001), whereas early-onset infections increased slightly (p=0.002).Escherichia coliwas the most common Gram-negative pathogen isolated and accounted for 27.2% of the overall rise in Gram-negative infant disease incidence. Polymicrobial infections almost doubled, increasing from 29.2 to 57.7 per 100 000 live births (p<0.001), and mostly involved two species (81.3%, 1604/1974 episodes).

Conclusions

The incidence of Gram-negative invasive bacterial infections in infants increased between 2011/2012 and 2018/2019 in England, driven mainly by an increase in late-onset infections. Further work is required to elucidate the risk factors and drivers of this increased incidence so that opportunities for prevention can be identified.
How much does it cost to implement a community-based walking football programme for patients with type 2 diabetes?
Authors: Barbosa Ana , Brito João , Figueiredo Pedro , Seabra André , Ding Ding , Mendes Romeu
Published: June 2023

Objectives

The current study analysed the implementation costs of a community-based walking football exercise programme for patients with type 2 diabetes.

Methods

The direct costs of a community-based walking football programme for middle-aged and older male patients with type 2 diabetes, designed and tested in Porto (Portugal), were calculated from the payer’s perspective. One season of this programme consists of three sessions per week (60 min per session) for nine months (October to June). Cost calculations were based on two groups of 20 patients and included the sports infrastructure and equipment, human resources, pre-exercise clinical evaluation, medical equipment, technical training and other consumable costs. An economic depreciation of 1 year using the linear method for sports and electronic materials was considered. Cost analysis dated December 2021 and is expressed in international dollars ($).

Results

This programme was estimated to have a total implementation cost of $22 923.07; $2547.01/month; $573.08/patient; $106.13/session; $63.68/patient/month and $5.31/patient/session.

Conclusion

A community-based walking football programme for patients with type 2 diabetes is affordable and can be scaled up by local communities to promote physical activity and manage type 2 diabetes with the involvement of multiple stakeholders such as the football clubs, municipalities and primary healthcare units.
Why is pain management so difficult in the Emergency Department? A systematic mixed studies review and thematic synthesis of staff perceptions of enablers and barriers to pain management within the Emergency Department
Authors: Sampson Fiona C , Johnson Maxine
Published: June 2023

Introduction

Pain is the most common presenting feature within the ED, yet undertreatment of pain in the ED is a well-documented problem worldwide. Despite the development of interventions to address this problem, there is still limited understanding of how pain management can be improved within the ED. This systematic mixed studies review aims to identify and critically synthesise research exploring staff views of barriers and enablers to pain management to understand why pain continues to be undertreated in the ED.

Methods

We systematically searched five databases for qualitative, quantitative and mixed methods studies reporting ED staff views of barriers and enablers to pain management in the ED. Studies were quality assessed using the Mixed Methods Appraisal Tool. Data were extracted and qualitative themes were generated by deconstructing data then developing interpretative themes. Data were analysed using convergent qualitative synthesis design.

Results

We identified 15 297 articles for title/abstract review, reviewed 138 and included 24 in the results. Studies were not excluded due to low quality, although lower scoring studies contributed less data to the analysis. Quantitative surveys focused more on environmental factors (eg, high workload and bureaucratic restrictions), while qualitative studies revealed more insight about attitudes. We developed five interpretative themes from the thematic synthesis: (1) pain management is seen as important but not a clinical priority; (2) staff do not recognise the need to improve pain management; (3) the ED environment makes it difficult to improve pain management; (4) pain management is based on experience, not knowledge; and (5) staff lack trust in the patient’s ability to judge pain or manage it appropriately.

Conclusions

Overly focusing on environmental barriers as principal barriers to pain management may mask underlying beliefs that hinder improvements. Improving feedback on performance and addressing these beliefs may enable staff to understand how to prioritise pain management.
What can death records tell us about multimorbidity?
Authors: Baneshi Mohammad Reza , Eynstone-Hinkins James , McElwee Paul , Mishra Gita D , Moran Lauren , Waller Michael , Dobson Annette
Published: June 2023

Background

Multimorbidity has been measured from many data sources which show that prevalence increases with age and is usually greater among women than men and in more recent periods. Analyses of multiple cause of death data have shown different patterns of multimorbidity associated with demographic and other characteristics.

Methods

Deaths in Australia among over 1.7 million decedents aged 55+ were stratified into three types: medically certified deaths, coroner-referred deaths with natural underlying causes and coroner-referred deaths with external underlying causes. Multimorbidity was measured by prevalence of ≥2 causes and analysed over three periods based on administrative changes: 2006–2012, 2013–2016 and 2017–2018. Poisson regression was used to examine the influence of gender, age and period.

Results

The prevalence of deaths with multimorbidity was 81.0% for medically certified deaths, 61.1% for coroner-referred deaths with natural underlying causes and 82.4% for coroner-referred deaths with external underlying causes. For medically certified deaths, multimorbidity increased with age: incidence rate ratio (IRR 1.070, 95% CI 1.068, 1.072) was lower for women than men (0.954, 95% CI 0.952, 0.956) and changed little over time. For coroner-referred deaths with natural underlying causes, multimorbidity showed the expected pattern increasing with age (1.066, 95% CI 1.062, 1.070) and being higher for women than men (1.025, 95% CI 1.015, 1.035) and in more recent periods. For coroner-referred deaths with external underlying causes, there were marked increases over time that differed by age group due to changes in coding processes.

Conclusion

Death records can be used to examine multimorbidity in national populations but, like other data sources, how the data were collected and coded impacts the conclusions.
Dynamics and survival associations of T cell receptor clusters in patients with pleural mesothelioma treated with immunotherapy
Authors: Desai Aakash P , Kosari Farhad , Disselhorst Maria , Yin Jun , Agahi Alireza , Peikert Tobias , Udell Julia , Johnson Sarah H , Smadbeck James , Murphy Stephen , Karagouga Giannoula , McCune Alexa , Schaefer-Klein Janet , Borad Mitesh J , Cheville John , Vasmatzis George , Baas Paul , Mansfield Aaron
Published: June 2023

Background

Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI.

Methods

We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes,NCT02497508) or nivolumab and ipilimumab (INITIATE,NCT03048474) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral blood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis.

Results

We identified 4.2 million and 12 thousand complementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with 2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p<0.04). Furthermore, a high number of shared TCR clones between pretreatment tissue and in circulation was associated with improved survival (p=0.01). To potentially select antitumor clusters, we filtered for clusters that were (1) not found in healthy controls, (2) recurrent in multiple patients with mesothelioma, and (3) more prevalent in post-treatment than pretreatment samples. The detection of two-specific TCR clusters provided significant survival benefit compared with detection of 1 cluster (HR<0.001, p=0.026) or the detection of no TCR clusters (HR=0.10, p=0.002). These two clusters were not found in bulk tissue RNA-seq data and have not been reported in public CDR3 databases.

Conclusions

We identified two unique TCR clusters that were associated with survival on treatment with ICI in patients with pleural mesothelioma. These clusters may enable approaches for antigen discovery and inform future targets for design of adoptive T cell therapies.
Is ageing undesirable? An ethical analysis
Authors: García-Barranquero Pablo , Llorca Albareda Joan , Díaz-Cobacho Gonzalo
Published: June 2023

The technical possibilities of biomedicine open up the opportunity to intervene in ageing itself with the aim of mitigating, reducing or eliminating it. However, before undertaking these changes or rejecting them outright, it is necessary to ask ourselves if what would be lost by doing so really has much value. This article will analyse the desirability of ageing from an individual point of view, without circumscribing this question to the desirability or undesirability of death. First, we will present the three most widely used arguments to reject biomedical interventions against ageing. We will argue that only the last of these arguments provides a consistent answer to the question of the desirability of ageing. Second, we will show that the third argument falls prey to a conceptual confusion that we will call the paradox of ageing: although ageing entails negative health effects, it leads to a life stage with valuable goods. Both valuations, one positive and the other negative, refer to two different dimensions of ageing: the chronological and the biological. We will defend that, by not adequately distinguishing these two types of ageing, it does not become apparent that all the valuable goods exclusive to ageing derive only from its chronological dimension. Third, we will argue that, if we just conceive ageing biologically, it is undesirable. We will elaborate on the two kinds of undesirable effects biological ageing has: direct and indirect. Finally, we will respond to potential objections by adducing that these are insufficient to weaken our argument.
A refresh of the top 10 research priorities in cystic fibrosis
Authors: Rowbotham Nicola Jane , Smith Sherie , Elliott Zoe C , Cupid Belinda , Allen Lorna J , Cowan Katherine , Allen Lucy , Smyth Alan Robert
Published: June 2023

In 2018 we published the James Lind Alliance (JLA) top 10 priorities for clinical research in cystic fibrosis (CF), chosen jointly by the patient and clinical communities. These priorities have led to new research funding. To establish whether priorities have changed with novel modulator therapies, we undertook an online international update through a series of surveys and a workshop. Patients and clinicians (n=1417) chose the refreshed top 10 from 971 new research questions (suggested by patients and clinicians) and 15 questions from 2018. We are working with the international community to promote research based on these refreshed top 10 priorities.
Centrifuge modelling of piled foundations in swelling clays
Authors: Gaspar T.A.V. , Jacobsz S.W. , Smit G. , Osman A.S.
Published: June 2023

A study aimed towards assessing the variation in shaft capacity of piled foundations in swelling clays is presented. At the clay's in-situ water content, the results of pull-out tests on short-length piles revealed no dependency of shaft capacity on overburden stress. Conversely, after achieving a targeted value of swell, a strong dependency on overburden stress was observed. In upper portions of the profile where swell can occur relatively freely, swell-induced softening results in a reduction in pile shaft capacity. However, at greater depths where swell is largely suppressed, so too are the effects of swell-induced softening. For this reason, shaft capacity at depth was found to remain relatively constant before and after swell. The results of an instrumented pile test revealed an overriding dependency of lateral induced swell pressure on the magnitude of heave which has occurred. Irrespective of the level of overburden stress, lateral pressures against the pile were found to increase at early stages of the swelling process, but then reduce as swell continued and softening began to occur. Such a result highlights the importance of carefully considering the level of swell at which shaft capacity should be assessed if a conservative design is to be obtained.
Covariant light-front approach for $$B_c$$ decays into charmonium: implications on form factors and branching ratios
Authors: Zhang Zhi-Qing , Sun Zhi-Jie , Zhao Yan-Chao , Yang You-Ya , Zhang Zi-Yu
Published: June 2023

In this work, we investigate the form factors of $$B_c$$

B
c

decays into $$J/\Psi , \psi (2S,3S),\eta _c,$$

J
/
Ψ
,
ψ

(
2
S
,
3
S
)

,

η
c

,

$$ \eta _c(2\,S,3\,S), \chi _{c0}, \chi _{c1}, h_c$$

η
c

(
2

S
,
3

S
)

,

χ

c
0

,

χ

c
1

,

h
c

, and X(3872) mesons in the covariant light-front quark model (CLFQM). For the purpose of the branching ratio calculation, the form factors of $$B_c\rightarrow D^{(*)}, D^{(*)}_s$$

B
c

→

D

(

∗
)

,

D
s

(

∗
)

transitions are also included. In order to obtain the form factors for the physical transition processes, we need to extend these form factors from the space-like region to the time-like region. The $$q^2$$

q
2

dependence for each transition form factor is also plotted. Then, using the factorization method, we calculate the branching ratios of 80 $$B_c$$

B
c

decay channels with a charmonium involved in each mode. Most of our predictions are comparable to the results given by other approaches. As to the decays with the radially excited-state S-wave charmonia involved, such as $$\psi (2S,3S)$$

ψ
(
2
S
,
3
S
)

and $$\eta _c(2S,3S)$$

η
c

(
2
S
,
3
S
)

, two sets of parameters for their light-front wave functions, corresponding to scenario I (SI) and scenario II (SII), are adopted to calculate the branching ratios. By comparing with the future experimental data, one can discriminate which parameters are more favored.
Variation of nanoparticle shapes using the Hamilton–Crosser conductivity model for the gold–water nanofluid through a channel
Authors: Behera S. , Pattnaik P. K. , Mishra S. R. , Dash A. K.
Published: June 2023

The analysis brings out the investigation of the impact of thermal buoyancy on conducting the flow of an unsteady nanofluid within parallel moving walls embedded with a porous matrix. However, the medium is also embedded with permeable materials. Additionally, the impact of a uniform heat source is assumed to affect the designed model. The special attraction of the model is the variation of differently shaped nanoparticles using Hamilton–Crosser conductivity in which the base fluid is concatenated with the gold nanoparticles. The simulation is carried out for the governing equations numerically followed by requisite similarity rules used for the conversion of nonlinear problems of PDEs to ODEs. Further, shooting-based Runge–Kutta fourth-order scheme is imposed for the set of first-order ODEs. The behavior of several characterizing components within their range is presented for both the flow profiles via graphs and numerical results of the rate constants are deployed through the tabular form. Finally, the important outcomes are the particle concentration shows its greater impact in enhancing the fluid velocity neat the plate region and smooth retardation occurs at the central region further, the heat transfer rate retards significantly.
Quantum well-shape dependence of optical harmonic radiation
Authors: Kuang Yue , Zhang Chaojin , Zhao Bo , Du Henglei , Liu Chengpu
Published: June 2023

We theoretically investigate the spatial-non-homogeneous laser pulse propagation through the quantum well. It is shown that the odd-order and even-order harmonic generations can be found due to breaking the inversion symmetry of the system. Importantly, the spectral intensity of high-order harmonics can be enhanced by changing the propagation distances and spatial-non-homogeneity of incident laser field. Moreover, the quantum well’s shape has an important influence on the peak intensities of high-order harmonic generations, which may provide a new way to improve the spectral intensity of high-order harmonic generations.
Using shallow hydroacoustic data to image seafloor mass transport deposits on the North West Shelf of Australia: links to neotectonics
Authors: Keep M. , Lindhorst K. , Kuhnt W. , Holbourn A.
Published: June 2023

Mass transport deposits have long been known on the Exmouth Plateau, offshore NW Australia, identified in 2D and 3D industry seismic lines. The expedition SO257 in 2017 collected 30 high-resolution, shallow seismic lines along targeted transects on the northern Australian margin. Many of these imaged mass transport deposits, with the top 700–800 m of the section captured in detail not available with industry seismic data. We present nine new high-resolution seismic lines from three separate areas of the North West Shelf. Slides in the Roebuck Basin show complex anastomosing ductile extensional mechanisms, with multiple slip surfaces and no headscarps or adjacent faults. Slides on the Exmouth Plateau have fault control, with surface fault offsets of up to 300 m, indicating seismicity as a likely triggering mechanism. Slumps along the western margin of Western Australia are more limited in extent, associated with surface notches, with indications of previous activity at depth. All areas show a repeated history of mass transport deposits. The area of the active landslide province offshore of NW Australia is far larger than the individual slides recognized on the Exmouth Plateau.
The Mondot-1 Core, Aínsa Basin, Spanish Pyrenees: a deltaic reservoir teaching set with augmented reality
Authors: Marshall John D. , Grötsch Jürgen , Pöppelreiter Michael C.
Published: June 2023

Well Mondot-1 was drilled, cored and logged behind an outcrop of the Eocene Sobrarbe deltaic complex in the Aínsa Basin, Spanish Pyrenees. The data acquired represent a fluvial-dominated delta system prograding over a carbonate slope in the presence of active tectonism, and form part of a basin-to-grain teaching set for subsurface professionals.

This paper highlights the workflow step(s) to move from a 1D core description to 2D and 3D correlations, including some of the pitfalls caused by rapid lateral facies variability, which is a common challenge in subsurface reservoir description. The core allows direct log-to-lithology comparison across a full deltaic succession. In the proximal and distal delta fronts, there are clear differences from the closely adjacent outcrop that are ascribed to lateral facies changes and delta front slumping.

Two approaches to core display are described, as means towards making such data available to a wider audience: an augmented reality display run over a slabbed core, and a virtual whiteboard display carrying easily scalable viewing possibilities. These approaches can be deployed for other cores, allowing visualization and analysis where people are otherwise unable to travel to the physical location, or in circumstances where the core is now inaccessible.
Improvements to SLEPc in Releases 3.14–3.18
Authors: Roman Jose E. , Alvarruiz Fernando , Campos Carmen , Dalcin Lisandro , Jolivet Pierre , Lamas Daviña Alejandro
Published: June 2023

This short article describes the main new features added to SLEPc, the Scalable Library for Eigenvalue Problem Computations, in the past two and a half years, corresponding to five release versions. The main novelty is the extension of the
SVD
module with new problem types, such as the generalized SVD or the hyperbolic SVD. Additionally, many improvements have been incorporated in different parts of the library, including contour integral eigensolvers, preconditioning, and GPU support.
Stylized Data-to-text Generation: A Case Study in the E-Commerce Domain
Authors: Jing Liqiang , Song Xuemeng , Lin Xuming , Zhao Zhongzhou , Zhou Wei , Nie Liqiang
Published: June 2023

Existing data-to-text generation efforts mainly focus on generating a coherent text from non-linguistic input data, such as tables and attribute–value pairs, but overlook that different application scenarios may require texts of different styles. Inspired by this, we define a new task, namely stylized data-to-text generation, whose aim is to generate coherent text for the given non-linguistic data according to a specific style. This task is non-trivial, due to three challenges: the logic of the generated text, unstructured style reference and biased training samples. To address these challenges, we propose a novel stylized data-to-text generation model, named StyleD2T, comprising three components: logic planning-enhanced data embedding, mask-based style embedding, and unbiased stylized text generation. In the first component, we introduce a graph-guided logic planner for attribute organization to ensure the logic of generated text. In the second component, we devise feature-level mask-based style embedding to extract the essential style signal from the given unstructured style reference. In the last one, pseudo triplet augmentation is utilized to achieve unbiased text generation, and a multi-condition based confidence assignment function is designed to ensure the quality of pseudo samples. Extensive experiments on a newly collected dataset from Taobao

1

have been conducted, and the results show the superiority of our model over existing methods.
Scale-Semantic Joint Decoupling Network for Image-Text Retrieval in Remote Sensing
Authors: Zheng Chengyu , Song Ning , Zhang Ruoyu , Huang Lei , Wei Zhiqiang , Nie Jie
Published: June 2023

Image-text retrieval in remote sensing aims to provide flexible information for data analysis and application. In recent years, state-of-the-art methods are dedicated to “scale decoupling” and “semantic decoupling” strategies to further enhance the capability of representation. However, these previous approaches focus on either the disentangling scale or semantics but ignore merging these two ideas in a union model, which extremely limits the performance of cross-modal retrieval models. To address these issues, we propose a novel Scale-Semantic Joint Decoupling Network (SSJDN) for remote sensing image-text retrieval. Specifically, we design the Bidirectional Scale Decoupling (BSD) module, which exploits Salience Extraction Map (SEM) and Salience Suppression Map (SSM) units to adaptively extract potential features and suppress cumbersome features at other scales in a bidirectional pattern to yield different scale clues. Besides, we design the Label-supervised Semantic Decoupling (LSD) module by leveraging the category semantic labels as prior knowledge to supervise images and texts probing significant semantic-related information. Finally, we design a Semantic-guided Triple Loss (STL), which adaptively generates a constant to adjust the loss function to improve the probability of matching the same semantic image and text and shorten the convergence time of the retrieval model. Our proposed SSJDN outperforms state-of-the-art approaches in numerical experiments conducted on four benchmark remote sensing datasets.
Maternal high-fat diet increases airway sensory innervation and reflex bronchoconstriction in adult offspring
Authors: Calco Gina N. , Alharithi Yem J. , Williams Kayla R. , Jacoby David B. , Fryer Allison D. , Maloyan Alina , Nie Zhenying
Published: June 2023

Our study reveals a novel potential mechanism, by which maternal high-fat diet increases the risk and severity of asthma in offspring. We found that exposure to maternal high-fat diet in mice leads to hyperinnervation of airway sensory nerves and increased reflex bronchoconstriction in offspring fed a regular diet only. These findings have important clinical implications and provide new insights into the pathophysiology of asthma, highlighting the need for preventive strategies in this patient population.
Pupil dilation scales with movement distance of real but not of imagined reaching movements
Authors: Voudouris Dimitris , Schuetz Immo , Schinke Tabea , Fiehler Katja
Published: June 2023

Pupil size is influenced by the performance of cognitive and motor tasks. Here, we demonstrate that pupil size increases not only during execution but also during mental simulation of goal-directed reaching movements. However, pupil dilations scale with movement amplitude of executed but not of imagined movement, whereas they are similar during motor imagery and a nonmotor imagery task.
Information processing in the dorsal pathway: from “where” to “what we do with it”
Authors: Kang Jung Uk
Published: June 2023

Visual processing in the brain has been understood as the ventral and dorsal pathways processing “what” and “where” information, respectively. Mocz et al. (Mocz V, Vaziri-Pashkam M, Chun M, Xu Y. J Cogn Neurosci 34: 2406–2435, 2022), however, report that the two pathways code object features in a parallel manner. These results support that information processing in the dorsal pathway is not strictly limited to “where” and that the two pathways work in parallel to process task-relevant information (“what we do with it”).
A systematic review of how cannabinoids affect motoneuron output
Authors: Haynes Elijah M. K. , Kalmar Jayne M. , Vis-Dunbar Mathew , Crosby Kathryn M. , Mriduraj Angitha , Jakobi Jennifer M.
Published: June 2023

Spinal motoneurons contain many ion channels and receptors upon which various cannabinoids are known to act. This scoping review involved the synthesis of evidence from literature published before August 2022 about the effects of cannabinoids on quantifiable measures of motoneuron output. Four databases (MEDLINE, Embase, PsycINFO, and Web of Science CoreCollection) were queried and 4,237 unique articles were retrieved. Twenty-three studies met the inclusion criteria, and the findings from these studies were grouped according to four emergent themes: rhythmic motoneuron output, afferent feedback integration, membrane excitability, and neuromuscular junction transmission. This synthesis of evidence suggests that CB1 agonists can increase the frequency of cyclical patterns of motoneuron output (i.e., fictive locomotion). Furthermore, a majority of the evidence indicates that activating CB1 receptors at motoneuron synapses promotes excitation of motoneurons by enhancing excitatory synaptic transmission and depressing inhibitory synaptic transmission. The collated study results reveal variable effects of cannabinoids on acetylcholine release at the neuromuscular junction, and the influence of cannabinoids in this area requires more work to ensure precision of findings for CB1 agonist and antagonist impact. Altogether, these reports indicate that the endocannabinoid system is integral within the final common pathway and can impact motor output. This review contributes to understanding the effects of endocannabinoids on synaptic integration at the motoneuron and modulation of motor output.
Association between Severity of Diabetic Retinopathy and Cardiac Function in Patients with Type 2 Diabetes
Authors: Chen YanYan , Li MengYing , Wang Yi , Fu JianFang , Liu XiangYang , Zhang Ying , Liu LiWen , Ta ShengJun , Lu ZuoWei , Li ZePing , Zhou Jie , Li XiaoMiao
Published: June 2023

Background. The purpose of this research was to assess the relationship between the severity of diabetic retinopathy (DR) and indexes of left ventricle (LV) structure and function in type 2 diabetes mellitus (T2DM). Methods. Retrospective analysis of 790 patients with T2DM and preserved LV ejection fraction. Retinopathy stages were classified as no DR, early nonproliferative DR, moderate to severe nonproliferative DR, or proliferative DR. The electrocardiogram was used to assess myocardial conduction function. Echocardiography was used to evaluate myocardial structure and function. Results. Patients were divided into three groups based on the DR status: no DR group (NDR,

n
=
475

), nonproliferative DR group (NPDR,

n
=
247

), and proliferative DR group (PDR,

n
=
68

). LV interventricular septal thickness (IVST) increased significantly with more severe retinopathy (NDR:

10.00
±
1.09

; NPDR:

10.42
±
1.21

; and PDR:

10.66
±
1.58

;

P

< 0.001). Multivariate logistic regression analysis showed that the significant correlation of IVST persisted between subjects with no retinopathy and proliferative DR (odds

ratio
=
1.35

,

P
=
0.026

). Indices of myocardial conduction function were assessed by electrocardiogram differences among groups of retinopathy (all

P
<
0.001

). In multiple-adjusted linear regression analyses, the increasing degree of retinopathy was closely correlated with heart rate (

β
=
1.593

,

P
=
0.027

), PR interval (

β
=
4.666

,

P
=
0.001

), and QTc interval (

β
=
8.807

,

P
=
0.005

). Conclusion. The proliferative DR was independently associated with worse cardiac structure and function by echocardiography. Furthermore, the severity of retinopathy significantly correlated with abnormalities of the electrocardiogram in patients with T2DM.
METTL3 Promotes Osteo/Odontogenic Differentiation of Stem Cells by Inhibiting miR-196b-5p Maturation
Authors: Han Xiao , Li Guoyue , Yang Haoqing , Zhang Chen , Cao Yangyang , Wang Ning , Ge Lihua , Fan Zhipeng
Published: June 2023

Mesenchymal stem cells (MSCs) have been considered a potential method for the regeneration of tooth and maxillofacial bone defects based on the multidirectional differentiation characteristics of MSCs. miRNAs have been found to play a key role in the differentiation of MSCs. However, its effectiveness still needs to be improved, and its internal mechanism is still unclear. In the present study, our data discovered that the knockdown of miR-196b-5p promoted alkaline phosphatase (ALP) activity assay, mineralization in vitro, and expressions of osteo/odontogenic differentiation markers DSPP and OCN and enhanced in vivo osteo/odontogenic differentiation of stem cells of the apical papilla (SCAPs). Mechanistically, the results indicated that METTL3-dependent N6-methyladenosine (m6A) methylation inhibited miR-196b-5p maturation by the microprocessor protein DGCR8. Moreover, miR-196b-5p indirectly negatively regulates METTL3 in SCAPs. Then, METTL3 was found to strengthen the ALP activity assay, mineralization, and expressions of osteo/dentinogenic differentiation markers. Taken together, our findings highlight the critical roles of the METTL3-miR-196b-5p signaling axis in an m6A-dependent manner in osteo/odontogenic differentiation of SCAPs, identifying some potential targets for tooth and maxillofacial bone defects.
Influence of Dimethyl Carbonate and Dispersant Added Graphene Nanoplatelets in Diesel-Biodiesel Blends: Combustion, Performance, and Emission Characteristics of Diesel Engine
Authors: Pullagura Gandhi , Vadapalli Srinivas , Varaha Siva Prasad V. , Bikkavolu Joga Rao , Chebattina Kodanda Rama Rao , Barik Debabrata , Dennison Milon Selvam
Published: June 2023

The aim of the current study is to investigate the combustion, performance, and emission characteristics of a diesel engine adopting graphene nanoplatelets and 10%

v
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dimethyl carbonate as fuel additives in a 30% biodiesel and 70% diesel blend. The novel findings are documented in the subsequent sections. The surface modification of graphene nanoplatelets using a lipophilic surfactant was used which gave highest stability in fuel samples which is a main distinctive in this research work. Nanofuels were prepared using 30, 60, and 90 ppm concentrations of nanoparticles through ultrasonication. The behaviour of graphene nanoplatelet was characterized using field emission scanning gun-electron microscopy, high-resolution transmission electron microscopy, Fourier transform infrared, and X-ray diffraction. A diesel engine having uniform speed of 1500 rpm was used for the experiment at various load conditions to assess the engine operating parameters for all the prepared samples, including baseline diesel. It was observed that the combustion characteristics were found to be greatly enhanced, such as cylinder pressure and heat release rate, increased by about 15.45% and 9.63%, respectively, for B30GNP60DMC10 sample than diesel at higher loads. Performance parameters such as brake thermal efficiency (elevated by 8.98%) and brake-specific fuel consumption (diminished by 25.54%) have been significantly analyzed and compared to diesel. While the emissions (such as hydrocarbons and carbon monoxide) were found to be reduced by 22.87% and 25.67%, respectively, for B30DMC10, the nitrous oxide and smoke opacity were also reduced by 9.57% and 12.4%, respectively, for the B30GNP60DMC10 sample. Hence, a combining operation of graphene nanoplatelets and dimethyl carbonate additives in a biodiesel blend presented great potential in terms of performance improvement and reduction in emission parameters in diesel engine.
Impact of BMI on Prevalence of Dense Breasts by Race and Ethnicity
Authors: Kerlikowske Karla , Bissell Michael C. S. , Sprague Brian L. , Tice Jeffrey A. , Tossas Katherine Y. , Bowles Erin J. A. , Ho Thao-Quyen H. , Keegan Theresa H. M. , Miglioretti Diana L.
Published: June 2023

Background:

Density notification laws require notifying women of dense breasts with dense breast prevalence varying by race/ethnicity. We evaluated whether differences in body mass index (BMI) account for differences in dense breasts prevalence by race/ethnicity.

Methods:

Prevalence of dense breasts (heterogeneously or extremely dense) according to Breast Imaging Reporting and Data System and obesity (BMI > 30 kg/m2) were estimated from 2,667,207 mammography examinations among 866,033 women in the Breast Cancer Surveillance Consortium (BCSC) from January 2005 through April 2021. Prevalence ratios (PR) for dense breasts relative to overall prevalence by race/ethnicity were estimated by standardizing race/ethnicity prevalence in the BCSC to the 2020 U.S. population, and adjusting for age, menopausal status, and BMI using logistic regression.

Results:

Dense breasts were most prevalent among Asian women (66.0%) followed by non-Hispanic/Latina (NH) White (45.5%), Hispanic/Latina (45.3%), and NH Black (37.0%) women. Obesity was most prevalent in Black women (58.4%) followed by Hispanic/Latina (39.3%), NH White (30.6%), and Asian (8.5%) women. The adjusted prevalence of dense breasts was 19% higher [PR = 1.19; 95% confidence interval (CI), 1.19–1.20] in Asian women, 8% higher (PR = 1.08; 95% CI, 1.07–1.08) in Black women, the same in Hispanic/Latina women (PR = 1.00; 95% CI, 0.99–1.01), and 4% lower (PR = 0.96; 95% CI, 0.96–0.97) in NH White women relative to the overall prevalence.

Conclusions:

Clinically important differences in breast density prevalence are present across racial/ethnic groups after accounting for age, menopausal status, and BMI.

Impact:

If breast density is the sole criterion used to notify women of dense breasts and discuss supplemental screening it may result in implementing inequitable screening strategies across racial/ethnic groups.

See related In the Spotlight, p. 1479
Outcomes in Patients with High-Risk Features after Fixed-Duration Ibrutinib plus Venetoclax: Phase II CAPTIVATE Study in First-Line Chronic Lymphocytic Leukemia
Authors: Allan John N. , Flinn Ian W. , Siddiqi Tanya , Ghia Paolo , Tam Constantine S. , Kipps Thomas J. , Barr Paul M. , Elinder Camburn Anna , Tedeschi Alessandra , Badoux Xavier C. , Jacobs Ryan , Kuss Bryone J. , Trentin Livio , Zhou Cathy , Szoke Anita , Abbazio Christopher , Wierda William G.
Published: June 2023

Purpose:

The CAPTIVATE study investigated first-line ibrutinib plus venetoclax for chronic lymphocytic leukemia in 2 cohorts: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and Fixed Duration (FD cohort). We report outcomes of fixed-duration ibrutinib plus venetoclax in patients with high-risk genomic features [del(17p), TP53 mutation, and/or unmutated immunoglobulin heavy chain (IGHV)] in CAPTIVATE.

Patients and Methods:

Patients received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day). FD cohort patients (n = 159) received no further treatment. Forty-three MRD cohort patients with confirmed undetectable MRD (uMRD) after 12 cycles of ibrutinib plus venetoclax received randomized placebo treatment.

Results:

Of 195 patients with known status of genomic risk features at baseline, 129 (66%) had ≥1 high-risk feature. Overall response rates were >95% regardless of high-risk features. In patients with and without high-risk features, respectively, complete response (CR) rates were 61% and 53%; best uMRD rates: 88% and 70% (peripheral blood) and 72% and 61% (bone marrow); 36-month progression-free survival (PFS) rates: 88% and 92%. In subsets with del(17p)/TP53 mutation (n = 29) and unmutated IGHV without del(17p)/TP53 mutation (n = 100), respectively, CR rates were 52% and 64%; uMRD rates: 83% and 90% (peripheral blood) and 45% and 80% (bone marrow); 36-month PFS rates: 81% and 90%. Thirty-six–month overall survival (OS) rates were >95% regardless of high-risk features.

Conclusions:

Deep, durable responses and sustained PFS seen with fixed-duration ibrutinib plus venetoclax are maintained in patients with high-risk genomic features, with similar PFS and OS to those without high-risk features.

See related commentary by Rogers, p. 2561
Autocrine 17-β-Estradiol/Estrogen Receptor-α Loop Determines the Response to Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer
Authors: Anobile Dario P. , Salaroglio Iris C. , Tabbò Fabrizio , La Vecchia Sofia , Akman Muhlis , Napoli Francesca , Bungaro Maristella , Benso Federica , Aldieri Elisabetta , Bironzo Paolo , Kopecka Joanna , Passiglia Francesco , Righi Luisella , Novello Silvia , Scagliotti Giorgio V. , Riganti Chiara
Published: June 2023

Purpose:

The response to immune checkpoint inhibitors (ICI) often differs between genders in non–small cell lung cancer (NSCLC), but metanalyses results are controversial, and no clear mechanisms are defined. We aim at clarifying the molecular circuitries explaining the differential gender-related response to anti–PD-1/anti–PD-L1 agents in NSCLC.

Experimental Design:

We prospectively analyzed a cohort of patients with NSCLC treated with ICI as a first-line approach, and we identified the molecular mechanisms determining the differential efficacy of ICI in 29 NSCLC cell lines of both genders, recapitulating patients’ phenotype. We validated new immunotherapy strategies in mice bearing NSCLC patient-derived xenografts and human reconstituted immune system (“immune-PDXs”).

Results:

In patients, we found that estrogen receptor α (ERα) was a predictive factor of response to pembrolizumab, stronger than gender and PD-L1 levels, and was directly correlated with PD-L1 expression, particularly in female patients. ERα transcriptionally upregulated CD274/PD-L1 gene, more in females than in males. This axis was activated by 17-β-estradiol, autocrinely produced by intratumor aromatase, and by the EGFR-downstream effectors Akt and ERK1/2 that activated ERα. The efficacy of pembrolizumab in immune-PDXs was significantly improved by the aromatase inhibitor letrozole, which reduced PD-L1 and increased the percentage of antitumor CD8+T-lymphocytes, NK cells, and Vγ9Vδ2 T-lymphocytes, producing durable control and even tumor regression after continuous administration, with maximal benefit in 17-β-estradiol/ERα highfemale immune-xenografts.

Conclusions:

Our work unveils that 17-β-estradiol/ERα status predicts the response to pembrolizumab in patients with NSCLC. Second, we propose aromatase inhibitors as new gender-tailored immune-adjuvants in NSCLC.

See related commentary by Valencia et al., p. 3832
Supplementary Figures from Single-Cell Profiling of CD8+ T Cells in Acute Myeloid Leukemia Reveals a Continuous Spectrum of Differentiation and Clonal Hyperexpansion
Authors: Desai Poonam N. , Wang Bofei , Fonseca Andre , Borges Pamella , Jelloul Fatima Zahra , Reville Patrick K. , Lee Eric , Ly Christopher , Basi Akshay , Root Jessica , Baran Natalia , Post Sean M. , Deng Qing , Sun Hanxiao , Harmanci Arif O. , Burks Jared K. , Gomez Javier A. , DiNardo Courtney D. , Daver Naval G. , Alatrash Gheath , Konopleva Marina , Green Michael R. , Antunes Dinler A. , Futreal Andrew , Hao Dapeng , Abbas Hussein A.
Published: June 2023

All Supplementary Figures
Data from Multi-institutional prognostic modelling in head and neck cancer:
evaluating impact and generalizability of deep learning and
radiomics
Authors: Kazmierski Michal , Welch Mattea , Kim Sejin , McIntosh Chris , Rey-McIntyre Katrina , Huang Shao Hui , Patel Tirth , Tadic Tony , Milosevic Michael , Liu Fei-Fei , Ryczkowski Adam , Kazmierska Joanna , Ye Zezhong , Plana Deborah , Aerts Hugo JWL , Kann Benjamin H , Bratman Scott V. , Hope Andrew J , Haibe-Kains Benjamin
Published: June 2023

Abstract
Artificial intelligence (AI) and machine learning (ML) are becoming critical in developing and deploying personalized medicine and targeted clinical trials. Recent advances in ML have enabled the integration of wider ranges of data including both medical records and imaging ({radiomics}). However, the development of prognostic models is complex as no modelling strategy is universally superior to others and validation of developed models requires large and diverse datasets to demonstrate that prognostic models developed (regardless of method) from one dataset are applicable to other datasets both internally and externally. Using a retrospective dataset of 2,552 patients from a single institution and a strict evaluation framework that included external validation on three external patient cohorts (873 patients), we crowdsourced the development of ML models to predict overall survival in head and neck cancer (HNC) using electronic medical records and pre-treatment radiological images. To assess the relative contributions of radiomics in predicting HNC prognosis, we compared 12 different models using imaging and/or electronic medical record (EMR) data. The model with the highest accuracy used multitask learning on clinical data and tumour volume, achieving high prognostic accuracy for 2-year and lifetime survival prediction, outperforming models relying on clinical data only, engineered radiomics, or complex deep neural network architecture. However, when we attempted to extend the best-performing models from this large training dataset to other institutions, we observed significant reductions in the performance of the model in those datasets, highlighting the importance of detailed population-based reporting for AI/ML model utility and stronger validation frameworks.