bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxidative Stress Caused by Ozone Exposure Induces Changes in P2X7 Receptors, Neuroinflammation, and Neurodegeneration in the Rat Hippocampus
Authors: Velázquez-Pérez Raúl , Rodríguez-Martínez Erika , Valdés-Fuentes Marlen , Gelista-Herrera Noemí , Gómez-Crisóstomo Nancy , Rivas-Arancibia Selva
Published: November 2021

Low‐ozone doses cause alterations in the oxidation‐reduction mechanisms due to the increase in reactive oxygen species, alter cell signaling, and produce deleterious metabolic responses for cells. Adenosine 5 ′triphosphate (ATP) can act as a mediator in intercellular communication between neurons and glial cells. When there is an increase in extracellular ATP, a modification is promoted in the regulation of inflammation, energy metabolism, by affecting the intracellular signaling pathways that participate in these processes. The objective of this work was to study changes in the P2X7 receptor, and their relationship with the inflammatory response and energy metabolism, in a model of progressive neurodegeneration in the hippocampus of rats chronically exposed to low‐ozone doses. Therefore, 72 male rats were exposed to low‐ozone doses for different periods of time. After exposure to ozone was finished, rats were processed for immunohistochemical techniques, western blot, quantitative polymerase chain reaction (qPCR), and histological techniques for periodic acid‐Schiff staining. The results showed immunoreactivity changes in the amount of the P2X7 protein. There was an increase in phosphorylation for glycogen synthase kinase 3‐β (GSK3‐β) as treatment continued. There were also increases in 27 interleukin 1 beta (IL‐1 β) and interleukin 17 (IL‐17) and a decrease in interleukin 10 (IL‐10). Furthermore, neuronal glycogen was found at 30 and 60 days, and an increase in caspase 3. An increase in mRNA was also shown for the P2X7 gene at 60 days, and GSK3‐β at 90 days of exposure. In conclusion, these results suggest that repeated exposure to low‐ozone doses, such as those that can occur during highly polluted days, causes a state of oxidative stress, leading to alterations in the P2X7 receptors, which promote changes in the activation of signaling pathways for inflammatory processes and cell death, converging at a progressive neurodegeneration process, as may be happening in Alzheimer’s disease.
Diagnostic Classification of Patients with Dilated Cardiomyopathy Using Ventricular Strain Analysis Algorithm
Authors: Li Mingliang , Chen Yidong , Mao Yujie , Jiang Mingfeng , Liu Yujun , Zhan Yuefu , Li Xiangying , Su Caixia , Zhang Guangming , Zhou Xiaobo
Published: November 2021

Dilated cardiomyopathy (DCM) is a cardiomyopathy with left ventricle or double ventricle enlargement and systolic dysfunction. It is an important cause of sudden cardiac death and heart failure and is the leading indication for cardiac transplantation. Major heart diseases like heart muscle damage and valvular problems are diagnosed using cardiac MRI. However, it takes time for cardiologists to measure DCM-related parameters to decide whether patients have this disease. We have presented a method for automatic ventricular segmentation, parameter extraction, and diagnosing DCM. In this paper, left ventricle and right ventricle are segmented by parasternal short-axis cardiac MR image sequence; then, related parameters are extracted in the end-diastole and end-systole of the heart. Machine learning classifiers use extracted parameters as input to predict normal people and patients with DCM, among which Random forest classifier gives the highest accuracy. The results show that the proposed system can be effectively utilized to detect and diagnose DCM automatically. The experimental results suggest the capabilities and advantages of the proposed method to diagnose DCM. A small amount of sample input can generate results comparable to more complex methods.
Oridonin Dose-Dependently Modulates the Cell Senescence and Apoptosis of Gastric Cancer Cells
Authors: Wang Yiping , Lv Hang , Dai Chunyan , Wang Xi , Yin Yifei , Chen Zhe
Published: November 2021

Gastric cancer (GC) is the fourth most lethal cancer. Effective treatments are lacking, and our knowledge of the pathogenic mechanisms in play is poor. Oridonin from the Chinese herb Rabdosia rubescens exerts various anticancer activities. However, the dose-dependent effects of oridonin on human GC remain unclear. Here, we found that oridonin inhibited GC cell growth in a time- and dose-dependent manner. Low-dose oridonin induced GC cell cycle arrest at G0/G1 and cell senescence by suppressing the c-Myc-AP4 pathway and enhancing p53-p21 signaling. AP4 overexpression partly abrogated the oridonin-induced senescence of GC cells. High-dose oridonin induced apoptosis and autophagy, with the autophagy inhibitor BafA1 attenuating oridonin-induced apoptosis. Together, the findings indicate that oridonin at different doses modulates GC cell senescence and apoptosis; oridonin may thus usefully treat GC.
A Literature Review: The History of Psychological Impact of Illness amongst People with Leprosy (PwL) in Countries across the Globe
Authors: Achdiat Pati Aji , Ariyanto Eko Fuji , Simanjuntak Michael Nobel
Published: November 2021

Background. Leprosy is a chronic infectious disease for which effective therapy has been long since invented. Thus, the morbidity has been decreased as technology has advanced, but the permanent disability has continuously generated stigma for centuries. The stigma causes the emergence of a poor psychological impact on people with leprosy (PwL). These impacts make new PwL reluctant to get appropriate therapy for their initial symptoms and are, thus, troublesome in accomplishing the goals of the leprosy elimination program. The aim of this review is to provide the history of psychological impact amongst PwL in countries across the globe. Methods. This is a literature review study. A keyword-based search was conducted in digital libraries. Articles reporting on PwL’s psychology and related issues, such as quality of life, opportunity of building a marriage, and getting hired, were included. The data were presented based on a leprosy history timeline with cutoff points, namely, the invention of promin (1941) and multidrug treatment (1970). Results. In total, 38 studies were included in this review. These studies showed that PwL’s knowledge towards leprosy has been increasing; nevertheless, their attitude is still lacking. The emotional response was described by various negative feelings that had persistently occurred. These poor psychological impacts were followed by poor treatment-seeking behavior and resulted in low quality of life. Conclusions. From year to year, the PwL’s knowledge about leprosy has been getting better; nevertheless, their attitude towards the disease is still poor. The emotional response, social participation, and quality of life of PwL are persistently poor due to the persistent stigma.
Breakthrough Pressure Prediction Based on Neural Network Model
Authors: Hao Shuren , Cao Jixiang , Zhang Hua , Liu Yulian , Liang Haian , Li Mingdong
Published: November 2021

The increasing carbon dioxide content is identified as the main cause of global warming. Capturing carbon dioxide in the atmosphere and transporting it to deep salt layer for storage have been proven and practiced in many aspects, which considered to be an effective way to reduce the content of carbon dioxide in the atmosphere. The sealing property of cap rocks is one of the key factors to determine whether CO2 can be effectively stored for a long time. In view of the disadvantages of tedious and time-consuming laboratory test methods for breakthrough pressure of cap rock, this paper explores the relationship between breakthrough pressure and other parameters such as porosity, permeability, density, specific surface area, maximum throat radius, and total organic carbon. The results show that the rock breakthrough pressure is closely related to the maximum throat radius and permeability determined by the mercury injection method, followed by the porosity and specific surface area, and less related to the density, depth, and TOC content of the rock itself. Then, with the selected parameters, a neural network model is established to predict the breakthrough pressure of cap rock, which can achieve good prediction results.
Robotic Partial Cystectomy for Urachal Carcinoma: A Case Report and Review of the Literature
Authors: Abou Zahr Rawad , Colinet Valentin , Mattlet Aurore , Jabbour Teddy , Diamand Romain
Published: November 2021

Urachal carcinoma is a very rare tumor, commonly found in the urachal remnant connecting the bladder dome to the umbilicus. Diagnosis is often challenging due to the location of the tumor and its late presentation. We hereby report the case of a 49-year-old female where the diagnosis of urachal carcinoma was made and a robotic partial cystectomy associated with en bloc resection of the umbilicus was performed. We aim to present the clinical aspects, presentation, and diagnosis of this rare entity along with a review of the literature.
Rh‐CXCL‐12 Attenuates Neuronal Pyroptosis after Subarachnoid Hemorrhage in Rats via Regulating the CXCR4/NLRP1 Pathway
Authors: Gu Ran , Wang Lu , Zhou Hao , Wang Xike , Lenahan Cameron , Qu Hao , Liu Yonghe , Li Shirong , Wei Changxiu , Han Lu , Hu Xiao , Zuo Gang
Published: November 2021

Subarachnoid hemorrhage (SAH) is a cerebrovascular disease associated with high morbidity and mortality. CXCR4 provides neuroprotective effects, which can alleviate brain injury and inflammation induced by stroke. Previous studies have suggested that CXCR4 reduces the pyroptosis of LPS‐stimulated BV2 cells. The purpose of this study was to evaluate the antipyroptosis effects and mechanisms of CXCR4 after SAH. SAH animal model was induced via endovascular perforation. A total of 136 male Sprague‐Dawley rats were used. Recombinant human cysteine‐X‐cysteine chemokine ligand 12 (rh‐CXCL‐12) was administered intranasally at 1 h after SAH induction. To investigate the underlying mechanism, the inhibitor of CXCR4, AMD3100, was administered intraperitoneally at 1 h before SAH. The neurobehavior tests were assessed, followed by performing Western blot and immunofluorescence staining. The Western blot results suggested that the expressions of endogenous CXCL‐12, CXCR4, and NLRP1 were increased and peaked at 24 h following SAH. Immunofluorescence staining showed that CXCR4 was expressed on neurons, microglia, and astrocytes. Rh‐CXCL‐12 treatment improved the neurological deficits and reduced the number of FJC‐positive cells, IL‐18‐positive neurons, and cleaved caspase‐1(CC‐1)‐positive neurons after SAH. Meanwhile, rh‐CXCL‐12 treatment increased the levels of CXCL‐12 and CXCR4, and reduced the levels of NLRP1, IL‐18, IL‐1β, and CC‐1. Moreover, the administration of AMD3100 abolished antipyroptosis effects of CXCL‐12 and its regulation of CXCR4 post‐SAH. The CXCR4/NLRP1 signaling pathway may be involved in CXCL‐12‐mediated neuronal pyroptosis after SAH. Early administration of CXCL‐12 may be a preventive and therapeutic strategy against brain injury after SAH.
A Relativistic Compact Stellar Model of Anisotropic Quark Matter Mixed with Dark Energy
Authors: Grammenos Theophanes , Rahaman Farook , Ray Saibal , Deb Debabrata , Chowdhury Sourav Roy
Published: November 2021

The possibility of strange stars mixed with dark energy to be one of the candidates for dark energy stars is the main issue of the present study. Our investigation shows that quark matter atcs as dark energy after a certain yet unknown critical condition inside the quark stars. Our proposed model reveals that strange stars mixed with dark energy feature a physically acceptable stable model and mimic characteristics of dark energy stars. The plausible connections are shown through the mass-radius relation as well as the entropy and temperature. We particularly note that a two-fluid distribution is a major reason for the anisotropic nature of the spherical stellar system.
Experimental and Numerical Investigations on the Ignition of RBCC Gas-Oxygen/Kerosene Rocket Ejector
Authors: Liu Bingyang , Jin Ping , Ma Yixin , Qi Yaqun , Cai Guobiao , Zhang Yuanjun
Published: November 2021

The rocket ejector refers to a core component of a rocket-based combined cycle (RBCC) engine. The ignition is of critical significance for rocket ejection. Reliable and stable ignition crucially determines the normal operation of the engine. In this paper, a thrust chamber with coaxial swirl injector for the RBCC rocket ejection was developed and tested. Gas oxygen (GOX) and kerosene acted as propellants. As revealed from the test results, the process of ignition pressurizing comprised four phases. The oxygen prefilling time before ignition slightly impacted the ignition time, whereas it affected the peak pressure of ignition. In a confined range, the peak pressure decreased as the prefilling time was extended. The ignition was simulated by building a numerical model, and the results well complied with the experimentally achieved results. The numerical model is capable of specifically indicating the position of the kernel of fire and the process of flame propagation. The simulation results reveal that the propellant could form a combustible condition within 4 ms. The kernel was 6 mm away from the injector, located at the oxygen and kerosene mixing interface and approaching the upper wall. The above results reflected the vital role of the central recirculation zone formed by the prefilled oxygen. The ignition energy was transported near the injector under the convection effect, which ignited the stoichiometric mixture, and the entire ignition could reach a stable state within 20 ms. The numerical model which was developed in this paper can help clarify the combustion mechanism.
Systematic Analysis Uncovers Associations of PGK1 with Prognosis and Immunological Characteristics in Breast Cancer
Authors: Li Liangdong , Bai Yang , Gao Yang , Li Deheng , Chen Lei , Zhou Changshuai , Feng Mingtao , Chen Xin , Jin Wei , Cao Yiqun
Published: November 2021

Objective. Phosphoglycerate kinase 1 (PGK1) is an essential enzyme in the process of glycolysis and mitochondrial metabolism. Herein, we conducted a systematic analysis to uncover the clinical implication of PGK1 deregulation in breast cancer. Methods. Expression pattern and prognostic significance of PGK1 were comprehensively assessed across pan-cancer based on RNA-seq profiles from the TCGA project. Associations of PGK1 with immunological features in the tumor microenvironment (immune checkpoints, immune response predictors (tumor mutation burden (TMB) and microsatellite instability (MSI)), and tumor-infiltrating immune cells) were systematically analyzed. The role of PGK1 in the prediction of breast cancer prognosis was also evaluated. GSEA was presented for investigating biological pathways involved in PGK1. Results. PGK1 was specifically overexpressed in most of cancer types, including breast cancer. High PGK1 expression was indicative of undesirable overall survival, progression-free interval, disease-specific survival, and disease-free interval for various cancers. Furthermore, high PGK1 levels exhibited prominent correlations to immune checkpoints and high response to immunotherapy across pan-cancer. Notably, ROC curves confirmed that PGK1 can robustly predict breast cancer prognosis. Furthermore, PGK1 might shape an inflamed tumor microenvironment following the evidence that PGK1 was positively correlated to the abundance levels of tumor-infiltrating immune cells such as CD8+ T cell and NK cell in breast cancer. GSEA results revealed that PGK1 participated in metabolism and carcinogenic pathways. Conclusion. Collectively, PGK1 was capable of robustly predicting the prognosis and response to cancer immunotherapy in breast cancer.
Combined Feedback Feedforward Control of a 3‐Link Musculoskeletal System Based on the Iterative Training Method
Authors: Valizadeh Amin , Akbari Ali Akbar
Published: November 2021

The investigation and study of the limbs, especially the human arm, have inspired a wide range of humanoid robots, such as movement and muscle redundancy, as a human motor system. One of the main issues related to musculoskeletal systems is the joint redundancy that causes no unique answer for each angle in return for an arm’s end effector’s arbitrary trajectory. As a result, there are many architectures like the torques applied to the joints. In this study, an iterative learning controller was applied to control the 3‐link musculoskeletal system’s motion with 6 muscles. In this controller, the robot’s task space was assumed as the feedforward of the controller and muscle space as the controller feedback. In both task and muscle spaces, some noises cause the system to be unstable, so a forgetting factor was used to a convergence task space output in the neighborhood of the desired trajectories. The results show that the controller performance has improved gradually by iterating the learning steps, and the error rate has decreased so that the trajectory passed by the end effector has practically matched the desired trajectory after 1000 iterations.
An Exhaustive Review on a Solar Still Coupled with a Flat Plate Collector
Authors: Ayoobi Ahmadreza , Ramezanizadeh Mahdi
Published: November 2021

In recent years, producing energy and potable water has become a contemporaneous issue in all areas, especially in rural and remote areas. It is due to the limitation of fossil fuels in generating energy and the daily increase of potable water topic pollution due to various development activities in the industries. Gradually, the use of renewable energies has been suggested as far as humans focus on using these energies in various activities, which is gratis and accessible in more areas without having negative anthropogenic hazards. Solar radiation has an important position in renewable energies and has played a significant role in the desalination process due to the convenience in applying and abundance in the areas with potable water shortages. However, one of the active solar stills is the coupling of conventional solar still with a flat plate collector. In this type, a flat plate collector is used to raise the temperature of saline water which increases the productivity. In this research, the solar still coupled with a flat plate collector is reviewed as the active solar still and the affecting parameters on its performance and efficiency are discussed. First, a summary of working research and their research of flat plate collectors is reviewed to be more familiar with flat plate collectors, their details, and technology. Then, solar still coupled with a flat plate collector is extensively reviewed and discussed in detail. Four types of studies on solar still coupled with a flat plate collector were done, including energy analysis, exergy analysis, economic analysis, and productivity evaluation.
Inhibition of FGFR Reactivates IFNγ Signaling in Tumor Cells to Enhance the Combined Antitumor Activity of Lenvatinib with Anti-PD-1 Antibodies
Authors: Adachi Yusuke , Kamiyama Hiroshi , Ichikawa Kenji , Fukushima Sayo , Ozawa Yoichi , Yamaguchi Shogo , Goda Satoshi , Kimura Takayuki , Kodama Kotaro , Matsuki Masahiro , Miyano Saori Watanabe , Yokoi Akira , Kato Yu , Funahashi Yasuhiro
Published: November 2021

Combination therapies consisting of immune checkpoint inhibitors plus anti-VEGF therapy show enhanced antitumor activity and are approved treatments for patients with renal cell carcinoma (RCC). The immunosuppressive roles of VEGF in the tumor microenvironment are well studied, but those of FGF/FGFR signaling remain largely unknown. Lenvatinib is a receptor tyrosine kinase inhibitor that targets both VEGFR and FGFR. Here, we examine the antitumor activity of anti-PD-1 mAb combined with either lenvatinib or axitinib, a VEGFR-selective inhibitor, in RCC. Both combination treatments showed greater antitumor activity and longer survival in mouse models versus either single agent treatment, whereas anti-PD-1 mAb plus lenvatinib had enhanced antitumor activity compared with anti-PD-1 mAb plus axitinib. Flow cytometry analysis showed that lenvatinib decreased the population of tumor-associated macrophages and increased that of IFNγ-positive CD8+ T cells. Activation of FGFR signaling inhibited the IFNγ-stimulated JAK/STAT signaling pathway and decreased expression of its target genes, including B2M, CXCL10, and PD-L1. Furthermore, inhibition of FGFR signaling by lenvatinib restored the tumor response to IFNγ stimulation in mouse and human RCC cell lines. These preclinical results reveal novel roles of tumor FGFR signaling in the regulation of cancer immunity through inhibition of the IFNγ pathway, and the inhibitory activity of lenvatinib against FGFRs likely contributes to the enhanced antitumor activity of combination treatment comprising lenvatinib plus anti-PD-1 mAb.

Significance:

FGFR pathway activation inhibits IFNγ signaling in tumor cells, and FGFR inhibition with lenvatinib enhances antitumor immunity and the activity of anti-PD-1 antibodies.
Nanoparticle Delivery of miR-122 Inhibits Colorectal Cancer Liver Metastasis
Authors: Sendi Hossein , Yazdimamaghani Mostafa , Hu Mengying , Sultanpuram Nikhila , Wang Jie , Moody Amber S. , McCabe Ellie , Zhang Jiajie , Graboski Amanda , Li Liantao , Rojas Juan D. , Dayton Paul A. , Huang Leaf , Wang Andrew Z.
Published: November 2021

Liver metastasis is a leading cause of cancer morbidity and mortality. Thus, there has been strong interest in the development of therapeutics that can effectively prevent liver metastasis. One potential strategy is to utilize molecules that have broad effects on the liver microenvironment, such as miR-122, a liver-specific miRNA that is a key regulator of diverse hepatic functions. Here we report the development of a nanoformulation miR-122 as a therapeutic agent for preventing liver metastasis. We engineered a galactose-targeted lipid calcium phosphate (Gal-LCP) nanoformulation of miR-122. This nanotherapeutic elicited no significant toxicity and delivered miR-122 into hepatocytes with specificity and high efficiency. Across multiple colorectal cancer liver metastasis models, treatment with Gal-LCP miR-122 treatment effectively prevented colorectal cancer liver metastasis and prolonged survival. Mechanistic studies revealed that delivery of miR-122 was associated with downregulation of key genes involved in metastatic and cancer inflammation pathways, including several proinflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. Moreover, Gal-LCP miR-122 treatment was associated with an increased CD8+/CD4+ T-cell ratio and decreased immunosuppressive cell infiltration, which makes the liver more conducive to antitumor immune response. Collectively, this work presents a strategy to improve cancer prevention and treatment with nanomedicine-based delivery of miRNA.

Significance:

Highly specific and efficient delivery of miRNA to hepatocytes using nanomedicine has therapeutic potential for the prevention and treatment of colorectal cancer liver metastasis.
Translational Activation of ATF4 through Mitochondrial Anaplerotic Metabolic Pathways Is Required for DLBCL Growth and Survival
Authors: Li Meng , Teater Matthew R. , Hong Jun Young , Park Noel R. , Duy Cihangir , Shen Hao , Wang Ling , Chen Zhengming , Cerchietti Leandro , Davidson Shawn M. , Lin Hening , Melnick Ari M.
Published: November 2021

Diffuse large B-cell lymphomas (DLBCL) are broadly dependent on anaplerotic metabolism regulated by mitochondrial SIRT3. Herein we find that translational upregulation of ATF4 is coupled with anaplerotic metabolism in DLBCLs due to nutrient deprivation caused by SIRT3 driving rapid flux of glutamine into the tricarboxylic acid (TCA) cycle. SIRT3 depletion led to ATF4 downregulation and cell death, which was rescued by ectopic ATF4 expression. Mechanistically, ATF4 translation is inhibited in SIRT3-deficient cells due to the increased pools of amino acids derived from compensatory autophagy and decreased glutamine consumption by the TCA cycle. Absence of ATF4 further aggravates this state through downregulation of its target genes, including genes for amino acid biosynthesis and import. Collectively, we identify a SIRT3–ATF4 axis required to maintain survival of DLBCL cells by enabling them to optimize amino acid uptake and utilization. Targeting ATF4 translation can potentiate the cytotoxic effect of SIRT3 inhibitor to DLBCL cells.

Significance:

We discovered the link between SIRT3 and ATF4 in DLBCL cells, which connected lymphoma amino acid metabolism with ATF4 translation via metabolic stress signals. SIRT3–ATF4 axis is required in DLBCL cells regardless of subtype, which indicates a common metabolic vulnerability in DLBCLs and can serve as a therapeutic target.

This article is highlighted in the In This Issue feature, p. 1
Person-Centered Psychiatry as Dialogical Psychiatry: The Significance of the Therapeutic Stance
Authors: Galbusera Laura , Fuchs Thomas , Holm-Hadulla Rainer M. , Thoma Samuel
Published: November 2021

In this article, we present holistic and person-centered perspectives in psychiatry, with the aim of better understanding what a focus on personhood might really mean and what clinical implications it might have. We first introduce classical and philosophical concepts of personhood, in order to then outline person-centered approaches in psychiatry, which mainly focus on the person of the patient. We then argue that, for it to really be person-centered, psychiatry must necessarily also focus on the person of professionals. We thus explore the notion of stance, as the expression of the therapist’s personhood. By unpacking the effects that a professional’s stance can have on patients, we finally turn to a consideration of the interpersonal sphere. More specifically, we propose clinical considerations on a therapeutic stance that strives to support and to help the person of the patient unfold. Such a stance must – we argue – necessarily be a dialogical one. Drawing on these considerations, we thus claim that a truly person-centered approach in psychiatry must necessarily and automatically be interperson-centered and dialogical. In the concluding remarks, we finally discuss broader societal implications and outline future research perspectives.
Is There a “Weekend Effect” in Intertrochanteric Fracture Surgery?
Authors: Guo Junfei , Ye Pengyu , Zhang Qi , Gao Xian , Wang Zhiqian , Wang Qiujun , Hou Zhiyong , Zhang Yingze
Published: November 2021

Introduction: Numerous studies reported poorer outcomes for patients who were admitted at weekends or off-hour, which relates to the underlying concept called the “weekend effect.” We aimed to assess the effect of adverse outcomes in older patients with intertrochanteric fracture surgery. Methods: A retrospective cohort study of patients aged ≥65 years with intertrochanteric fracture surgery. Data were collected from computerized medical records and all patients had a long-term follow-up. The association between weekend effect with adverse outcomes and factors for all-cause mortality was studied by 3-group comparison, Spearman and partial correlation analysis, univariate analysis, and multivariate Cox proportional-hazard model. Results: Our results showed no evidence supporting the existence of a weekend effect on adverse outcomes, including mortality rates (p = 0.950, log-rank), length of hospital stay, total hospital costs, rate and volume of transfusion, visual analog scale score, Harris Hip Score, and specific complications (all p > 0.05), except for an average of 0.5 days longer surgical delay found in patients admitted on Fridays relative to other days (p = 0.013). Instead, only age group (with a 10-year interval, HR 1.43, 1.28–1.59 95% CI, p < 0.001) and surgical delay (HR 1.05, 1.02–1.07 95% CI, p < 0.001) were identified as significantly associated with all-cause mortality. Conclusions: Older patients with intertrochanteric fracture surgery have similar mortality and adverse outcomes rates when admitted on weekends or holidays compared with weekdays. Our findings suggest that collaborative multidisciplinary team care seems both effective and efficient in the management of older patients with intertrochanteric fractures on any day of the week.
Molecular Cytogenetic Classification of Down Syndrome and Screening of Somatic Aneuploidy in Mothers
Authors: Jaiswal Sushil Kumar , Kumar Ashok , Rai Amit Kumar
Published: November 2021

Down Syndrome (DS) caused by trisomy 21 results in various congenital and developmental complications in children. It is crucial to cytogenetically diagnose the DS cases early for their proper health management and to reduce the risk of further DS childbirths in mothers. In this study, we performed a cytogenetic analysis of 436 suspected DS cases using karyotyping and fluorescent in situ hybridization. We detected free trisomies (95.3%), robertsonian translocations (2.4%), isochromosomes (0.6%), and mosaics (1.2%). We observed a slightly higher incidence of DS childbirth in younger mothers compared to mothers with advanced age. We compared the somatic aneuploidy in peripheral blood of mothers having DS children (MDS) and control mothers (CM) to identify biomarkers for predicting the risk for DS childbirths. No significant difference was observed. After induced demethylation in peripheral blood cells, we did not observe a significant difference in the frequency of aneuploidy between MDS and CM. In conclusion, free trisomy 21 is the most common type of chromosomal abnormality in DS. A small number of DS cases have translocations and mosaicism of chromosome 21. Additionally, somatic aneuploidy in the peripheral blood from the mother is not an effective marker to predict DS childbirths.
Pharmacokinetics and Pharmacodynamics of Sacubitril/Valsartan in Maintenance Hemodialysis Patients with Heart Failure
Authors: Feng Zhonglin , Wang Xipei , Zhang Li , Apaer Rizvangul , Xu Lixia , Ma Jianchao , Li Xinyi , Che Huimin , Tang Bin , Xiong Yuwang , Xia Yubin , Xiao Jie , Su Xiaoyan , Wang Yamei , Dou Xianrui , Chen Jinzhong , Mei Lifan , Xue Zhiqiang , Kong Yuanyuan , Li Sijia , Zhang Hong , Lin Ting , Wen Feng , Fu Xia , Tao Yiming , Fu Lei , Li Zhuo , Huang Renwei , Ye Zhiming , He Chaosheng , Shi Wei , Liang Xinling , Ke Guibao , Liu Shuangxin
Published: November 2021

Background: Heart failure (HF) is one of the main comorbidities in patients receiving maintenance hemodialysis (HD). Sacubitril/valsartan (SAC/VAL) is widely used in HF patients with reduced ejection fraction (HFrEF) or HF mid-range ejection fraction (HFmrEF). However, the pharmacokinetic (PK) and pharmacodynamic properties of SAC/VAL in HD patients with HF remain uncertain. Objectives: This study aimed to analyze the efficacy and PK properties of SAC/VAL in HD patients with HFrEF or HFmrEF. Methods: HD patients with HFrEF or HFmrEF were treated with SAC/VAL 50 or 100 mg twice a day (BID) and the concentrations of valsartan and LBQ657 (active metabolite of SAC) were determined by high-performance liquid chromatography-tandem mass spectrometry during HD and on the days between HD sessions (interval days). N-terminal-pro B-type natriuretic peptide and high-sensitivity troponin T were measured, and left ventricular ejection fraction (LVEF) was evaluated by echocardiography. Results: The mean maximum plasma concentrations (Cmax) of LBQ657 and VAL on the interval days were 15.46 ± 6.01 and 2.57 ± 1.23 mg/L, respectively. Compared with previous values in patients with severe renal impairment and healthy volunteers, these levels both remained within the safe concentration ranges during treatment with SAC/VAL 100 mg BID. Moreover, SAC/VAL significantly improved LVEF in HD patients with HFrEF or HFmrEF (p < 0.05). Conclusions: HD did not remove the SAC metabolite LBQ657 or VAL in patients with HF. However, SAC/VAL 100 mg BID was safe and effective in patients undergoing HD.
Metastatic Breast Cancer Presenting as Pulmonary Nodules and Right Axillary Lymph Node in a Male with Chronic Lymphocytic Leukemia
Authors: Acostamadiedo Marx Ana S. , Avendaño-Capriles Camilo Andrés , Lemos Julio A. , Gorman Eric , Acostamadiedo Jose M.
Published: November 2021

To our knowledge, this is the first case reported in the English literature of simultaneous occult male metastatic breast cancer presenting as pulmonary nodules and right axillary lymph node metastasis in a chronic lymphocytic leukemia (CLL) patient and is the second case of simultaneous male breast cancer and CLL reported. The first case was reported by Dubashi et al. [Curr Oncol. 2011;18(2):e101–2] in 2011. This unique clinical and pathological entity presents various challenges in its management, including early detection, screening, and treatment.
Long-Range Regulation of Key Sex Determination Genes
Authors: Migale Roberta , Neumann Michelle , Lovell-Badge Robin
Published: November 2021

The development of sexually dimorphic gonads is a unique process that starts with the specification of the bipotential genital ridges and culminates with the development of fully differentiated ovaries and testes in females and males, respectively. Research on sex determination has been mostly focused on the identification of sex determination genes, the majority of which encode for proteins and specifically transcription factors such as SOX9 in the testes and FOXL2 in the ovaries. Our understanding of which factors may be critical for sex determination have benefited from the study of human disorders of sex development (DSD) and animal models, such as the mouse and the goat, as these often replicate the same phenotypes observed in humans when mutations or chromosomic rearrangements arise in protein-coding genes. Despite the advances made so far in explaining the role of key factors such as SRY, SOX9, and FOXL2 and the genes they control, what may regulate these factors upstream is not entirely understood, often resulting in the inability to correctly diagnose DSD patients. The role of non-coding DNA, which represents 98% of the human genome, in sex determination has only recently begun to be fully appreciated. In this review, we summarize the current knowledge on the long-range regulation of 2 important sex determination genes, SOX9 and FOXL2, and discuss the challenges that lie ahead and the many avenues of research yet to be explored in the sex determination field.
The Chromatin State during Gonadal Sex Determination
Authors: Dupont Shannon , Capel Blanche
Published: November 2021

At embryonic day (E) 10.5, prior to gonadal sex determination, XX and XY gonads are bipotential and able to differentiate into either a testis or an ovary. At this point, they are transcriptionally and morphologically indistinguishable. Sex determination begins around E11.5 in the mouse when the supporting cell lineage commits to either Sertoli or granulosa cell fate. Testis-specific factors such as SRY and SOX9 drive differentiation of bipotential-supporting cells into the Sertoli cell pathway, whereas ovary-specific factors like WNT4 and FOXL2 guide differentiation into granulosa cells. It is known that these 2 pathways are mutually antagonistic, and repression of the alternative fate is critical for maintenance of the testis or ovary programs. While we understand much about the transcription factor networks guiding the process of sex determination, it is only more recently that we have begun to understand how this process is epigenetically controlled. Studies in the past decade have demonstrated the importance of the chromatin state for gene expression and cell fate commitment, with histone modifications and DNA accessibility having a direct role in gene regulation. It is now clear that the chromatin state during sex determination is dynamic and likely critical for the establishment and/or maintenance of the transcriptional programs. Prior to sex determination, supporting cells have similar chromatin structure and histone modification profiles, reflecting the bipotential nature of these cells. After differentiation to Sertoli or granulosa cells, the chromatin state acquires sex-specific profiles. The proteins that regulate the deposition of histone modifications or the opening of compact chromatin likely play an important role in Sertoli and granulosa cell fate commitment and gonad development. Here, we describe studies profiling the chromatin state during gonadal sex determination and one example in which depletion of Cbx2, a member of the Polycomb Repressive Complex 1 (PRC1), causes male-to-female sex reversal due to a failure to repress the ovarian pathway.
Long-Term Survival Outcomes of Patients with Small (≤1 cm) Node-Negative HER2-Positive Breast Cancer Not Treated with Adjuvant Anti-HER2-Targeted Therapy: A 10-Year Follow-Up Study
Authors: Liikanen Jenni S. , Leidenius Marjut , Joensuu Heikki , Meretoja Tuomo J.
Published: November 2021

Introduction: Human epidermal growth factor receptor 2 (HER2) expression is considered an unfavourable prognostic factor in early breast cancer when the patients are not treated with HER2-targeted therapy. However, the long-term prognostic importance of HER2 expression in small (≤1 cm, stage pT1a-b), node-negative HER2+ breast cancer is still incompletely known. Methods: A retrospective analysis was performed based on a prospectively collected database including patients with pT1 breast cancer operated at the Helsinki University Hospital, Finland, between March 2000 and April 2006. In this database, 44 patients with pT1a-bN0M0, HER2+ cancer, not treated with adjuvant anti-HER2-targeted therapy (the HER2+ group) and 291 pT1a-bN0M0, hormone receptor-positive, HER2-negative cancers (the ER+/HER2– group) were identified and included in the study. Survival outcomes were analysed using the Kaplan-Meier method. Results: The median follow-up time was 9.7 years after primary breast surgery. Ten-year distant disease-free survival (DDFS) was 84.0% in the HER2+ group and 98.2% in the ER+/HER2– group (p < 0.001). Ten-year overall survival was only 78.5% in the HER2+ group, but 91.7% in the ER+/HER2– group (p = 0.09). Conclusions: Cancer HER2 status is strongly associated with unfavourable DDFS during the first decade of follow-up in patients with small (pT1a-bN0M0) breast cancer when adjuvant anti-HER2-targeted treatment is not administered.
Corpo e Cidade
Authors: Silveira Danilo , Almeida Saulo Vinícius , Moreira Camila
Published: November 2021

Editorial
O tensionamento afetivo nas relações entre corpo e cidade através do Programa Performativo no espaço urbano
Authors: Faria Jéssica Sousa , Carvalho Marcelo Braga de , Pestana Sandra Regina Facioli
Published: November 2021

Este artigo tem como objetivo principal analisar a relação entre espaço urbano e corpo – transeunte através de uma abordagem artística e pedagógica. Sendo assim, este projeto utilizará como ferramenta investigativa o Programa Performativo que, segundo Eleonora Fabião, conduz o corpo a experiências que lhe propiciam a criação de relações e circulações afetivas. Para construção da ação do referido programa foram utilizados conceitos da Teoria da Deriva de Guy Debórd e as experiências artísticas e poéticas desenvolvidas por Renato Almeida. Como campo de estudo, as imediações da Praça das Artes, localizada no centro histórico da cidade de São Paulo. Este sítio urbano, que contém patrimônios históricos e culturais da cidade, revela-se um campo fértil para a experimentação e investigação de práticas artísticas aqui propostas e disparador para a criação de ações instalativas.
Dicotomias do espaço: abordagens anticoloniais nas práticas de Mujeres Creando
Authors: Gaulês Murilo Moraes
Published: November 2021

O artigo aborda as propostas de rupturas epistemológica nas relações corpo-espaço-performance desenvolvidas pelo coletivo anarcofeminista Mujeres Creando e sua fundadora Maria Galindo. A partir de conceitos da filosofia anticolonial com autores como Paul Preciado, Jota Mombaça e Sayak Valência, realiza-se uma análise profunda dessas proposições em contraponto a realidade normativa da compreensão espacial da arte contemporânea ocidentalizada e eurocentrada.
Suppression of Arctic Sea Ice Growth in the Eurasian–Pacific Seas by Winter Clouds and Snowfall
Authors: Lim Won-Il , Park Hyo-Seok , Stewart Andrew L. , Seo Kyong-Hwan
Published: November 2021

The ongoing Arctic warming has been pronounced in winter and has been associated with an increase in downward longwave radiation. While previous studies have demonstrated that poleward moisture flux into the Arctic strengthens downward longwave radiation, less attention has been given to the impact of the accompanying increase in snowfall. Here, utilizing state-of-the-art sea ice models, we show that typical winter snowfall (snow water equivalent) anomalies of around 1.0 cm, accompanied by positive downward longwave radiation anomalies of ∼5 W m−2, can cause basinwide sea ice thinning by around 5 cm in the following spring over the Arctic seas in the Eurasian–Pacific seas. In extreme cases, this is followed by a shrinking of summer ice extent. In the winter of 2016/17, anomalously strong warm, moist air transport combined with ∼2.5-cm increase in snowfall (snow water equivalent) decreased spring ice thickness by ∼10 cm and decreased the following summer sea ice extent by 5%–30%. This study suggests that small changes in the pattern and volume of winter snowfall can strongly impact the sea ice thickness and extent in the following seasons.
ENSO Predictability over the Past 137 Years Based on a CESM Ensemble Prediction System
Authors: Liu Ting , Song Xunshu , Tang Youmin , Shen Zheqi , Tan Xiaoxiao
Published: November 2021

In this study, we conducted an ensemble retrospective prediction from 1881 to 2017 using the Community Earth System Model to evaluate El Niño–Southern Oscillation (ENSO) predictability and its variability on different time scales. To our knowledge, this is the first assessment of ENSO predictability using a long-term ensemble hindcast with a complicated coupled general circulation model (CGCM). Our results indicate that both the dispersion component (DC) and signal component (SC) contribute to the interannual variation of ENSO predictability (measured by relative entropy). Specifically, the SC is more important for ENSO events, whereas the DC is of comparable importance for short lead times and in weak ENSO signal years. The SC dominates the seasonal variation of ENSO predictability, and an abrupt decrease in signal intensity results in the spring predictability barrier feature of ENSO. At the interdecadal scale, the SC controls the variability of ENSO predictability, while the magnitude of ENSO predictability is determined by the DC. The seasonal and interdecadal variations of ENSO predictability in the CGCM are generally consistent with results based on intermediate complexity and hybrid coupled models. However, the DC has a greater contribution in the CGCM than that in the intermediate complexity and hybrid coupled models.

Significance Statement

El Niño–Southern Oscillation (ENSO) is a prominent interannual signal in the global climate system with widespread climatic influence. Our current understanding of ENSO predictability is based mainly on long-term retrospective forecasts obtained from intermediate complexity and hybrid coupled models. Compared with those models, complicated coupled general circulation models (CGCMs) include more realistic physical processes and have the potential to reproduce the ENSO complexity. However, hindcast studies based on CGCMs have only focused on the last 20–60 years. In this study, we conducted an ensemble retrospective prediction from 1881 to 2017 using the Community Earth System Model in order to evaluate ENSO predictability and examine its variability on different time scales. To our knowledge, this is the first assessment of ENSO predictability using a long-term ensemble hindcast with a CGCM.
Book review: Pradumna B. Rana and Xianbai Ji, China’s Belt and Road Initiative: Impacts on Asia and Policy Agenda
Authors: Shahriar Saleh
Published: November 2021

Pradumna B. Rana and Xianbai Ji, China’s Belt and Road Initiative: Impacts on Asia and Policy Agenda. Singapore: Palgrave Macmillan, 2020, xx + 186 pp., 51, €99 (Hardcover).
Impact of Order-Set Modifications and Provider Education Following Guideline Updates on Broad-Spectrum Antibiotic Use in Patients Admitted With Community Acquired Pneumonia
Authors: Colmerauer Jessica L. , Linder Kristin E. , Dempsey Casey J. , Kuti Joseph L. , Nicolau David P. , Bilinskaya Anastasia
Published: November 2021

Purpose: Following updates to the Infectious Diseases Society of America (IDSA) practice guidelines for the Diagnosis and Treatment of Adults with Community-acquired Pneumonia in 2019, Hartford HealthCare implemented changes to the community acquired pneumonia (CAP) order-set in August 2020 to reflect criteria for the prescribing of broad-spectrum antimicrobial therapy. The objective of the study was to evaluate changes in broad-spectrum antibiotic days of therapy (DOT) following these order-set updates with accompanying provider education. Methods: This was a multi-center, quasi-experimental, retrospective study of patients with a diagnosis of CAP from September 1, 2019 to October 31, 2019 (pre-intervention) and September 1, 2020 to October 31, 2020 (post-intervention). Patients were identified using ICD-10 codes (A48.1, J10.00-J18.9) indicating lower respiratory tract infection. Data collected included demographics, labs and vitals, radiographic, microbiological, and antibiotic data. The primary outcome was change in broad-spectrum antibiotic DOT, specifically anti-pseudomonal β-lactams and anti-MRSA antibiotics. Secondary outcomes included guideline-concordance of initial antibiotics, utilization of an order-set to prescribe antibiotics, and length of stay (LOS). Results: A total of 331 and 352 patients were included in the pre- and post-intervention cohorts, respectively. There were no differences in order-set usage (10% vs 11.3%, P = .642) between the pre- and post-intervention cohort, respectively. The overall duration of broad-spectrum therapy was a median of 2 days (IQR 0-8 days) in the pre-intervention period and 0 days (IQR 0-4 days) in the post-intervention period ( P < .001). Patients in whom the order-set was used in the post-intervention period were more likely to have guideline-concordant regimens ([36/40] 90% vs [190/312] 60.9%; P = .003). Hospital LOS was shorter in the post-intervention cohort (4.8 days [2.9-7.2 days] vs 5.3 days [IQR 3.5-8.5 days], P = .002). Conclusion: Implementation of an updated CAP order-set with accompanying provider education was associated with reduced use of broad-spectrum antibiotics. Opportunities to improve compliance and thus further increase guideline-concordant therapy require investigation.