bluuebunny/crossref_metadata_2025 huggingface dataset:
Double
bla
KPC-2
copies quadrupled minimum inhibitory concentration of ceftazidime–avibactam in hospital-derived
Klebsiella pneumoniae
Authors: Hu Dakang , Wang Shijie , Xu Mengqiao , Zhang Jin , Luo Xinhua , Zhou Wei , Ma Qinfei , Ma Xiaobo
Published: July 2024

To illustrate the genomic and drug resistance traits of the
Klebsiella pneumoniae
Kpn_XM9, which harbors a transposon (Tn) As1 and was barely susceptible to ceftazidime–avibactam (CZA). Whole-genome sequencing, gene deletion, antimicrobial susceptibility, and conjugation tests were carried out to illustrate the traits of Kpn_XM9. As confirmed by whole-genome sequencing, the Kpn_XM9 harbored a 5,523,536 bp chromosome and five plasmids with lengths being 128,129, 196,512, 84,812, 43,695, and 5,596 bp, respectively. Plasmid p1_Kpn_XM9 (128,219 bp) contained four resistance genes,
bla
CTX-M-65
,
bla
TEM-1B
,
rmt
B, and two copies of
bla
KPC-2
. Genes
bla
KPC-2
were bracketed by ISKpn17 and ISKpn16 within a new composite Tn3-like TnAs1. The two tandem repeats, positioned opposite each other, were spaced 93,447 bp apart in p1_Kpn_XM9. Kpn_XM9 belonged to K64 and sequence type (ST) 11. The Kpn_XM9 was resistant to amikacin, aztreonam, ticarcillin/clavulanic acid, piperacillin/tazobactam, ceftazidime, cefepime, imipenem, meropenem, tobramycin, ciprofloxacin, levofloxacin, doxycycline, minocycline, tigecycline, colistin, and trimethoprim/sulfamethoxazole; it was barely susceptible to CZA with a minimum inhibitory concentration of 8/4 µg/mL, which declined to 2/4 µg/mL after a 18,555 bp nucleotide was knocked out and one copy of
bla
KPC-2
was sustained on p1_Kpn_XM9. Kpn_XM9 had virulence genes encoding Types 1 and 3 fimbriae, four siderophores, and capsular polysaccharide anchoring protein but no genes upregulating capsular polysaccharide synthesis. The Kpn_XM9 presented a classical phenotype with extreme drug resistance. The emergence of double copies of
bla
KPC-2
in a single plasmid from the predominant ST11
K. pneumoniae
represents a new therapeutic challenge.

IMPORTANCE

With the wide use of ceftazidime–avibactam against carbapenem-resistant organisms, its resistance is increasingly documented; among the corresponding resistance mechanisms, mutations of
bla
KPC-2
or
bla
KPC-3
into other subtypes are dominant to date. However, more copies of
bla
KPC-2
may also greatly increase the minimum inhibitory concentration of ceftazidime–avibactam, which could be conferred by transposon As1 and insertion sequence 26 and should be of concern.
Phenotypic expression, genotypic profiling and clinical outcomes of infantile hypertrophic cardiomyopathy: a retrospective study
Authors: Ahamed Hisham , Varghese Shruti , Gutajahr Georg , Vaidyanathan Balu , Kappanayil Mahesh , Sasikumar Navaneetha , Kumar Shine , Hari Aparna , Krishnakumar Malavika , Kumar Raman Krishna
Published: July 2024

Background

Infantile hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder. Apart from registries in high-income nations, there is a shortage of data on the aetiological basis of infantile HCM in low- and middle-income nations. This study attempts to characterise the phenotypic expression, genetic architecture and short-term clinical outcomes of infantile HCM from a South Asian tertiary referral centre.

Methods

This study includes all infants from the Amrita HCM cohort between January 2011 and July 2021. Clinical history, ECG, echocardiographic data, and genetic analyses were evaluated.

Results

34 patients with infantile HCM were diagnosed at a median age of 3.7 months (IQR 1–6 months). Underlying aetiologies were RASopathy (n=13; 38%), non-syndromic (n=12; 35%) and inborn errors of metabolism (n=9; 27%). Genetic analysis was done in 20 patients (59%) with a yield of 90%. Clinical presentation included failure to thrive (n=29; 85%), dyspnoea on exertion (n=23; 68%) and clinical heart failure (n=24; 71%). Echo showed concentric left ventricular hypertrophy in 22 patients (65%), obstructive HCM in 11 patients (32%) and left ventricular systolic dysfunction in 6 patients (18%). The mortality rate was 10.0 deaths per 100 patient years over a median follow-up period of 3.1 years. The main risk markers for mortality were the age at diagnosis, gender and concentric Left ventricular hypertrophy.

Conclusions

This cohort demonstrates the morphological, functional and genetical heterogeneity of infantile HCM, enunciating the need for integration of cardiology, metabolic and genetic services to achieve optimum outcomes in these patients.
Associations between adverse childhood experiences and trust in health and other information from public services, professionals and wider sources: national cross sectional survey
Authors: Bellis Mark A , Hughes Karen , Ford Kat , Sharp Catherine , Hill Rebecca
Published: July 2024

Introduction

Trust in health and other systems can affect uptake of public health advice and engagement with health services. Individuals who had adverse childhood experiences (ACEs) are more likely to experience ill health at earlier ages. Ensuring their engagement with health and other services is important in improving their life course prospects, but little is known about how ACEs affect trust in such services and the information they provide.

Methods

Data were collected via a national household survey of residents in Wales (aged ≥18 years, n=1880, November 2022–March 2023). Questions measured ACE exposure and trust in health, social, police, charities and government, and health and general information provided by a variety of professionals and sources.

Results

Individuals with ACEs were more likely to report low trust in health advice from hospital doctors, general practitioners (GPs), nurses, pharmacists, and NHS 111, an online and telephone urgent care service (eg, adjusted low trust prevalence: GPs, 0 ACEs 5.3%, ≥4 ACEs 10.4%; NHS 111, 0 ACEs 11.9%, ≥4 ACEs 24.1%). Low trust in services also increased with ACEs, with low trust in police being 3.8 times more likely with ≥4 ACEs (vs 0 ACEs). The highest adjusted prevalence of low trust in a service was for government, rising from 48.4% (0 ACEs) to 73.7% (≥4 ACEs). Low trust in general advice and information from TV/radio programmes rose from 17.6% (0 ACEs) to 30.1% (≥4 ACEs); low trust in social media was higher with an equivalent rise from 61.6% to 75.6%.

Conclusion

Breaking intergenerational cycles of ill health and inequity requires engaging and influencing those with ACEs. However, a history of ACEs was associated with lower trust in supporting institutions, systems and professionals. Empirical data on which resources are most trusted by those with ACEs should be used to facilitate better communications with this vulnerable group.
Association between chronic pain and risk of cardiometabolic multimorbidity: a prospective cohort study
Authors: Yin Xin , Chen Yanchun , Zhou Lihui , Yang Hongxi , Wang Yaogang
Published: July 2024

Background

Although chronic pain was deleteriously related to single cardiometabolic diseases, the relationship between chronic pain and cardiometabolic multimorbidity remains unclear. The purpose of this study was to investigate the association between chronic pain with the risk of cardiometabolic multimorbidity.

Methods

A prospective cohort study included 452 818 participants who were free of cardiometabolic multimorbidity at baseline. Chronic pain was assessed in diverse anatomical sites including the head, face, neck/shoulder, stomach/abdominal area, back, hip and knee or ‘all over the body’. Participants were classified into six groups according to the amount of chronic pain sites: no chronic pain, chronic pain at one, two, three and four or more sites, and those reporting pain ‘all over the body’. Cardiometabolic multimorbidity was defined as the occurrence of at least two cardiometabolic diseases, involving type 2 diabetes, ischaemic heart disease and stroke.

Results

After a median follow-up of 13.7 years, 4445 participants developed cardiometabolic multimorbidity. Compared with individuals without chronic pain, those experiencing chronic pain in four or more sites were associated with a 1.82-fold (HR: 1.82, 95% CI: 1.61, 2.06) higher risk of cardiometabolic multimorbidity. Pain distributed ‘all over the body’ was associated with a 59% (HR: 1.59, 95% CI: 1.30, 1.93) increased risk of cardiometabolic multimorbidity Additionally, individuals who had chronic pain in both the head and stomach/abdomen showed the highest risk with cardiometabolic multimorbidity (HR: 1.88, 95% CI: 1.60, 2.20).

Conclusions

Our findings suggested that there was an elevated risk of cardiometabolic multimorbidity associated with an increased amount of chronic pain sites.
Distributed Independent Sets in Interval and Segment Intersection Graphs
Authors: Bhatt Nirmala , Gorain Barun , Mondal Kaushik , Pandit Supantha
Published: July 2024

The Maximum Independent Set problem is well-studied in graph theory and related areas. An independent set of a graph is a subset of non-adjacent vertices of the graph. A maximum independent set is an independent set of maximum size. This paper studies the Maximum Independent Set problem in some classes of geometric intersection graphs in a distributed setting. More precisely, we study the Maximum Independent Set problem on two geometric intersection graphs, interval and axis-parallel segment intersection graphs, and present deterministic distributed algorithms in a model that is similar but a little weaker than the local communication model. We compute the maximum independent set on interval graphs in [Formula: see text] rounds and [Formula: see text] messages, where [Formula: see text] is the size of the maximum independent set and [Formula: see text] is the number of nodes in the graph. We provide a matching lower bound of [Formula: see text] on the number of rounds, whereas [Formula: see text] is a trivial lower bound on message complexity. Thus, our algorithm is both time and message-optimal. We also study the Maximum Independent Set problem in interval count [Formula: see text] graphs, a special case of the interval graphs where the intervals have exactly [Formula: see text] different lengths. We propose an [Formula: see text]-approximation algorithm that runs in [Formula: see text] round. For axis-parallel segment intersection graphs, we design an [Formula: see text]-approximation algorithm that obtains a solution in [Formula: see text] rounds. The results in this paper extend the results of Molla et al. [J. Parallel Distrib. Comput. 2019].
Thermal analysis on Ferro Casson nanofluid flow over a Riga plate with thermal radiation and non-uniform heat source/sink
Authors: Ahmed Mohammed Zulfeqar , Dhanalaxmi V. , Panda Subhajit
Published: July 2024

Ferro hybrid nanofluids can be used in electronics and microelectronics cooling applications to reduce heat accumulation and efficiently remove surplus heat. These nanofluids aid to maintain optimum operating temperatures and reduce device overheating by enhancing the heat transfer rate. With this motivation, the aim of the present numerical analysis is to study the three-dimensional incompressible hybrid nanofluid flow over a slippery Riga surface by combining the Casson fluid model. Mathematical modeling is constructed with nanoparticles as Fe3O4 and CoFe2O4 with base fluid as water. The non-uniform heat source/sink and thermal linear radiation effects are taken into account with the Hamilton–Crosser thermal conductivity model. A system of nonlinear PDEs is produced by the proposed problem and then the relevant similarity variables are implemented to transform the set of partial differential equations and their accompanying boundary conditions into the coupled nonlinear differential equations with one independent variable. These modified ordinary differential equations (ODEs) were then successfully solved with the Runge–Kutta fourth-order method by combining via the shooting technique. With the aid of graphical representations, the effects of various influencing parameters were presented and analyzed comprehensively. Furthermore, the impacts of relevant parameters on heat transfer rates and shear stress are concisely discussed and illustrated in tabular forms. The significant findings include the enhancement of the radiation parameter increases the thermal boundary layer thickness and the thickness increases whenever surface experiences slippery conditions. The axial and transverse momentum of the fluid are controlled with the Casson parameter. An effective connection is noticed once the current numerical solutions are verified under particular conditions that were previously described.
Modified Whale Algorithm and Morley PSO-ML-Based Hyperparameter Optimization for Intrusion Detection
Authors: Razzaq Hasanain Hayder , Al-Rammahi Laith F. M. H. , Mahdi Ahmed Mounaf
Published: July 2024

Intrusion detection averts a network from probable intrusions by inspecting network traffic to ensure its integrity, availability, and confidentiality. Though IDS seems to eliminate malicious traffic, intruders have endeavored to use different approaches for undertaking attacks. Hence, effective intrusion detection is vital to detect attacks. Concurrently, the evolvement of machine learning (ML), attacks could be identified by evaluating the patterns and learning from them. Considering this, conventional works have attempted to perform intrusion detection. Nevertheless, they lacked about high false alarm rate (FAR) and low accuracy rate due to inefficient feature selection. To resolve these existing pitfalls, this research proposed a modified whale algorithm (MWA) based on nonlinear information gain to select significant and relevant features. This algorithm assures huge initialization to improve local search ability as the agent’s positions are usually near the optimal solution. It is also utilized for an adaptive search for an optimal combination of features. Following this, the research proposes Morlet particle swarm optimization hyperparameter optimization (MPSO-HO) to improve the convergence rate of the algorithm by consenting it to produce from the local optimization by improving its capability. Standard metrics assess the proposed system to confirm the optimal performance of the proposed system. Outcomes explore the effective ability of the proposed system in intrusion detection.
Dual canonical bases for unipotent groups and base affine spaces
Authors: Li Jian-Rong
Published: July 2024

Denote by [Formula: see text] the subgroup of unipotent upper triangular matrices. In this paper, we show that the dual canonical basis of [Formula: see text] (and base affine spaces) can be parametrized by semi-standard Young tableaux. Moreover, we give an explicit formula for every element in the dual canonical basis using the data of the corresponding semi-standard Young tableau. We apply our results to study cluster variables in [Formula: see text].
Sleep and Neuroaffective Development from Early to Late Adolescence
Authors: Baker Amanda E. , McMakin Dana L.
Published: July 2024

Sleep is fundamental to human existence—especially during periods of extensive neurodevelopment such as adolescence. Importantly, poor sleep health in the transition into puberty can impact developing neural systems, contributing to the onset and maintenance of emotional disorders such as anxiety and depression. This review explores the complex interplay between sleep and neuroaffective development in adolescence, when changes in sleep architecture, circadian rhythms, and hormonal fluctuations interact with ongoing brain maturation to impact cognitive and emotional functioning. By synthesizing extant literature and charting future directions for research and intervention, this review elucidates the bidirectional associations between sleep and neuroaffective processes during puberty and highlights how sleep architecture and neurophysiology can inform our understanding of adolescent brain development. Ultimately, this article argues that promoting sleep health and addressing sleep-related challenges, especially in early adolescence, are promising strategies for enhancing well-being and fostering positive neurodevelopmental outcomes across both healthy and clinical populations.
Study of Rapid Evaluation Method for Structural Load‐Bearing Capacity of Typical Rural Masonry Residential Buildings in Shandong Province, China
Authors: Zheng Xu , Wu Hongbin , Lu Zilin , Su Sili , Song Runzhao
Published: July 2024

Typical rural masonry residential buildings mainly include brick–wood and brick–concrete structures, and they occupy a significant proportion among individual buildings in Shandong Province, and their structural reliability directly affects the safety of life and property. Structural load‐bearing capacity can be used for quantitative judgment of structural reliability level. For evaluating the structural load‐bearing capacity of rural masonry residential buildings rapidly, factors affecting the structural bearing capacity and positions with weak structural bearing capacity are determined by field investigation and modeling analysis with software for structural calculation. The ratio of structural resistance to action effect is taken as the evaluation index of structural bearing capacity, and the quantitative relationships between this index and the masonry compressive strength, mortar strength, window–hole ratio, and the cantilever width are established through regression analysis. The accuracy and applicability are verified by Elman neural network model as well as comparison results between rapid evaluation formula and modeling analysis. The results show that the rapid evaluation model for structural load‐bearing capacity in this paper can be used to accurately describe the relationships between the ratio of structural resistance to action effect with affecting factors, and it can play a role in screening structural monomers with irregular load‐bearing capacity in group evaluation of structural bearing capacity.
Cancer Risk in Nepal: An Analysis from Population‐Based Cancer Registry of Urban, Suburban, and Rural Regions
Authors: Dahal Uma Kafle , Khadka Kopila , Neupane Kiran , Acharya Sandhya Chapagain , Jha Anjani Kumar , Gyanwali Pradip , Baral Gehanath
Published: July 2024

Background. Cancer is one of the leading causes of death globally. The low and middle‐income countries (LMICs) cover a major share of the global cancer burden; however, most of the LMICs including Nepal still lack national cancer control and prevention strategies. Since 1st January 2018, the Nepal Health Research Council (NHRC) started the population‐based cancer registry (PBCR) in urban, suburban, and rural regions to support evidence‐based cancer control intervention in each geographical region. Methods. Data regarding incidence and mortality was collected by the PBCR in Nepal. Indirect and direct methods were used to collect data from health facilities and communities, respectively. Registered cases of incidence and mortality from 1st January 2019 to 31st December 2019 were used. Each case was verified for correctness and duplication followed by residence confirmation via phone call. Guidelines and principles of the International Association of Cancer Registry were followed for the overall registration process including data quality control. Ethical approval was taken from the Ethical Review Board of the NHRC. Result. Age‐adjusted incidence (AAR) and mortality rates in Nepal were found 65.6 and 29 per 100,000 people, respectively. Every 1 in 14 men and 1 in 13 women were at risk of getting, and 1 in 28 men and 1 in 33 women were dying of cancer before age 75 in Nepal. The highest risk was found for lung cancer (1 in 80) followed by stomach and mouth among men, and in women, breast cancer (1 in 76) was the commonest among all followed by lung and cervix. Conclusion. Cancer has been growing as one of the major public health burdens in Nepal. Screening with cost‐effective technology, awareness, and vaccination against HPV should be a government priority including revision of treatment protocols for cancers that have higher mortality to prevent further preventable life loss from malignancies.
Study on Machinability Behaviour and Simultaneous Optimisation of Multiple Responses Using Taguchi‐Based Grey Relational Analysis in End Milling of Aluminum Hybrid Composites
Authors: S. Kumar , G. Mohan Dhanesh
Published: July 2024

The present work reveals the machinability characteristics of Al7068/Si3N4/BN hybrid composite materials. The composite materials were prepared through the liquid metallurgy technique with various weight fractions (0, 5, 10) of silicon nitride and hexagonal boron nitride particles. The experimental studies were performed on a CNC milling machine by varying cutting speed (600, 1200 and 1800 rpm), feed rate (150, 300 and 450 mm/min), and depth of cut (0.8, 1.2 and 1.6 mm). Taguchi’s plan of experiments (L27 orthogonal array design) and analysis of variance (ANOVA) were employed to investigate the effect of process parameters on surface roughness (Ra), cutting temperature, and material removal rate (MRR). Taguchi‐based grey relational analysis (GRA) was performed to identify the best process parameters combination for optimising the multiple responses simultaneously. ANOVA results revealed that the weight fraction of Si3N4 is the most contributing parameter for multiple response characteristics.
Perceptions of Emerging Adults With Type 1 Diabetes Mellitus on How the Condition Influences Sleep Quality: A Qualitative Study
Authors: Núñez-Baila María-Ángeles , Gómez-Aragón Anjhara , González-López José Rafael
Published: July 2024

Background: Emerging adulthood is a phase characterized by exploration which potentially affecting sleep quality. While many emerging adults are healthy, the effects of chronic diseases such as Type 1 Diabetes Mellitus (T1DM) on sleep may be underestimated. Considering the frequency of nocturnal glycemic alterations that cause awakenings, this study explored the perceptions of emerging adults in Andalusia on the influence of T1DM on their sleep quality.

Methods: A qualitative approach was used for this study. Purposive sampling through diabetes associations was initially utilized, supplemented by snowball sampling, in order to conduct semistructured interviews with 73 emerging adults (aged 18–29) diagnosed with T1DM, to explore their perceptions of the influence of T1DM on sleep quality. Interpretative Phenomenological Analysis was used for data analysis.

Results: Sleep disruptions caused by overnight hyperglycemia and hypoglycemia were identified as significant factors. However, 62% of participants did not perceive the influence of diabetes on their sleep quality, despite experiencing frequent overnight glycemic alterations (reported by 40.9%).

Conclusions: Perception of the impact of T1DM on sleep quality does not always align with the frequency of disruptions. Nonetheless, promoting healthy sleep and systematically assessing sleep quality can benefit both sleep and glycemic outcomes, regardless of individual perceptions.
Supplemental Figure S2 from The Tumor Microbiome Reacts to Hypoxia and Can Influence Response to Radiation Treatment in Colorectal Cancer
Authors: Benej Martin , Hoyd Rebecca , Kreamer McKenzie , Wheeler Caroline E. , Grencewicz Dennis J. , Choueiry Fouad , Chan Carlos H.F. , Zakharia Yousef , Ma Qin , Dodd Rebecca D. , Ulrich Cornelia M. , Hardikar Sheetal , Churchman Michelle L. , Tarhini Ahmad A. , Robinson Lary A. , Singer Eric A. , Ikeguchi Alexandra P. , McCarter Martin D. , Tinoco Gabriel , Husain Marium , Jin Ning , Tan Aik C. , Osman Afaf E.G. , Eljilany Islam , Riedlinger Gregory , Schneider Bryan P. , Benejova Katarina , Kery Martin , Papandreou Ioanna , Zhu Jiangjiang , Denko Nicholas , Spakowicz Daniel
Published: July 2024

Boxplots comparing immune fractions in low and high hypoxia groups in the ORIEN radiation cohort, displaying cells with significantly different abundance with an adjusted p-value <0.05.
Tumor-Intrinsic Activity of Chromobox 2 Remodels the Tumor Microenvironment in High-grade Serous Carcinoma
Authors: Iwanaga Ritsuko , Yamamoto Tomomi M. , Gomez Karina , Nguyen Lily L. , Woodruff Elizabeth R. , Post Miriam D. , Mikeska Railey G. , Danis Etienne , Danhorn Thomas , Boorgula Meher P. , Mitra Siddhartha S. , Marjon Nicole A. , Bitler Benjamin G. , Brubaker Lindsay W.
Published: July 2024

Chromobox 2 (CBX2), an epigenetic reader and component of polycomb repressor complex 1, is highly expressed in >75% of high-grade serous carcinoma. Increased CBX2 expression is associated with poorer survival, whereas CBX2 knockdown leads to improved chemotherapy sensitivity. In a high-grade serous carcinoma immune-competent murine model, knockdown of CBX2 decreased tumor progression. We sought to explore the impact of modulation of CBX2 on the tumor immune microenvironment (TIME), understanding that the TIME plays a critical role in disease progression and development of therapy resistance. Exploration of existing datasets demonstrated that elevated CBX2 expression significantly correlated with specific immune cell types in the TIME. RNA sequencing and pathway analysis of differentially expressed genes demonstrated immune signature enrichment. Confocal microscopy and co-culture experiments found that modulation of CBX2 leads to increased recruitment and infiltration of macrophages. Flow cytometry of macrophages cultured with CBX2-overexpressing cells showed increased M2-like macrophages and decreased phagocytosis activity. Cbx2 knockdown in the Trp53-null, Brca2-null ID8 syngeneic murine model (ID8 Trp53−/−Brca2−/−) led to decreased tumor progression compared with the control. NanoString immuno-oncology panel analysis suggested that knockdown in Cbx2 shifts immune cell composition, with an increase in macrophages. Multispectral immunohistochemistry (mIHC) further confirmed an increase in macrophage infiltration. Increased CBX2 expression leads to recruitment and polarization of protumor macrophages, and targeting CBX2 may serve to modulate the TIME to enhance the efficacy of immune therapies.

Significance:

CBX2 expression correlates with the TIME. CBX2 modulation shifts the macrophage population, potentially leading to an immunosuppressive microenvironment, highlighting CBX2 as a target to improve efficacy of immunotherapy.
Inhibition of Notch4 Using Novel Neutralizing Antibodies Reduces Tumor Growth in Murine Cancer Models by Targeting the Tumor Endothelium
Authors: Eng Jason W.-L. , Kato Yu , Adachi Yusuke , Swaminathan Bhairavi , Naiche L.A. , Vadakath Rahul , Sakamoto Yoshimasa , Nakazawa Youya , Tachino Sho , Ito Ken , Abe Takanori , Minoshima Yukinori , Hoshino-Negishi Kana , Ogasawara Hideaki , Kawakatsu Tomomi , Nishimura Miyuki , Katayama Masahiko , Shimizu Masashi , Tahara Kazuhiro , Sato Toshitaka , Suzuki Katsuhisa , Agarwala Kishan , Iwata Masao , Nomoto Kenichi , Ozawa Yoichi , Imai Toshio , Funahashi Yasuhiro , Matsui Junji , Kitajewski Jan
Published: July 2024

Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade can interfere with tumor vessel function but causes tissue hypoxia and gastrointestinal toxicity. Notch4 is primarily expressed in endothelial cells, where it may promote angiogenesis; however, effective therapeutic targeting of Notch4 has not been successful. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 to be assessed in tumor models. Notch4 was expressed in tumor endothelial cells in multiple cancer models, and endothelial expression was associated with response to E7011/6-3-A6. Anti-Notch4 treatment significantly delayed tumor growth in mouse models of breast, skin, and lung cancers. Enhanced tumor inhibition occurred when anti-Notch4 treatment was used in combination with chemotherapeutics. Endothelial transcriptomic analysis of murine breast tumors treated with 6-3-A6 identified significant changes in pathways of vascular function but caused only modest change in canonical Notch signaling. Analysis of early and late treatment timepoints revealed significant differences in vessel area and perfusion in response to anti-Notch4 treatment. We conclude that targeting Notch4 improves tumor growth control through endothelial intrinsic mechanisms.

Significance:

A first-in-class anti-Notch4 agent, E7011, demonstrates strong antitumor effects in murine tumor models including breast carcinoma. Endothelial Notch4 blockade reduces perfusion and vessel area.
Exploring the diversity of the Java fern genus Leptochilus (Polypodiaceae) in the Indo-Burma Biodiversity Hotspot
Authors: ZHANG LIANG , LU NGAN THI , ZHOU XIN-MAO , ZHOU ZHUO , THEPKAYSON KHAMPHANH , LUONG THIEN TAM , ZHANG LI-BING
Published: July 2024

The species diversity of certain groups of ferns in Indo-Burma Biodiversity Hotspot remains largely unexplored using combined molecular and morphological approaches. Here, based on morphology and an updated phylogeny of Leptochilus with 121 (115% increase of the latest sampling) new samples across Asia added, specifically those of three systematically significant “old” species, L. ovatus, L. pedunculatus, and L. pothifolius, we discovered 11 new species of the genus and made two new combinations. The new species are described in detail, the taxonomic treatment is given, and a key to the 51 currently known species of the genus is provided.
Classification of Ice Particle Shapes Using Machine Learning on Forward Light Scattering Images
Authors: Schmitt Carl G. , Järvinen Emma , Schnaiter Martin , Vas Dragos , Hartl Lea , Wong Telayna , Stuefer Martin
Published: July 2024

Machine learning (ML) has rapidly transitioned from a niche activity to a mainstream tool for environmental research applications including atmospheric science cloud microphysics studies. Two recently developed cloud particle probes measure the light scattered in the near forward direction and save digital images of the scattering light. Scattering pattern images collected by the Particle Phase Discriminator mark 2, Karlsruhe edition (PPD-2K), and the Small Ice Detector, version 3 (SID-3) provide valuable information for particle shape and size characterization. Since different particle shapes have distinctly different light scattering characteristics, the images are ideally suited for ML. Here, results of a ML project to characterize ice particle shapes sampled by the PPD-2K in ice fog and diamond dust during a 3-yr project in Fairbanks, Alaska. About 2.15 million light-scattering pattern images were collected during 3 years of measurements with the PPD-2K. Visual Geometry Group (VGG) convolutional neural network (CNN) was trained to categorize light-scattering patterns into eight categories. Initial training images (120 each category) were selected by human visual examination of data, and the training dataset was augmented using an automated iterative method for image identification of further images which were all visually inspected by a human. Results were well correlated to similar categories identified from previously developed classification algorithms. ML identifies characteristics not included in automated analysis such as sublimation. Of the 2.15 million images analyzed, 1.3% were categorized as spherical (liquid), 43.5% were categorized as having rough surfaces, 15.3% were pristine, 16.3% were categorized as sublimating, and the remaining 23.6% did not fit into any of those categories (irregular or saturated).

Significance Statement

The shapes and sizes of cloud particles can be extremely important for understanding the conditions that exist in the cloud. In this study, we show that more information about cloud particle characteristics can be identified by using machine learning than by traditional means. To demonstrate this, data are analyzed from a 3-yr study of ice fog and diamond dust events in Fairbanks, Alaska. The Particle Phase Discriminator instrument collected 2.15 million light-scattering pattern images of cloud particles during ground-based measurements. Neither traditional techniques nor machine learning were able to identify all categories, but a combination of both techniques led to a more complete view of ice particle shapes.
Associations between acute and chronic graft-versus-host disease
Authors: Tamaki Masaharu , Akahoshi Yu , Inamoto Yoshihiro , Morita Kaoru , Uchida Naoyuki , Doki Noriko , Tanaka Masatsugu , Nishida Tetsuya , Ohigashi Hiroyuki , Nakamae Hirohisa , Onizuka Makoto , Katayama Yuta , Matsuoka Ken-ichi , Sawa Masashi , Ishimaru Fumihiko , Kanda Yoshinobu , Fukuda Takahiro , Atsuta Yoshiko , Terakura Seitaro , Kanda Junya
Published: July 2024

Chronic graft-versus-host disease (GVHD) is 1 of the major complications after allogeneic hematopoietic cell transplantation (allo-HCT). Although various risk factors for chronic GVHD have been reported, limited data are available regarding the impact of acute GVHD on chronic GVHD. We examined the association between acute and chronic GVHD using a Japanese registry data set. The landmark point was set at day 100 after allo-HCT, and patients who died or relapsed before the landmark point were excluded. In total, 14 618 and 6135 patients who underwent allo-HCT with bone marrow or peripheral blood (BM/PB) and with umbilical cord blood (UCB), respectively, were analyzed. In the BM/PB cohort, the risk for chronic GVHD that requires systemic steroids increased with each increase in acute GVHD grade from 0 to 2 (grade 0 vs 1 [hazard ratio (HR), 1.32; 95% confidence interval (CI), 1.19-1.46; P < .001]; grade 1 vs 2 [HR, 1.41; 95% CI, 1.28-1.56; P < .001]), but the risk was similar between acute GVHD grade 2 and grade 3 to 4 (HR, 1.02; 95% CI, 0.91-1.15; P = 1.0). These findings were confirmed in the UCB cohort. We further observed that the risk for severe chronic GVHD increased with each increment in the grade of acute GVHD, even between acute GVHD grade 2 and grade 3 to (grade 2 vs 3-4: HR, 1.70; 95% CI, 1.12-2.58; P = .025). In conclusion, the preceding profiles of acute GVHD should help to stratify the risk for chronic GVHD and its severity, which might be useful for the development of risk-adopted preemptive strategies for chronic GVHD.
Correlation between bioluminescent blinks and swimming behavior in the splitfin flashlight fish Anomalops katoptron
Authors: Jägers Peter , Frischmuth Timo , Herlitze Stefan
Published: July 2024

Background

The light organs of the splitfin flashlight fish Anomalops katoptron are necessary for schooling behavior, to determine nearest neighbor distance, and to feed on zooplankton under dim light conditions. Each behavior is coupled to context-dependent blink frequencies and can be regulated via mechanical occlusion of light organs. During shoaling in the laboratory individuals show moderate blink frequencies around 100 blinks per minute. In this study, we correlated bioluminescent blinks with the spatio-temporal dynamics of swimming profiles in three dimensions, using a stereoscopic, infrared camera system.

Results

Groups of flashlight fish showed intermediate levels of polarization and distances to the group centroid. Individuals showed higher swimming speeds and curved swimming profiles during light organ occlusion. The largest changes in swimming direction occurred when darkening the light organs. Before A. katoptron exposed light organs again, they adapted a nearly straight movement direction.

Conclusions

We conclude that a change in movement direction coupled to light organ occlusion in A. katoptron is an important behavioral trait in shoaling of flashlight fish.
Comparison between head rotation and standard techniques for i-gel™ insertion: a randomized controlled trial
Authors: Lee Seohee , Nam Karam , Park Sang Joon , Ju Jae-Woo , Cho Youn Joung , Jeon Yunseok
Published: July 2024

Background

This study evaluated the effect of head rotation on the first-attempt success rate of i-gel insertion, aiming to alleviate the effect of gravity on the tongue and reduce resistance between the device and the tongue.

Methods

Adult surgical patients were randomized to standard and head rotation technique groups. In the head rotation technique group, patients’ heads were maximally rotated to the left before i-gel insertion. The primary endpoint was the first-attempt success rate. Secondary endpoints included the success rate within two attempts (using the allocated technique), time required for successful i-gel placement within two attempts, and success rate at the third attempt (using the opposite technique).

Results

Among 158 patients, the head rotation technique group showed a significantly higher first-attempt success rate (60/80, 75.0%) compared to the standard technique group (45/78, 57.7%; P = 0.021). The success rate within two attempts was similar between the groups (95.0% vs. 91.0%, P = 0.326). The time required for successful i-gel placement was significantly shorter in the head rotation technique (mean [SD], 13.4 [3.7] s vs. 16.3 [7.8] s; P = 0.030). When the head rotation technique failed, the standard technique also failed in all cases (n = 4), whereas the head rotation technique succeeded in five out of the seven patients where the standard technique failed.

Conclusions

The head rotation technique significantly improved the first-attempt success rate and reduced the time required for successful i-gel insertion. It was effective when the standard technique failed. The head rotation technique may be an effective primary or alternative method for i-gel insertion.

Clinical trial registration

ClinicalTrials.gov (NCT05201339).
A longitudinal evaluation of oxidative stress - mitochondrial dysfunction - ferroptosis genes in anthracycline-induced cardiotoxicity
Authors: Qianqian Ren , Peng Zhu , Licai Zhang , Ruizhi Zhang , Tianhe Ye , xiangwen Xia , Chuansheng Zheng , Fan Yang
Published: July 2024

Background

Antineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study.

Methods

The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines’s interaction with key genes.

Results

The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines.

Conclusion

This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.
Multimorbidity and patient experience with general practice: A national cross-sectional survey in Norway
Authors: Norman Rebecka Maria , Jelin Elma , Bjertnaes Oyvind
Published: July 2024

Background

Patient experience is an important indicator of the quality of healthcare. Patients with multimorbidity often face adverse health outcomes and increased healthcare utilisation. General practitioners play a crucial role in managing these patients. The main aim of our study was to perform an in-depth assessment of differences in patient-reported experience with general practice between patients living with chronic conditions and multimorbidity, and those with no chronic conditions.

Methods

We performed secondary analyses of a national survey of patient experience with general practice in 2021 (response rate 41.9%, n = 7,912). We described the characteristics of all survey respondents with no, one, two, and three or more self-reported chronic conditions. We assessed patient experience using four scales from the Norwegian patient experience with GP questionnaire (PEQ-GP). These scales were used as dependent variables in bivariate and multivariate analyses and for testing the measurement model, including confirmatory factor analysis and a multigroup CFA to assess measurement invariance. Sentiment and content analysis of free-text comments was also performed.

Results

Patients with chronic conditions consistently reported lower scores on the GP and GP practice experience scales, compared to those without chronic conditions. This pattern persisted even after adjustment for patient background variables. The strongest associations were found for the scale of “Enablement”, followed by the scales of “GP” and “Practice”. The subscale “Accessibility” did not correlate statistically significantly with any number of chronic conditions. The analysis of free-text comments echoed the quantitative results. Patients with multimorbidity stressed the importance of time spent on consultations, meeting the same GP, follow-up and relationship more often than patients with no chronic conditions. Our study also confirmed measurement invariance across patients with no chronic conditions and patients with multimorbidity, indicating that the observed differences in patient experience were a result of true differences, rather than artifacts of measurement bias.

Conclusions

The findings highlight the need for the healthcare system to provide customised support for patients with chronic conditions and multimorbidity. Addressing the specific needs of patients with multimorbidity is a critical step towards enhancing patient experience and the quality of care in general practice.
Assessment of eye health programme reach by comparison with rapid assessment of avoidable blindness (RAAB) survey data, Talagang, Pakistan
Authors: Jadoon Muhammad Zahid , Awan Zahid , Moin Muhammad , Younas Rizwan , Latorre-Arteaga Sergio , Watts Elanor , Katibeh Marzieh , Bastawrous Andrew
Published: July 2024

Background

The purpose of this study was to quantify how much of the burden of visual impairment (VI) and unmet need in Talagang, identified by Rapid Assessment of Avoidable Blindness (RAAB) survey data, has been addressed by Community Eye Health (CEH) programme efforts.

Methods

A RAAB survey was carried out in November 2018, with 2,824 participants in Talagang Tehsil, Punjab, Pakistan, aged 50 and over. Census data were used to extrapolate survey data to the population. Alongside this, a CEH programme was launched, consisting of community eye screening, and onward referral to rural health centres, secondary or tertiary ophthalmological services, as required. This health intervention aimed to address the eye care needs surfaced by the initial survey. From 2018 to 2022, 30,383 people aged 50 or over were screened; 14,054 needed referral to further steps of the treatment pathway and more detailed data collection. Programme data were compared to estimates of population unmet needs. Main outcome measures were prevalence of VI, and proportion of need met by CEH Programme, by cause and level of VI.

Results

Among those aged 50 and over, 51.0% had VI in at least one eye. The leading causes were cataract (46.2%) and uncorrected refractive error (URE) (25.0%). In its first four years, the programme reached an estimated 18.3% of the unmet need from cataract, and 21.1% of URE, equally in both men and women.

Conclusions

Robustly collected survey and programme data can improve eye health planning, monitoring and evaluation, address inequities, and quantify the resources required for improving eye health. This study quantifies the time required to reach eye health needs at the community level.
Association between different obesity patterns and the risk of NAFLD detected by transient elastography: a cross-sectional study
Authors: Sun Jingjing , Yan Chun , Wen Jing , Wang Fang , Wu Han , Xu Fang
Published: July 2024

Background

Obesity has become a major global public health challenge. Studies examining the associations between different obesity patterns and the risk of nonalcoholic fatty liver disease (NAFLD) are limited. This study aimed to investigate the relationships between different obesity patterns and the risk of NAFLD in a large male population in the US.

Methods

Data from the 2017 to March 2020 National Health and Nutrition Examination Survey (NHANES) were utilized. Liver steatosis and fibrosis were assessed with FibroScan using the controlled attenuation parameter (CAP) and liver stiffness measurements (LSM). Steatosis was identified with a CAP value of 248 dB/m or higher. Abdominal obesity was defined by a waist circumference (WC) of 102 cm or more for males and 88 cm or more for females. Overweight was defined as a body mass index (BMI) of 24.0 kg/m2 and above. General obesity was identified with a BMI of 28.0 kg/m2 or higher. Obesity status was categorized into four types: overweight, general obesity, abdominal obesity, and combined obesity. Multivariate logistic regression, adjusting for potential confounders, was used to examine the link between obesity patterns and NAFLD risk. Subgroup analysis further explored these associations.

Results

A total of 5,858 adults were included. After multivariable adjustment, compared to the normal weight group, the odds ratios (ORs) [95% confidence interval (CI)] for NAFLD in individuals with overweight, general obesity, abdominal obesity, and combined obesity were 6.90 [3.74–12.70], 2.84 [2.38–3.39], 3.02 [2.02–4.51], and 9.53 [7.79–11.64], respectively. Subgroup analysis showed the effect of different obesity patterns on NAFLD risk was stable among individuals with different clinical conditions. In the fully adjusted multivariate logistic regression model, WC was positively associated with NAFLD risk (OR: 1.48; 95% CI: 1.42–1.53; P < 0.001). WC also demonstrated strong discriminatory ability for NAFLD in Receiver Operating Characteristic (ROC) analysis, achieving an Area Under the Curve (AUC) of 0.802.

Conclusions

Different patterns of obesity are risk factors for NAFLD. An increase in WC significantly increased NAFLD risk. More attention should be paid to preventing different patterns of obesity among adults.