bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of ζ‐Ta4C3−xon the mechanical properties of tantalum carbide at elevated temperatures
Authors: Schwind Evan C. , Fahrenholtz Bill , Watts Jeremy , Hilmas Greg
Published: August 2022

Tantalum carbide ceramics containing at least 75‐wt% ζ‐Ta4C3−xwere synthesized and densified to ∼99% of the theoretical density. Flexural strength in four‐point bending was measured from room temperature up to 1600°C, achieving strengths of 710 ± 36.5 MPa at room temperature and decreasing to 180 ± 19.7 MPa at 1600°C. Fracture toughness was measured via the chevron notch method from room temperature up to 1600°C, with a toughness of 10.2 ± 0.4 MPa m1/2at room temperature and decreasing to 4.7 ± 0.1 MPa m1/2at 1600°C. At 1600°C, ductile behavior was observed during testing, and mixed mode fracture was observed on all fracture surfaces. Vickers indentations were used at room temperature to damage the surface of specimens and shed some light on damage mechanisms in the material. Kinking and delamination were observed around the indentations. At elevated temperatures, these deformation mechanisms may activate more often, causing a decrease in strength and resulting in ductility between 1400 and 1600°C. The Griffith analysis was also used to identify critical flaws. The long axis of high aspect ratio grains appears to be the critical flaw from room temperature up to 1400°C, prior to any ductile behavior. Overall, the nanolaminate microstructures, and the kinking and delamination deformation mechanisms that result from it, are reminiscent of MAX phase and kinking nonlinear elastic materials.
The chromatin remodeler BRAHMA recruits HISTONE DEACETYLASE6 to regulate root growth inhibition in response to phosphate starvation in Arabidopsis
Authors: Li Tao , Zhang Ruyue , Satheesh Viswanathan , Wang Peng , Ma Guojie , Guo Jianfei , An Guo‐Yong , Lei Mingguang
Published: August 2022

Plasticity in root system architecture (RSA) allows plants to adapt to changing nutritional status in the soil. Phosphorus availability is a major determinant of crop yield, and RSA remodeling is critical to increasing the efficiency of phosphorus acquisition. Although substantial progress has been made in understanding the signaling mechanism driving phosphate starvation responses in plants, whether and how epigenetic regulatory mechanisms contribute is poorly understood. Here, we report that the Switch defective/sucrose non‐fermentable (SWI/SNF) ATPase BRAHMA (BRM) is involved in the local response to phosphate (Pi) starvation. The loss of BRM function induces iron (Fe) accumulation through increased LOW PHOSPHATE ROOT1 (LPR1) and LPR2 expression, reducing primary root length under Pi deficiency. We also demonstrate that BRM recruits the histone deacetylase (HDA) complex HDA6‐HDC1 to facilitate histone H3 deacetylation at LPR loci, thereby negatively regulating local Pi deficiency responses. BRM is degraded under Pi deficiency conditions through the 26 S proteasome pathway, leading to increased histone H3 acetylation at the LPR loci. Collectively, our data suggest that the chromatin remodeler BRM, in concert with HDA6, negatively regulates Fe‐dependent local Pi starvation responses by transcriptionally repressing the RSA‐related genes LPR1 and LPR2 in Arabidopsis thaliana.
Optimising the educational value of indirect patient care
Authors: O'Toole Danielle , Sadik Marina , Inglis Gabrielle , Weresch Justin , Vanstone Meredith
Published: August 2022

Introduction

Indirect patient care activities (IPCA) such as documentation, reviewing investigations and filling out forms require an increasing amount of physician time. While an essential part of patient care, rising rates of IPCA work correspond with increases in physician burnout and job dissatisfaction. It is not known how best to prepare residents in IPCA‐heavy specialties (e.g. family medicine) for this aspect of their career. This study investigates how educators and residency programmes can optimise IPCA work during residency to best prepare residents for future practice.

Methods

Using Constructivist Grounded Theory, we conducted focus groups and individual interviews with 42 clinicians (19 family medicine residents, 16 family physicians in the first 5 years of practice and 7 family physician educators). All participants were connected to one family medicine residency programme. We analysed interview data iteratively, using a staged approach to constant comparative analysis.

Results

While residents, early career physicians and educators perceived the educational value of IPCAs differently, they all reported IPCAs as a necessary weight that family physicians carry throughout their career. Some residents described IPCAs as a burden, creating inequities in workload and interfering with other learning and personal opportunities. In contrast, educators conceptualised IPCAs as an opportunity to build and develop the skills required to carry the weight of IPCAs throughout their career. We make specific recommendations for helping residents recognise this educational opportunity, such as clarifying expectations, navigating equity, understanding purpose and maintaining consistency when teaching IPCAs.

Conclusion

IPCAs are a key competency for many medical residents but require explicit pedagogical attention. If the educational opportunities are not made explicit, residents may miss the opportunity to develop strategies for practice management, professional boundaries, and administrative efficiencies.
Phylogenomic structure and speciation in an emerging model: the Sphagnum magellanicum complex (Bryophyta)
Authors: Shaw A. Jonathan , Piatkowski Bryan , Duffy Aaron M. , Aguero Blanka , Imwattana Karn , Nieto‐Lugilde Marta , Healey Adam , Weston David J. , Patel Megan N. , Schmutz Jeremy , Grimwood Jane , Yavitt Joseph B. , Hassel Kristian , Stenøien Hans K. , Flatberg Kjell‐Ivar , Bickford Christopher P. , Hicks Karen A.
Published: August 2022

Sphagnum magellanicum is one of two Sphagnum species for which a reference‐quality genome exists to facilitate research in ecological genomics.

Phylogenetic and comparative genomic analyses were conducted based on resequencing data from 48 samples and RADseq analyses based on 187 samples.

We report herein that there are four clades/species within the S. magellanicum complex in eastern North America and that the reference genome belongs to Sphagnum divinum. The species exhibit tens of thousands (RADseq) to millions (resequencing) of fixed nucleotide differences. Two species, however, referred to informally as S. diabolicum and S. magni because they have not been formally described, are differentiated by only 100 (RADseq) to 1000 (resequencing) of differences. Introgression among species in the complex is demonstrated using D‐statistics and f4 ratios. One ecologically important functional trait, tissue decomposability, which underlies peat (carbon) accumulation, does not differ between segregates in the S. magellanicum complex, although previous research showed that many closely related Sphagnum species have evolved differences in decomposability/carbon sequestration.

Phylogenetic resolution and more accurate species delimitation in the S. magellanicum complex substantially increase the value of this group for studying the early evolutionary stages of climate adaptation and ecological evolution more broadly.
Understanding the organizational learning culture—Innovative behavior relation in local government: The roles of knowledge sharing and job autonomy
Authors: Lee Jaeyong , Jin Myung H.
Published: August 2022

Drawing from research on organizational learning culture, knowledge sharing (KS), and job characteristics theory, this study investigates the mediating role of KS in the link between organizational learning culture (OLC) and employee's innovative behavior (IB), as well as how this mediating effect might be moderated by job autonomy (JA). Data captured from 1420 public employees of 33 local governments in South Korea shows that OLC affects employees' IB, while the effect size is reduced when controlling for the role of KS. Further, JA moderates the positive relationship between KS and IB, such that the relationship becomes invigorated at higher levels of JA. The findings also reveal that the indirect effect of OLC on IB through KS is more pronounced at higher levels of JA, which offers evidence of moderated mediation. We discuss the significant implications of our findings for future research and practice.
Public health in undergraduate nursing education and workforce readiness
Authors: Schofield Ruth , Chircop Andrea , Filice Sylvane , Filion Francoise , Lalonde Shona , Riselli Dawn Mercer , Ryan Maureen M. , Vukic Adele
Published: August 2022

Student engagement with the community is a cornerstone of undergraduate nursing education in Canada. Working with community from perspectives of social justice, health equity, advocacy, and political action are essential for workforce readiness. We suggest that the erosion of public health theory and clinical courses in baccalaureate nursing programs undermines the potential capability of nurses to address the intersectionality of the social determinants of health. The impact of the COVID‐19 pandemic on populations further demonstrates inequities, particularly among marginalized populations. Public health nursing education supports students’ understanding about the health impacts of social injustice, how systemic racism is embedded in colonial and Eurocentric structures, and practices of superiority and privileges.We, as a national group of public health nursing educators, set out to investigate how existing guidelines and competencies support public health in undergraduate education across Canada. Results from a national questionnaire of educators, and of PHN leaders on new graduate practice readiness are presented. Questionnaire responses confirm an erosion of PHN theory and practice in baccalaureate nursing education (BNE) curricula. The results of the questionnaires combined with evidence of PHN since the global pandemic provide educators and practitioners more insight to inform future directions to respond to workforce readiness.
Photolabile Protecting Groups Based on the Excited State Meta Effect: Development and Application†
Authors: Wang Pengfei , Lim Chaeeun
Published: August 2022

This review focuses on utilization of the excited state meta effect (ESME) in the development of photolabile protecting groups (PPGs). Structurally simple ESME‐based PPGs for release of various functional groups (such as carbonyl, hydroxyl, carboxyl, amino and thiol groups) are discussed. Examples that demonstrate the appealing advantages of these new PPGs are provided, including their efficient release of “poor” leaving groups such as hydroxyl or amino group directly instead of in their respective carbonate or carbamate form. Applications of these PPGs in synthesis, release of biologically important molecules, materials science and biomedical engineering are also described.
IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells
Authors: Remsing Rix Lily L. , Sumi Natalia J. , Hu Qianqian , Desai Bina , Bryant Annamarie T. , Li Xueli , Welsh Eric A. , Fang Bin , Kinose Fumi , Kuenzi Brent M. , Chen Y. Ann , Antonia Scott J. , Lovly Christine M. , Koomen John M. , Haura Eric B. , Marusyk Andriy , Rix Uwe
Published: August 2022

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are often linked to drug resistance. Here, we found that coculture with CAFs or culture in CAF-conditioned medium unexpectedly induced drug sensitivity in certain lung cancer cell lines. Gene expression and secretome analyses of CAFs and normal lung–associated fibroblasts (NAFs) revealed differential abundance of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs), which promoted or inhibited, respectively, signaling by the receptor IGF1R and the kinase FAK. Similar drug sensitization was seen in gefitinib-resistant,
EGFR
-mutant PC9GR lung cancer cells treated with recombinant IGFBPs. Conversely, drug sensitivity was decreased by recombinant IGFs or conditioned medium from CAFs in which
IGFBP5
or
IGFBP6
was silenced. Phosphoproteomics and receptor tyrosine kinase (RTK) array analyses indicated that exposure of PC9GR cells to CAF-conditioned medium also inhibited compensatory IGF1R and FAK signaling induced by the EGFR inhibitor osimertinib. Combined small-molecule inhibition of IGF1R and FAK phenocopied the CAF-mediated effects in culture and increased the antitumor effect of osimertinib in mice. Cells that were osimertinib resistant and had
MET
amplification or showed epithelial-to-mesenchymal transition also displayed residual sensitivity to IGFBPs. Thus, CAFs promote or reduce drug resistance in a context-dependent manner, and deciphering the relationship between the differential content of CAF secretomes and the signaling dependencies of the tumor may reveal effective combination treatment strategies.
Direct Capsid Labeling of Infectious HIV-1 by Genetic Code Expansion Allows Detection of Largely Complete Nuclear Capsids and Suggests Nuclear Entry of HIV-1 Complexes via Common Routes
Authors: Schifferdecker Sandra , Zila Vojtech , Müller Thorsten G. , Sakin Volkan , Anders-Össwein Maria , Laketa Vibor , Kräusslich Hans-Georg , Müller Barbara
Published: August 2022

The cone-shaped capsid of HIV-1 has recently been recognized as a master organizer of events from cell entry of the virus to the integration of the viral genome into the host cell DNA. Fluorescent labeling of the capsid is essential to study its role in these dynamic events by microscopy, but viral capsid proteins are extremely challenging targets for the introduction of labels.
Bacterial Keystone Taxa Regulate Carbon Metabolism in the Earthworm Gut
Authors: Zhu Guofan , Schmidt Olaf , Luan Lu , Xue Jingrong , Fan Jianbo , Geisen Stefan , Sun Bo , Jiang Yuji
Published: August 2022

The intestinal microbiome of earthworms is a crucial component of the soil microbial community and nutrient cycling processes. If we could elucidate the role of this microbiome in regulating soil carbon metabolism, we would make a crucial contribution to understanding the ecological role of these gut bacterial taxa and to promoting sustainable agricultural development.
Emergence and Molecular Epidemiology of Campylobacter jejuni ST-2993 Associated with a Large Outbreak of Guillain-Barré Syndrome in Peru
Authors: Quino Willi , Caro-Castro Junior , Mestanza Orson , Hurtado Verónica , Zamudio María Luz , Cruz-Gonzales Gloria , Gavilan Ronnie G.
Published: August 2022

This article describes the molecular epidemiology of
C. jejuni
strains (ST-2993) associated with a large Guillain-Barré Syndrome (GBS) outbreak in Peru, sequencing several strains recovered from GBS patients and chickens from 2019 to 2020. Phylogenetic analysis showed a connection between Peruvian and Chinese GBS strains, both of them having lipooligosaccharides (LOS) locus genes related to molecular mimicry with gangliosides in peripheral nerves.
Multi-Omics Analysis Reveals the Protection of Gasdermin D in Concanavalin A-Induced Autoimmune Hepatitis
Authors: Wang Kaicen , Wu Wenrui , Jiang Xianwan , Xia Jiafeng , Lv Longxian , Li Shengjie , Zhuge Aoxiang , Wu Zhengjie , Wang Qiangqiang , Wang Shuting , Li Lanjuan
Published: August 2022

Our study provides the first direct clues to the protective role of gasdermin D (GSDMD) in autoimmune hepatitis (AIH). We demonstrated thatGsdmdknockout exacerbated concanavalin A (ConA)-induced AIH in mice.
Sports-related concussion (SRC) in track cycling: SRC assessment protocol for elite track cycling
Authors: Gomes Clint , Jones Nigel , Heron Neil
Published: August 2022

Track cycling is a fast, exciting sport and requires a specific sports-related concussion (SRC) assessment protocol. This paper proposes the first SRC assessment protocol for use in track cycling and proposes that this should occur in three stages. Stage 1 will occur at the trackside, whilst stage 2 occurs in the changing room immediately after the event and stage 3 the day following the suspected SRC. This SRC protocol is in its first iteration and we hope it stimulates debate to allow further refinement.
Negative Gradient Differential Biogeography-based Optimization for Mobile Robot Path Planning
Authors: Wang Jiaqian , Na Xiaodong , Li Zhihui , Han Min , Li Decai
Published: August 2022

Mobile robot path planning (MRPP) plays an irreplaceable role in the process of intelligent robots and practical artificial intelligence. The traditional global path planning methods have some shortcomings, such as difficulty in digging into environmental information and finding the optimal path effectively. To solve the above problems, this paper proposes a negative gradient differential biogeography-based optimization (NG-DBBO), which has strong local search ability and global optimization ability. Firstly, we present a differential migration approach to increase the population diversity in the iterative process of NG-DBBO, which can realize the information sharing between feature solutions effectively. Then a negative gradient descent strategy based on negative gradient descent is introduced to improve the learning rate, which not only enhances initial global search ability, but also avoids premature convergence. Noteworthily, the convergence of the algorithm is analyzed for single-peak and multi-peak problems respectively. After that, NG-DBBO is combined with the cubic spline interpolation to realize MRPP by the defined coding method and fitness function. The simulation experiments are used to demonstrate the availability of our method, which consist of two parts. In the first part, we select 23 benchmark functions to verify the accuracy and convergence speed of the NG-DBBO algorithm. The practicability of path planning in different environments is demonstrated in the second part.
A Multifunctional Flexible Ferroelectric Transistor Sensor Based on Si/Fe‐Doped Indium Oxide for Electronic Skin
Authors: Wang Xu
Published: August 2022

As the sensing basis and data source of the new generation of information technology, sensors play a vital role in today’s information age. The purpose of this work is to construct a flexible ferroelectric field‐effect transistor (FeFET) as a prototype for a multifunctional sensor for electronic skin. The FeFET device is fabricated from poly(vinylidene fluoride‐dimethylsiloxane) (P(VDF‐DMS)) and Si/Fe‐doped indium oxide (SFIO). Furthermore, this device is capable of three‐in‐one sensing. Specifically, it can detect temperature changes from 0°C to 70°C and monitors external forces with a linear sensitivity of 4.6 nA·kPa-1 across a pressure range of 50 kPa to 150 kPa. Additionally, electrostatic interaction enables the gadget to detect the approach of a charged item. Furthermore, this gadget was built to detect physiological signals produced by the human body, such as pulse, respiration, and finger movements. It is very bend‐resistant and retains transmission properties after 1200 cycles of bending. Moreover, we will examine the device’s sensitivity to temperature variations and charged particles when bent to a radius of 1.09 mm. This design will promote the next generation multifunctional E‐skin.
Balance and Vestibular Deficits in Pediatric Patients with Autism Spectrum Disorder: An Underappreciated Clinical Aspect
Authors: Oster Linda M. , Zhou Guangwei
Published: August 2022

Children with autism spectrum disorder (ASD) not only have communication and social difficulties, but also exhibit poor balance and motor control ability, which frequently affect daily activities. Effective balance and motor control rely on the integration of somatosensory, visual, and vestibular inputs. Although reports of balance dysfunction in ASD have been documented, comprehensive studies of balance and vestibular function in children with ASD are scarce. In this study, we retrospectively reviewed 36 pediatric patients diagnosed with ASD who underwent balance/vestibular laboratory testing in our speciality clinic. Results from sensory organization test (SOT) or modified clinical test for sensory integration of balance (mCTSIB) found that out of 15 patients, 80% had abnormal findings. Of the children who successfully completed each vestibular test, abnormal responses were observed in 12 (80%) sensory organization tests, 5 (24%) vestibular evoked myogenic potential (VEMP), 22 (66%) videonystagmography (VNG), and 11 (32%) sinusoidal rotary chair tests. These results indicate that balance and vestibular testing may be of diagnostic value for clinicians and providers as an aid in early detection, intervention, and the development of appropriate management and therapies for this patient population. Increased awareness of this topic is warranted to promote better clinical management of this special group of patients and improve their quality of life.
MiR-96-5p Facilitates Lung Adenocarcinoma Cell Phenotypes by Inhibiting FHL1
Authors: Zhou Feng , Qian Chaojie , Chen Tingting , Zang Xiaoliang
Published: August 2022

Objective. FHL1 is understood as a tumor repressor gene in various cancers and a possible target for cancer treatment. We investigated the influences of FHL1 on cell functions as well as its molecular mechanisms in lung adenocarcinoma (LUAD) cells. Methods. The miRNA-mRNA modulatory axis was predicted by bioinformatics. The expression levels of FHL1 mRNA and protein in LUAD cells were, respectively, analyzed by qRT-PCR and western blot. Dual luciferase analysis was introduced to verify the interaction between miR-96-5p and FHL1. CCK-8, cell colony formation, and Transwell assays were utilized to analyze proliferation, colony formation, migration, and invasion of A549 cells. Results. Expression of FHL1 mRNA and protein in LUAD tissue and cells was downregulated, which was linked with poor prognoses of patients. In addition, FHL1 overexpression could hamper colony formation, proliferation, invasion, and migration of LUAD cells. In addition, dual-luciferase analysis verified miR-96-5p as an upstream regulator of FHL1. Overexpression of miR-96-5p suppressed FHL1 expression in LUAD cells and promoted proliferation, invasion, and migration of LUAD cells, while overexpression of FHL1 could simultaneously restore the above-mentioned promoting effect. Conclusion. MiR-96-5p fostered cell malignant behaviors by targeting FHL1. This research uncovered the regulatory mechanism of FHL1 in LUAD and offered optional therapeutic targets for LUAD patients.
Hybrid RSA-ROA Scheduling Algorithm for Minimization of Power Loss and Improving the Renewable with Sustainable Energy Harvesting in Power System
Authors: Anitha Cuddapah , Sangtani Virendra Swaroop , Bansal Ajay Kumar , R. Mahaveerakannan , Sharma R. Rajesh , M. S. Saravanan
Published: August 2022

Recently, it has been very common for wireless sensor networks (WSNs) to be used in several applications (surveillance, home automation, and vehicle tracking), as well as in environmental monitoring and wildlife tracking. A typical sensor node has a limited amount of battery life. To overcome this, one method is to use an energy harvesting device to recharge the batteries of sensor nodes. Energy reaping WSNs still lack intelligent strategies for intelligently using both energy organization and harvesting systems, though. To maximize the harvesting of renewable energy sources (RES) and minimize power scheme losses, this study provides an optimal generation scheduling strategy for a power scheme combined with distributed generation (DG) and sustainable energy storage systems (ESSs). The major goal of this work is to make it possible to use RES in a power system while still maintaining a profit. By using ESS management, we are able to get the most out of our renewable energy resources and maximize our harvesting potential. It is also possible to reduce operating losses in the power system by scheduling ESS and controlled generation at the optimal times. Near global optimal solutions are sought using a hybrid algorithm combining Reptile Search Algorithm and Remora Optimization Algorithm (RSA-ROA). The power system operational restrictions are taken into account when formulating and evaluating the optimization issue. It has been tested in a variety of circumstances to see if the proposed strategy is effective. The proposed model has 0.260 J of remaining energy, when the number of rounds is 5000, but the existing techniques have only 0.110 J and 0.045 J for the same number of rounds.
The Investigation of the Application Value of Musculoskeletal Ultrasound in the Diagnosis and Conservative Treatment of Knee Osteoarthritis
Authors: Pan Yan , Wang Liying , Zhou Lingling
Published: August 2022

Objective. To explore the application value of musculoskeletal ultrasound in the diagnosis and conservative treatment of knee osteoarthritis. Methods. Patients with knee osteoarthritis who were treated in our hospital from January 1, 2020 to August 31, 2021 were selected as the research subjects. The subjects underwent musculoskeletal ultrasonography to record the thickness of the lateral femoral malleolus cartilage, the thickness of the medial femoral malleolus cartilage, the depth of the suprapatellar bursa effusion, and the thickness of the suprapatellar bursa synovium. All patients in the study group received acupuncture treatment after musculoskeletal ultrasonography, and musculoskeletal ultrasonography was performed again after 2 weeks of treatment. The differences in musculoskeletal ultrasound-related parameters were compared between the two groups. Results. The thickness of the lateral femoral malleolus cartilage and medial femoral malleolus cartilage in the study group was significantly smaller than those in the control group. The depth of the effusion in the suprapatellar bursa and the thickness of the synovial membrane in the suprapatellar bursa were significantly greater than those in the control group. Ultrasonography showed no significant difference in abnormal status compared with arthroscopy, and musculoskeletal ultrasonography revealed knee osteoarthritis, such as cruciate ligament injury, joint effusion, synovial hyperplasia, meniscus injury, and patellar ligament injury. The cartilage thickness of the lateral femoral malleolus and medial malleolus of femur after treatment were significantly greater than those before treatment. The depth of the deep suprapatellar bursa effusion and the thickness of the suprapatellar bursa synovium were significantly smaller than those before treatment. Conclusion. Musculoskeletal ultrasound has high diagnostic value in knee osteoarthritis. It can detect the lesion as soon as possible and can be used to evaluate the effect of conservative treatment, so as to provide reference basis for clinical formulation or adjustment of further intervention plan.
Pan-Cancer Analysis of Microbiome Quantitative Trait Loci
Authors: Chen Can , Cai Yimin , Liu Yizhuo , Chen Shuoni , Li Yanmin , Zhang Fuwei , Zhang Ming , Lu Zequn , Ying Pingting , Huang Jinyu , Fan Linyun , Cai Xiaomin , Ning Caibo , Wang Wenzhuo , Jiang Yuan , Zhang Heng , Yang Shuhui , Wang Zhihua , Wang Xiaoyang , Zhang Shaokai , Huang Chaoqun , Xu Bin , Fu Zhenming , Song Qibin , Jin Mingjuan , Chen Kun , Chen Hongda , Dai Min , Miao Xiaoping , Yang Xiaojun , Zhu Ying , Tian Jianbo
Published: August 2022

Microorganisms are commonly detected in tumor tissues, and the species and abundance have been reported to affect cancer initiation, progression, and therapy. Host genetics have been associated with gut microbial abundances, while the relationships between genetic variants and the cancer microbiome still require systematic interrogation. Therefore, identification of cancer microbiome quantitative trait loci (mbQTL) across cancer types might elucidate the contributions of genetic variants to tumor development. Using genotype data from The Cancer Genome Atlas and microbial abundance levels from Kraken-derived data, we developed a computational pipeline to identify mbQTLs in 32 cancer types. This study systematically identified 38,660 mbQTLs across cancers, ranging 50 in endometrial carcinoma to 3,133 in thyroid carcinoma. Furthermore, a strong enrichment of mbQTLs was observed among transcription factor binding sites and chromatin regulatory elements, such as H3K27ac. Notably, mbQTLs were significantly enriched in cancer genome-wide association studies (GWAS) loci and explained an average of 2% for cancer heritability, indicating that mbQTLs could provide additional insights into cancer etiology. Correspondingly, 24,443 mbQTLs overlapping with GWAS linkage disequilibrium regions were identified. Survival analyses identified 318 mbQTLs associated with patient overall survival. Moreover, we uncovered 135,248 microbiome–immune infiltration associations and 166,603 microbiome–drug response associations that might provide clues for microbiome-based biomarkers. Finally, a user-friendly database, Cancer-mbQTL (http://canmbqtl.whu.edu.cn/#/), was constructed for users to browse, search, and download data of interest. This study provides a valuable resource for investigating the roles of genetics and microorganisms in human cancer.

Significance:

This study provides insights into the host–microbiome interactions for multiple cancer types, which could help the research community understand the effects of inherited variants in tumorigenesis and development.
Leptomeningeal Metastasis from Non–Small Cell Lung Cancer and Current Landscape of Treatments
Authors: Ozcan Gonca , Singh Meghana , Vredenburgh James J.
Published: August 2022

Leptomeningeal metastasis (LM), also known as leptomeningeal carcinomatosis (LC), is a devastating complication of metastatic cancer that occurs when neoplastic cells invade the meningeal space. Diagnosis of LM remains challenging given the heterogeneous signs and symptoms at presentation and requires thorough neurological examination, cerebrospinal fluid (CSF) analysis, and MRI of the brain and spine with gadolinium. Detecting neoplastic cells in the CSF is the gold standard for diagnosing leptomeningeal metastases; however, it has low sensitivity and may require multiple CSF samples. New emerging technologies, such as liquid biopsy of CSF, have increased sensitivity and specificity for detecting circulating tumor cells in CSF. The management of LM in patients with NSCLC requires an individualized multidisciplinary approach. Treatment options include surgery for ventricular shunt placement, radiation therapy to bulky or symptomatic disease sites, systemic or intrathecal chemotherapy, molecularly targeted agents, and, more recently, immunotherapy. Targeting actionable mutations in LM from NSCLC, such as EGFR tyrosine kinase inhibitors or anaplastic lymphoma kinase gene rearrangement inhibitors, has shown encouraging results in terms of disease control and survival. Although there are limited data regarding the use of immunotherapy in LM, immunotherapy has produced promising results in several case reports. In this review, we focused on the epidemiology, pathophysiology, clinical presentation, diagnosis, and current treatment strategies, with a special emphasis on novel agents, including targeted therapies and immunotherapy of LM in patients with NSCLC.
Combined TRIP13 and Aurora Kinase Inhibition Induces Apoptosis in Human Papillomavirus–Driven Cancers
Authors: Ghosh Soma , Mazumdar Tuhina , Xu Wei , Powell Reid T. , Stephan Clifford , Shen Li , Shah Pooja A. , Pickering Curtis R. , Myers Jeffery N. , Wang Jing , Frederick Mitchell J. , Johnson Faye M.
Published: August 2022

Purpose:

Human papillomavirus (HPV) causes >5% of cancers, but no therapies uniquely target HPV-driven cancers.

Experimental Design:

We tested the cytotoxic effect of 864 drugs in 16 HPV-positive and 17 HPV-negative human squamous cancer cell lines. We confirmed apoptosis in vitro and in vivo using patient-derived xenografts. Mitotic pathway components were manipulated with drugs, knockdown, and overexpression.

Results:

Aurora kinase inhibitors were more effective in vitro and in vivo in HPV-positive than in HPV-negative models. We hypothesized that the mechanism of sensitivity involves retinoblastoma (Rb) expression because the viral oncoprotein E7 leads to Rb protein degradation, and basal Rb protein expression correlates with Aurora inhibition–induced apoptosis. Manipulating Rb directly, or by inducing E7 expression, altered cells’ sensitivity to Aurora kinase inhibitors. Rb affects expression of the mitotic checkpoint genes MAD2L1 and BUB1B, which we found to be highly expressed in HPV-positive patient tumors. Knockdown of MAD2L1 or BUB1B reduced Aurora kinase inhibition–induced apoptosis, whereas depletion of the MAD2L1 regulator TRIP13 enhanced it. TRIP13 is a potentially druggable AAA-ATPase. Combining Aurora kinase inhibition with TRIP13 depletion led to extensive apoptosis in HPV-positive cancer cells but not in HPV-negative cancer cells.

Conclusions:

Our data support a model in which HPV-positive cancer cells maintain a balance of MAD2L1 and TRIP13 to allow mitotic exit and survival in the absence of Rb. Because it does not affect cells with intact Rb function, this novel combination may have a wide therapeutic window, enabling the effective treatment of Rb-deficient cancers.
Constructing Understandings
Authors: Duckworth Eleanor , Hooper Paula K. , McKinney Alythea , Schneier Lisa
Published: August 2022

In this 50th anniversary of the Jean Piaget Society, we have been asked to celebrate The Having of Wonderful Ideas and Other Essays on Teaching and Learning (Duckworth, 2006) – winner of the 1988 AERA award for outstanding research contribution in the areas of teaching and teacher education, now in its 3rd edition, published on four continents, in 7 languages. We have taken the name that Inhelder gave to Piaget’s research method – Critical Exploration – as the basis for the name of our approach to teaching – Critical Exploration in the Classroom. In this paper, we talk about what that name and this book mean to our teaching and to constructivism. Each one of the four authors has written one section, allowing us to present several different aspects of the book.
Associations Between Adherence to Evidence-Based, Stroke Quality Indicators and Outcomes of Acute Reperfusion Therapy
Authors: Ren Nice , Ogata Soshiro , Kiyoshige Eri , Nishimura Kunihiro , Nishimura Ataru , Matsuo Ryu , Kitazono Takanari , Higashi Takahiro , Ogasawara Kuniaki , Iihara Koji ,   on behalf of Close The Gap-Stroke, J-ASPECT Study Collaborators*
Published: August 2022

Background:

Quality indicators (QIs) are an accepted tool for measuring a hospital’s performance in routine care. We examined national trends in adherence to the QIs developed by the Close The Gap-Stroke program by combining data from the health insurance claims database and electronic medical records, and the association between adherence to these QIs and early outcomes in patients with acute ischemic stroke in Japan.

Methods:

In the present study, patients with acute ischemic stroke who received acute reperfusion therapy in 351 Close The Gap-Stroke-participating hospitals were analyzed retrospectively. The primary outcomes were changes in trends for adherence to the defined QIs by difference-in-difference analysis and the effects of adherence to distinct QIs on in-hospital outcomes at the individual level. A mixed logistic regression model was adjusted for patient and hospital characteristics (eg, age, sex, number of beds) and hospital units as random effects.

Results:

Between 2013 and 2017, 21 651 patients (median age, 77 years; 43.0% female) were assessed. Of the 25 defined measures, marked and sustainable improvement in the adherence rates was observed for door-to-needle time, door-to-puncture time, proper use of endovascular thrombectomy, and successful revascularization. The in-hospital mortality rate was 11.6%. Adherence to 14 QIs lowered the odds of in-hospital mortality (odds ratio [95% CI], door-to-needle <60 min, 0.80 [0.69–0.93], door-to-puncture <90 min, 0.80 [0.67–0.96], successful revascularization, 0.40 [0.34–0.48]), and adherence to 11 QIs increased the odds of functional independence (modified Rankin Scale score 0–2) at discharge.

Conclusions:

We demonstrated national marked and sustainable improvement in adherence to door-to-needle time, door-to-puncture time, and successful reperfusion from 2013 to 2017 in Japan in patients with acute ischemic stroke. Adhering to the key QIs substantially affected in-hospital outcomes, underlining the importance of monitoring the quality of care using evidence-based QIs and the nationwide Close The Gap-Stroke program.
Cardiometabolic Disease Results in Sex‐ and Age‐Dependent Cerebrovascular Degeneration and Arteriolar Morphological Changes
Authors: Jestus Jack , Kondrasov Sasha , Yager Brock , McMullen Nate , Contillo Nicholas , Ryalat Fatima , Xiang Zhidan , Diz Debra I. , Wolfe Stacey Q.
Published: August 2022

In the past 20 years, no drug therapies have been successfully translated into human use for intracerebral hemorrhage (ICH), the most devastating stroke subset. One likely factor is lack of effective animal models of human disease including common comorbidities, such as hypertension and diabetes. We evaluated the cardiometabolic rodent model, (mRen2)27, where overexpression of Ren2 results in extreme hypertension, glucose intolerance and obesity, as an appropriate ICH model. Methods: Sprague Dawley (SD) and (mRen2)27 rats were sacrificed at 14‐, 32‐, and 52‐weeks. Brains were sectioned sagittally at 5 μm. Whole‐brain sections were stained using Hematoxylin & Eosin (H&E) and Van Geison (VG) collagen staining to visualize the pial blood vessels. Wall‐to‐lumen ratios for vessels were calculated and compared using a student t‐test to determine significance. Results: There was no significant difference in arteriolar morphology at 14‐weeks between male SD and mRen animals (SD, n=16 and mRen, n=16). At 32‐weeks, there was a significant difference in mRen male rats (SD, n=13 and mRen, n=17; p<0.0001), with significantly increased wall thickness and decreased Lumen size in the mRen animals (increased W:L ratio). However, at this timeframe, there was no significant difference between the female SD and mRen cohorts (SD, n=6 and mRen, n=8). At 52‐weeks, there was a significant increase in W:L ratios in both male (SD, n=4 and mRen, n=7; p<0.01) and female (SD, n=9 and mRen, n=8; p<0.05) mRen animals compared to control. Conclusion: The (mRen2)27 cardiometabolic animal model demonstrates age‐related sex changes in the wall:lumen ratio of cerebral vasculature consistent with cerebrovascular disease seen in ischemic and hemorrhagic stroke patients. Males develop these vascular changes earlier than females, but both sexes in this model develop cerebral vascular changes by 1 year of age. The (mRen2)27 model appears to recapitulate human disease and sex differences, and may serve as an appropriate translational model of ICH.
Imaging Indicators for Parenchymal Hemorrhage After Mechanical Thrombectomy in Acute Stroke
Authors: Kimura Ryutaro , Shoda Sotaro , Saito Tomonari , Suzuki Kentaro , Kutsuna Akihito , Kanamaru Takuya , Katano Takehiro , Nakagami Toru , Numao Shinichiro , Suda Satoshi , Nishiyama Yasuhiro , Kimura Kazumi
Published: August 2022

Background

In patients with acute ischemic stroke with large vessel occlusion, the presence of hyperintense lesions on fluid‐attenuated inversion recovery (FLAIR‐positive) before mechanical thrombectomy (MT) and that of hyperdense lesions on noncontrast computed tomography (CT‐positive) after MT are associated with parenchymal hemorrhage, but the significance of these findings is unclear.

Methods

Patients with acute stroke with large vessel occlusion underwent magnetic resonance imaging, including diffusion‐weighted imaging and FLAIR, before MT. Noncontrast CT was obtained within 60 minutes after MT. The occurrence of parenchymal hemorrhage type 2 (PH2) was assessed on CT within 7 days after MT. FLAIR and CT‐positive were defined as a case with hyperintense and hyperdense lesions immediately before and after MT, respectively. Clinical and imaging factors associated with PH2 were evaluated by multivariate regression analysis.

Results

Enrolled were 412 patients (median age, 76 years; men, 58.3%; median National Institutes of Health Stroke Scale score, 16). The site of occlusion was the internal carotid artery (n=122, 29.6%), M1 (n=180, 43.7%), and M2 (n=96, 23.3%). FLAIR‐positive, CT‐positive, and PH2 were found in 149 (36.2%), 223 (54.1%), and 34 patients (8.3%), respectively. PH2 was significantly more frequent in CT‐positive than CT‐negative patients (14.3% versus 1.1%;
P
<0.001), but not in FLAIR‐positive than FLAIR‐negative patients (10.7% versus 6.8%;
P
=0.193). Regardless of FLAIR status, PH2 was significantly more frequent in CT‐positive than CT‐negative patients (12.8% versus 0.8% [
P
<0.001] for FLAIR‐negative, and 16.7% versus 1.7% [
P
=0.003] for FLAIR‐positive). Multivariate regression analysis demonstrated that CT‐positive was the only independent factor associated with PH2 (odds ratio, 12.699 [95% CI, 2.964–54.416];
P
<0.001). Sensitivity, specificity, positive predictive value, and negative predictive values of CT‐positive for predicting PH2 occurrence were 94.1%, 49.5%, 14.3%, and 98.9%, respectively.

Conclusion

In patients with acute ischemic stroke with large vessel occlusion, CT‐positive immediately after MT was strongly predictive of PH2, but no such relationship was found for FLAIR‐positive before MT.
“Human vs Machine” Validation of a Deep Learning Algorithm for Pediatric Middle Ear Infection Diagnosis
Authors: Crowson Matthew G. , Bates David W. , Suresh Krish , Cohen Michael S. , Hartnick Christopher J.
Published: August 2022

Objective

We compared the diagnostic performance of human clinicians with that of a neural network algorithm developed using a library of tympanic membrane images derived from children taken to the operating room with the intent of performing myringotomy and possible tube placement for recurrent acute otitis media (AOM) or otitis media with effusion (OME).

Study Design

Retrospective cohort study.

Setting

Tertiary academic medical center from 2018 to 2021.

Methods

A training set of 639 images of tympanic membranes representing normal, OME, and AOM was used to train a neural network as well as a proprietary commercial image classifier from Google. Model diagnostic prediction performance in differentiating normal vs nonpurulent vs purulent effusion was scored based on classification accuracy. A web‐based survey was developed to test human clinicians’ diagnostic accuracy on a novel image set, and this was compared head to head against our model.

Results

Our model achieved a mean prediction accuracy of 80.8% (95% CI, 77.0%‐84.6%). The Google model achieved a prediction accuracy of 85.4%. In a validation survey of 39 clinicians analyzing a sample of 22 endoscopic ear images, the average diagnostic accuracy was 65.0%. On the same data set, our model achieved an accuracy of 95.5%.

Conclusion

Our model outperformed certain groups of human clinicians in assessing images of tympanic membranes for effusions in children. Reduced diagnostic error rates using machine learning models may have implications in reducing rates of misdiagnosis, potentially leading to fewer missed diagnoses, unnecessary antibiotic prescriptions, and surgical procedures.
Characteristics of clinical trials related to hip fractures and factors associated with completion
Authors: Wang Shengjie , Xiong Fan , Gao Yanzheng , Lei Mingxing , Zhang Xianlong
Published: August 2022

Background

This study aimed at investigating the characteristics of clinical trials related to hip fractures that were registered at ClinicalTrials.gov. It also aimed to identify potential risk factors associated with completion.

Main body

We obtained 733 clinical studies related to hip fractures from the ClinicalTrials.gov database and included 470 studies in the analysis. These clinical trials were divided into behavioral, drug/biological, device, procedure, and other categories based on intervention types. Clinical trials investigating drugs or biologics were categorized based on the specific agents administered in each trial. Multiple logistic and Cox regression models were used to test the ability of 24 potential risk factors in predicting recruitment status and completion time, respectively. Among the included clinical trials, 44.89% (211/470) had complete recruitment status. The overall median completion time was 931.00 days (95% confidence interval [CI]: 822.56–1039.44 days). The results of only 8.94% (42/470) of clinical trials were presented on the ClinicalTrials.gov website. Bupivacaine (a local anesthetic) was most commonly investigated (in 25 clinical trials); this was followed by ropivacaine (another local anesthetic, 23 clinical trials) and tranexamic acid (a hemostatic, 21 clinical trials). Multivariate analysis showed that trials including children (P = 0.03) and having National Institutes of Health funds (P < 0.01) had significantly higher rates of complete recruitment. Higher enrollment (P < 0.01), National Institutes of Health funding (P < 0.01), location in the United States (P = 0.04), and location in Europe (P = 0.03) predisposed to longer completion time, while studies involving drugs/biologics (P < 0.01) had shorter completion times.

Conclusions

A considerable proportion of clinical trials related to hip fractures were completed, but the results of only a small fraction were presented on the ClinicalTrials.gov website. The commonly investigated drugs focused on anesthesia, pain relief, and hemostasis. Several independent risk factors that affect recruitment status and completion time were identified. These factors may guide the design of clinical trials relating to hip fractures.
A qualitative exploration of the provision and prioritisation of smoking cessation support to patient carers in a paediatric ward in Australia
Authors: Moyo Sukoluhle , Hefler Marita , Carson-Chahhoud Kristin V. , Thomas David P
Published: August 2022

Background

Hospitalisation of a child is a unique opportunity for health staff to offer smoking cessation support; that is screening for carer smoking status, discussing cessation and providing interventions to carers who smoke. This has the potential to reduce the child’s exposure to second-hand smoke, and in turn tobacco related illnesses in children. However, these interventions are not always offered in paediatric wards. The aim of this study was to explore the provision and prioritisation of smoking cessation support to patient carers in a paediatric ward with a high proportion of Aboriginal patients and carers in a regional area of Australia’s Northern Territory.

Methods

This is a qualitative descriptive study of data collected through semi-structured interviews with 19 health staff. The interviews were audio recorded and transcribed verbatim. Thematic analysis was performed on the transcripts.

Results

We found low prioritisation of addressing carer smoking due to, a lack of systems and procedures to screen for smoking and provide quitting advice and unclear systems for providing more detailed cessation support to carers. Staff were demotivated by the lack of clear referral pathways. There were gaps in skills and knowledge, and health staff expressed a need for training opportunities in smoking cessation.

Conclusion

Health staff perceived they would provide more cessation support if there was a systematic approach with evidence-based resources for smoking cessation. These resources would include guidelines and clinical record systems with screening tools, clear action plans and referral pathways to guide clinical practice. Health staff requested support to identify existing training opportunities on smoking cessation.