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1. Genetic studies of body mass index yield new insights for obesity biology

Author

Locke, Adam E, Kahali, Bratati, Berndt, Sonja I, Justice, Anne E, Pers, Tune H, Day, Felix R, Powell, Corey, Vedantam, Sailaja, Buchkovich, Martin L, Yang, Jian, Croteau-Chonka, Damien C, Esko, Tonu, Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Kutalik, Zoltán, Luan, Jian’an, Mägi, Reedik, Randall, Joshua C, Winkler, Thomas W, Wood, Andrew R, Workalemahu, Tsegaselassie, Faul, Jessica D, Smith, Jennifer A, Hua Zhao, Jing, Zhao, Wei, Chen, Jin, Fehrmann, Rudolf, Hedman, Åsa K, Karjalainen, Juha, Schmidt, Ellen M, Absher, Devin, Amin, Najaf, Anderson, Denise, Beekman, Marian, Bolton, Jennifer L, Bragg-Gresham, Jennifer L, Buyske, Steven, Demirkan, Ayse, Deng, Guohong, Ehret, Georg B, Feenstra, Bjarke, Feitosa, Mary F, Fischer, Krista, Goel, Anuj, Gong, Jian, Jackson, Anne U, Kanoni, Stavroula, Kleber, Marcus E, Kristiansson, Kati, Lim, Unhee, Lotay, Vaneet, Mangino, Massimo, Mateo Leach, Irene, Medina-Gomez, Carolina, Medland, Sarah E, Nalls, Michael A, Palmer, Cameron D, Pasko, Dorota, Pechlivanis, Sonali, Peters, Marjolein J, Prokopenko, Inga, Shungin, Dmitry, Stančáková, Alena, Strawbridge, Rona J, Ju Sung, Yun, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, van der Laan, Sander W, van Setten, Jessica, Van Vliet-Ostaptchouk, Jana V, Wang, Zhaoming, Yengo, Loïc, Zhang, Weihua, Isaacs, Aaron, Albrecht, Eva, Ärnlöv, Johan, Arscott, Gillian M, Attwood, Antony P, Bandinelli, Stefania, Barrett, Amy, Bas, Isabelita N, Bellis, Claire, Bennett, Amanda J, Berne, Christian, Blagieva, Roza, Blüher, Matthias, Böhringer, Stefan, Bonnycastle, Lori L, Böttcher, Yvonne, Boyd, Heather A, Bruinenberg, Marcel, Caspersen, Ida H, Ida Chen, Yii-Der, Clarke, Robert, Warwick Daw, E, de Craen, Anton JM, Delgado, Graciela, and Dimitriou, Maria

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Nutrition, Obesity, Prevention, Aetiology, 2.1 Biological and endogenous factors, Stroke, Cardiovascular, Metabolic and endocrine, Oral and gastrointestinal, Cancer, Adipogenesis, Adiposity, Age Factors, Body Mass Index, Energy Metabolism, Europe, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glutamic Acid, Humans, Insulin, Insulin Secretion, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Racial Groups, Synapses, LifeLines Cohort Study, ADIPOGen Consortium, AGEN-BMI Working Group, CARDIOGRAMplusC4D Consortium, CKDGen Consortium, GLGC, ICBP, MAGIC Investigators, MuTHER Consortium, MIGen Consortium, PAGE Consortium, ReproGen Consortium, GENIE Consortium, International Endogene Consortium, General Science & Technology
Abstract

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P 20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Published
2015

2. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Author

Perry, John RB, Day, Felix, Elks, Cathy E, Sulem, Patrick, Thompson, Deborah J, Ferreira, Teresa, He, Chunyan, Chasman, Daniel I, Esko, Tõnu, Thorleifsson, Gudmar, Albrecht, Eva, Ang, Wei Q, Corre, Tanguy, Cousminer, Diana L, Feenstra, Bjarke, Franceschini, Nora, Ganna, Andrea, Johnson, Andrew D, Kjellqvist, Sanela, Lunetta, Kathryn L, McMahon, George, Nolte, Ilja M, Paternoster, Lavinia, Porcu, Eleonora, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Tšernikova, Natalia, Tikkanen, Emmi, Ulivi, Sheila, Wagner, Erin K, Amin, Najaf, Bierut, Laura J, Byrne, Enda M, Hottenga, Jouke-Jan, Koller, Daniel L, Mangino, Massimo, Pers, Tune H, Yerges-Armstrong, Laura M, Hua Zhao, Jing, Andrulis, Irene L, Anton-Culver, Hoda, Atsma, Femke, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Buring, Julie E, Chang-Claude, Jenny, Chanock, Stephen, Chen, Jinhui, Chenevix-Trench, Georgia, Collée, J Margriet, Couch, Fergus J, Couper, David, Coviello, Andrea D, Cox, Angela, Czene, Kamila, D’adamo, Adamo Pio, Davey Smith, George, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dieffenbach, Aida K, Dunning, Alison M, Eiriksdottir, Gudny, Eriksson, Johan G, Fasching, Peter A, Ferrucci, Luigi, Flesch-Janys, Dieter, Flyger, Henrik, Foroud, Tatiana, Franke, Lude, Garcia, Melissa E, García-Closas, Montserrat, Geller, Frank, de Geus, Eco EJ, Giles, Graham G, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Guo, Suiqun, Hall, Per, Hamann, Ute, Haring, Robin, Hartman, Catharina A, Heath, Andrew C, Hofman, Albert, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Hunter, David J, Karasik, David, and Kiel, Douglas P

Subjects
Paediatrics, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Contraception/Reproduction, Pediatric, Biotechnology, Human Genome, Clinical Research, Adolescent, Age Factors, Alleles, Body Mass Index, Breast Neoplasms, Calcium-Binding Proteins, Cardiovascular Diseases, Child, Diabetes Mellitus, Type 2, Europe, Female, Genetic Loci, Genome-Wide Association Study, Genomic Imprinting, Humans, Hypothalamo-Hypophyseal System, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Obesity, Ovary, Parents, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain, Proteins, Quantitative Trait Loci, Receptors, GABA-B, Receptors, Retinoic Acid, Ribonucleoproteins, Ubiquitin-Protein Ligases, Australian Ovarian Cancer Study, GENICA Network, kConFab, LifeLines Cohort Study, InterAct Consortium, Early Growth Genetics (EGG) Consortium, General Science & Technology
Abstract

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P

Published
2014

3. Biological, clinical and population relevance of 95 loci for blood lipids

Author

Teslovich, Tanya M, Musunuru, Kiran, Smith, Albert V, Edmondson, Andrew C, Stylianou, Ioannis M, Koseki, Masahiro, Pirruccello, James P, Ripatti, Samuli, Chasman, Daniel I, Willer, Cristen J, Johansen, Christopher T, Fouchier, Sigrid W, Isaacs, Aaron, Peloso, Gina M, Barbalic, Maja, Ricketts, Sally L, Bis, Joshua C, Aulchenko, Yurii S, Thorleifsson, Gudmar, Feitosa, Mary F, Chambers, John, Orho-Melander, Marju, Melander, Olle, Johnson, Toby, Li, Xiaohui, Guo, Xiuqing, Li, Mingyao, Shin Cho, Yoon, Jin Go, Min, Jin Kim, Young, Lee, Jong-Young, Park, Taesung, Kim, Kyunga, Sim, Xueling, Twee-Hee Ong, Rick, Croteau-Chonka, Damien C, Lange, Leslie A, Smith, Joshua D, Song, Kijoung, Hua Zhao, Jing, Yuan, Xin, Luan, Jian’an, Lamina, Claudia, Ziegler, Andreas, Zhang, Weihua, Zee, Robert YL, Wright, Alan F, Witteman, Jacqueline CM, Wilson, James F, Willemsen, Gonneke, Wichmann, H-Erich, Whitfield, John B, Waterworth, Dawn M, Wareham, Nicholas J, Waeber, Gérard, Vollenweider, Peter, Voight, Benjamin F, Vitart, Veronique, Uitterlinden, Andre G, Uda, Manuela, Tuomilehto, Jaakko, Thompson, John R, Tanaka, Toshiko, Surakka, Ida, Stringham, Heather M, Spector, Tim D, Soranzo, Nicole, Smit, Johannes H, Sinisalo, Juha, Silander, Kaisa, Sijbrands, Eric JG, Scuteri, Angelo, Scott, James, Schlessinger, David, Sanna, Serena, Salomaa, Veikko, Saharinen, Juha, Sabatti, Chiara, Ruokonen, Aimo, Rudan, Igor, Rose, Lynda M, Roberts, Robert, Rieder, Mark, Psaty, Bruce M, Pramstaller, Peter P, Pichler, Irene, Perola, Markus, Penninx, Brenda WJH, Pedersen, Nancy L, Pattaro, Cristian, Parker, Alex N, Pare, Guillaume, Oostra, Ben A, O’Donnell, Christopher J, Nieminen, Markku S, Nickerson, Deborah A, Montgomery, Grant W, Meitinger, Thomas, McPherson, Ruth, and McCarthy, Mark I

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Heart Disease, Human Genome, Cardiovascular, Prevention, Atherosclerosis, Heart Disease - Coronary Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Black or African American, Animals, Asian People, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Europe, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Lipid Metabolism, Lipids, Liver, Male, Mice, N-Acetylgalactosaminyltransferases, Phenotype, Polymorphism, Single Nucleotide, Protein Phosphatase 1, Reproducibility of Results, Triglycerides, White People, Polypeptide N-acetylgalactosaminyltransferase, General Science & Technology
Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Published
2010

4. Magnetic Resonance Imaging Guided Prostate Biopsy in Patients with ≥ One Negative Systematic Transrectal Ultrasound-Guided Biopsy: A Systemic Review and Meta-Analysis

Author

Hailong, Lan, Yanling, Zhou, Guisen, Lin, Hua, Zhao, and Guantu, Wu

Subjects
Image-Guided Biopsy, Male, Cancer Research, Oncology, Prostate, Humans, Prostatic Neoplasms, General Medicine, Magnetic Resonance Imaging, Ultrasonography, Interventional
Abstract

The present study aimed to compare prostate cancer (PCa) and clinically significant PCa (csPCa) detection sensitivity between magnetic resonance imaging guided-biopsy (MRI-GB) and transrectal ultrasound-guided biopsy (TRUS-GB) in patients with ≥ 1 negative TRUS-GB, and to explore the additive value of TRUS-GB to MRI-GB. The meta-analysis of 18 studies demonstrated that MRI-GB had a similar sensitivity for PCa detection but a higher sensitivity for csPCa than TRUS-GB. In conclusion, there was limited value in combining TRUS-GB with MRI-GB compared with MRI-GB alone for csPCa detection in patients with one or more negative TRUS-GBs that were suspicious of having PCa.

Published
2022

5. A targeted extracellular vesicles loaded with montelukast in the treatment of demyelinating diseases

Author

Yun, Xiao, Yuan, Zhang, Yu-Han, Gao, Zhuo-Hua, Zhao, Jin, He, Rui, Gao, Yu-Xin, Guo, Li-Bin, Wang, and Xing, Li

Subjects
Cyclopropanes, Male, Receptor, Platelet-Derived Growth Factor alpha, Biophysics, Acetates, In Vitro Techniques, Sulfides, Exosomes, Ligands, Biochemistry, Cuprizone, Extracellular Vesicles, Mice, Drug Delivery Systems, Phagocytosis, Animals, Regeneration, Cell Lineage, Molecular Biology, Myelin Sheath, Neurons, Oligodendrocyte Precursor Cells, Stem Cells, Cell Differentiation, Myelin Basic Protein, Cell Biology, Mice, Inbred C57BL, Disease Models, Animal, Oligodendroglia, Quinolines, Demyelinating Diseases
Abstract

The main pathological characteristics of demyelinating diseases are central nervous system (CNS) myelin damage, and the differentiation of oligodendrocyte precursor cells is the therapeutic target of myelin repair. Previous studies have found that a large number of platelet-derived growth factor receptor α(PDGFRα) positive oligodendrocyte progenitor cells (OPCs) accumulate in the lesion area of myelin injury, and differentiation is blocked. However, the therapeutic effects of drugs currently used clinically on OPCs differentiation and myelin repair are limited. The main reason is that it is difficult to reach the effective concentration of the drug in the lesion area. Therefore, efficiently delivering into the CNS lesion area is of great significance for the treatment of MS. Natural exosomes have good biocompatibility and are ideal drug carriers. The delivery of drugs to lesion areas can be achieved by giving the exosomes armed targeting ligand. Therefore, in this study, combining exosomes with PDGFA helps them accumulate in OPCs in vitro and in vivo. Further, load montelukast into exosomes to achieve targeted therapy for cuprizone-induced demyelination animal model. The implementation of this research will help provide effective treatments for demyelinating diseases and lay a theoretical foundation for its application in the clinical treatment of different demyelinating diseases.

Published
2022

6. How to Improve the Effect of Microvascular Decompression for Hemifacial Spasm: A Retrospective Study of 32 Cases with Unsuccessful First Time MVD

Author

Shiting Li, Xuhui Wang, Ying Zhang, Yan-zhen Li, Yun-fei Xia, Hua Zhao, and Wei-ping Zhou

Subjects
Male, medicine.medical_specialty, Decompression, medicine.medical_treatment, Muscle response, Microvascular decompression, medicine.artery, medicine, Humans, Hemifacial Spasm, Retrospective Studies, business.industry, Mean age, Retrospective cohort study, Middle Aged, medicine.disease, digestive system diseases, Microvascular Decompression Surgery, Surgery, Anterior inferior cerebellar artery, Treatment Outcome, Basilar Artery, cardiovascular system, Female, Neurology (clinical), business, Hemifacial spasm
Abstract

Background Microvascular decompression (MVD) has become accepted as an effective therapeutic option for hemifacial spasm (HFS); however, the curative rate of MVD for HFS varies widely (50–98%) in different medical centers. This study could contribute to the improvement of the MVD procedure. Methods We retrospectively analyzed 32 patients in whom initial MVD failed in other hospitals and who underwent a second MVD at our center. The clinical characteristics, operative findings, outcome of the second MVD, and complications were recorded. Results There were 18 women and 14 men (56.3 and 43.7%, respectively). The left-to-right ratio was 19:13. The mean age of the patients was 59.8 years. We found an undiscovered conflict site located in zone 4 in 10 patients and in the root entry zone in 8 patients. The initial MVD failed in nine patients because of ignorance of the arterioles that originate from the anterior inferior cerebellar artery. There were no special findings in four patients. No Teflon felts were found in the whole surgical field in one patient. Conclusion Omission of the offending vessel is the most common cause of an unsuccessful MVD. Intraoperative abnormal muscle response associated with the Z-L response is a good measure to correctly identify the involved arterioles.

Published
2021

7. Effect of dietary leucine supplementation on skeletal muscle fiber type transformation in weaning piglets

Author

Zhiqing Huang, Gang Jia, Lu Xiang, Guangmang Liu, Xiaoling Chen, and Hua Zhao

Subjects
Male, medicine.medical_specialty, Swine, Muscle Fibers, Skeletal, Bioengineering, Weaning, macromolecular substances, AMP-Activated Protein Kinases, chemistry.chemical_compound, Leucine, Internal medicine, Lactate dehydrogenase, medicine, Animals, RNA, Messenger, Muscle, Skeletal, Protein kinase A, Adiponectin receptor 1, biology, Myoglobin, Skeletal muscle, musculoskeletal system, Troponin, Endocrinology, medicine.anatomical_structure, chemistry, Dietary Supplements, biology.protein, Animal Science and Zoology, Biotechnology
Abstract

To investigate the effects of dietary leucine supplementation on muscle fiber type transformation in weaning piglets, 54 21-day-old male DLY (Duroc × Landrace × Yorkshire) weaned piglets were randomly divided into control, 0.25% and 0.5% leucine groups. The experiment lasted for 42 d. The results showed that dietary supplementation of 0.25% leucine significantly increased the protein expressions of slow MyHC, myoglobin and Troponin I-SS and the mRNA expressions of MyHC I, MyHC IIa, Tnni1, Tnnc1, Tnnt1 and myoglobin, while decreased the protein level of fast MyHC and the mRNA level of MyHC IIb in longissimus dorsi (LD) muscle. Furthermore, 0.25% leucine significantly increased succinic dehydrogenase (SDH) activity and decreased lactate dehydrogenase (LDH) activity. In addition, our data found that 0.25% leucine significantly increased serum adiponectin (AdipoQ) concentration, and the protein levels of AdipoQ, adiponectin receptor 1 (AdipoR1), phosphorylated AMP-activated protein kinase (p-AMPK) and PPAR-γ coactivator-1α (PGC-1α) and the mRNA levels of AdipoQ, AdipoR1 and AMPKα2. Together, our findings indicate that leucine promotes porcine skeletal muscle fiber type transformation from fast-twitch to slow-twitch, and the effect may be mediated by AdipoQ-AMPK-PGC-1α signaling pathway.

Published
2021

8. Naringin induces skeletal muscle fiber type transformation via AMPK/PGC-1α signaling pathway in mice and C2C12 myotubes

Author

Zhiqing Huang, Xiaoling Chen, Gang Jia, Guangmang Liu, Yonghong Xue, and Hua Zhao

Subjects
Male, Citrus, Endocrinology, Diabetes and Metabolism, Muscle Fibers, Skeletal, AMP-Activated Protein Kinases, Random Allocation, chemistry.chemical_compound, Endocrinology, Malate Dehydrogenase, Lactate dehydrogenase, Troponin I, Myosin, medicine, Animals, Muscle, Skeletal, Naringin, Mice, Inbred BALB C, Nutrition and Dietetics, L-Lactate Dehydrogenase, Myosin Heavy Chains, Plant Extracts, Myogenesis, AMPK, Skeletal muscle, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Troponin, Cell biology, PPAR gamma, Succinate Dehydrogenase, Muscle Fibers, Slow-Twitch, medicine.anatomical_structure, chemistry, Flavanones, Muscle Fibers, Fast-Twitch, Signal transduction, Signal Transduction
Abstract

A large number of studies have shown that polyphenols can regulate skeletal muscle fiber type transformation through AMPK signal. However, the effects and mechanism of naringin (a natural polyphenol) on muscle fiber type transformation still remains unclear. Thus, we hypothesized that naringin would induce the transformation of skeletal muscle fibers from type II to type I by AMPK signaling. C2C12 myotubes and BALB/c mice models were used to test this hypothesis. We found that naringin significantly increased the protein expression of slow myosin heavy chain (MyHC), myoglobin and troponin I type I slow skeletal (Troponin I-SS) and the activities of succinate dehydrogenase (SDH) and malate dehydrogenase (MDH), and significantly decreased fast MyHC protein expression and lactate dehydrogenase (LDH) activity, accompanied by the activation of AMPK and the activity of peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α) in mice and C2C12 myotubes. Further inhibition of AMPK activity by compound C showed that the above effects were significantly inhibited in C2C12 myotubes. In conclusion, naringin promotes the transformation of skeletal muscle fibers from type II to type I through AMPK/PGC-1α signaling pathway, which not only enriches the nutritional and physiological functions of naringin, but also provides a theoretical basis for the regulation of muscle fiber type transformation by nutritional approaches.

Published
2021

9. A new nairo-like virus associated with human febrile illness in China

Author

Zhen Han, Jian-Wei Shao, Xu Zhang, Zedong Wang, Wei Wang, Junqi Niu, Bo Wang, Youchun Wang, Ming Liao, Ying-Hua Zhao, Zhijun Hou, Shu-Zheng Han, Quan Liu, Liyan Sui, Changfa Fan, Chang Li, Jun Ma, Xiao-Long Lv, Yan-Chun Wang, Zhengtao Yang, Chen Chen, Yong Zhang, Zhengkai Wei, and Ningyi Jin

Subjects
0301 basic medicine, myalgia, Male, Epidemiology, nairo-like virus, Antibodies, Viral, patients, Communicable Diseases, Emerging, Mice, Interquartile range, Drug Discovery, Medicine, Depression (differential diagnoses), Nairovirus, biology, General Medicine, Middle Aged, Infectious Diseases, Tick-Borne Diseases, Female, medicine.symptom, Research Article, Adult, China, Fever, 030106 microbiology, Immunology, Beiji nairovirus, Viremia, Genome, Viral, Tick, Bunyaviridae Infections, Microbiology, Virus, Incubation period, ticks, 03 medical and health sciences, Virology, Animals, Humans, business.industry, biology.organism_classification, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Parasitology, business
Abstract

Several nairo-like viruses have been discovered in ticks in recent years, but their relevance to public health remains unknown. Here, we found a patient who had a history of tick bite and suffered from a febrile illness was infected with a previously discovered RNA virus, Beiji nairovirus (BJNV), in the nairo-like virus group of the order Bunyavirales. We isolated the virus by cell culture assay. BJNV could induce cytopathic effects in the baby hamster kidney and human hepatocellular carcinoma cells. Negative-stain electron microscopy revealed enveloped and spherical viral particles, morphologically similar to those of nairoviruses. We identified 67 patients as BJNV infection in 2017–2018. The median age of patients was 48 years (interquartile range 41–53 years); the median incubation period was 7 days (interquartile range 3–12 days). Most patients were men (70%), and a few (10%) had underlying diseases. Common symptoms of infected patients included fever (100%), headache (99%), depression (63%), coma (63%), and fatigue (54%), myalgia or arthralgia (45%); two (3%) patients became critically ill and one died. BJNV could cause growth retardation, viremia and histopathological changes in infected suckling mice. BJNV was also detected in sheep, cattle, and multiple tick species. These findings demonstrated that the newly discovered nairo-like virus may be associated with a febrile illness, with the potential vectors of ticks and reservoirs of sheep and cattle, highlighting its public health significance and necessity of further investigation in the tick-endemic areas worldwide.

Published
2021

10. Notes on Stibochiona nicea (Gray, 1846) from China with description of a new subspecies from Hainan Island (Lepidoptera, Nymphalidae)

Author

Li, Hua-Zhao and Liu, Zhe

Subjects
Lepidoptera, Male, China, Insecta, Arthropoda, Animalia, Nymphalidae, Animals, Animal Science and Zoology, Biodiversity, Butterflies, Ecology, Evolution, Behavior and Systematics, Taxonomy
Abstract

New information of Stibochiona nicea is presented. Stibochiona nicea wangyukunae ssp. nov. is described from Hainan Island, S. China based on wing patterns, and S. nicea subucula is recorded from China for the first time. The adults and the male genitalia of all the three subspecies of N. nicea from China are illustrated.

Published
2022

11. A novel nonsense variant of the AGXT identified in a Chinese family: special variant research in the Chinese reference genome

Author

Hongen Xu, Xia Xue, Yong An Tian, Dan Hua Liu, Jian Cheng Guo, Chang Bao Xu, Yong Li Zhao, Xin Xin Hu, Jing Yuan Guan, Xing Hua Zhao, Xu Dong Zhou, and Wenxue Tang

Subjects
Male, 0301 basic medicine, Proband, China, medicine.medical_specialty, Population, 030232 urology & nephrology, Case Report, Whole-exome sequencing, case report, lcsh:RC870-923, Genetic analysis, Genome, 03 medical and health sciences, 0302 clinical medicine, Asian People, Internal medicine, Genotype, medicine, Humans, Missense mutation, AGXT, Child, education, Gene, Transaminases, Genetics, education.field_of_study, business.industry, Primary hyperoxaluria type1, Local genome reference, lcsh:Diseases of the genitourinary system. Urology, Pedigree, 030104 developmental biology, Codon, Nonsense, Nephrology, Hyperoxaluria, Primary, business, Reference genome
Abstract

Background Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. Case presentation In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband’s mother and has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. Conclusions Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome.

Published
2021

12. Sodium Butyrate Supplementation Inhibits Hepatic Steatosis by Stimulating Liver Kinase B1 and Insulin-Induced Gene

Author

Yuxiao Liu, Xiaozhen Dai, Xiao-Lin Liu, Aoyuan Cui, Feng Shen, Feng-Zhi Xin, Weitong Su, Jian-Gao Fan, Yamei Han, Ze-Hua Zhao, Feifei Zhang, Yaqian Xue, Yu Li, Genxiang Cai, Zhengshuai Liu, Zi-Xuan Wang, Qin Pan, Jinyun Bai, Zhimin Hu, Tian-Yi Ren, Fengguang Ma, and Da Zhou

Subjects
Male, 0301 basic medicine, HFD, high-fat diet, Hepatic Lipogenesis, RC799-869, ACC, acetyl-CoA carboxylase, AMP-Activated Protein Kinases, GST, glutathione S-transferase, Mice, chemistry.chemical_compound, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, Insulin, Phosphorylation, Insig, insulin-induced gene, Original Research, Chemistry, Kinase, Gastroenterology, Sodium butyrate, Diseases of the digestive system. Gastroenterology, 030211 gastroenterology & hepatology, medicine.medical_specialty, Insulin-Induced Gene, LKB1, ATP, adenosine triphosphate, MAP Kinase Signaling System, NaB, sodium butyrate, Butyrate, Diet, High-Fat, Models, Biological, 03 medical and health sciences, LKB1, liver kinase B1, NAFLD, Internal medicine, PYY, peptide YY, medicine, Animals, Humans, GLP-1, glucagon-like peptide 1, Protein kinase A, Hepatology, Lipogenesis, AMPK, Lipid Metabolism, medicine.disease, Sodium Butyrate, AMPK, AMP-activated protein kinase, Disease Models, Animal, 030104 developmental biology, Endocrinology, Gene Expression Regulation, AMP, adenosine monophosphate, Dietary Supplements, Hepatocytes, Butyric Acid, NAFLD, nonalcoholic fatty liver disease, Liver function, Steatosis
Abstract

Background and Aims Butyric acid is an intestinal microbiota-produced short-chain fatty acid, which exerts salutary effects on alleviating nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism of butyrate on regulating hepatic lipid metabolism is largely unexplored. Methods A mouse model of NAFLD was induced with high-fat diet feeding, and sodium butyrate (NaB) intervention was initiated at the eighth week and lasted for 8 weeks. Hepatic steatosis was evaluated and metabolic pathways concerning lipid homeostasis were analyzed. Results Here, we report that administration of NaB by gavage once daily for 8 weeks causes an augmentation of insulin-induced gene (Insig) activity and inhibition of lipogenic gene in mice fed with high-fat diet. Mechanistically, NaB is sufficient to enhance the interaction between Insig and its upstream kinase AMP-activated protein kinase (AMPK). The stimulatory effects of NaB on Insig-1 activity are abolished in AMPKα1/α2 double knockout (AMPK−/−) mouse primary hepatocytes. Moreover, AMPK activation by NaB is mediated by LKB1, as evidenced by the observations showing NaB-mediated induction of phosphorylation of AMPK, and its downstream target acetyl-CoA carboxylase is diminished in LKB1–/– mouse embryonic fibroblasts. Conclusions These studies indicate that NaB serves as a negative regulator of hepatic lipogenesis in NAFLD and that NaB attenuates hepatic steatosis and improves lipid profile and liver function largely through the activation of LKB1-AMPK-Insig signaling pathway. Therefore, NaB has therapeutic potential for treating NAFLD and related metabolic diseases., Graphical abstract

Published
2021

13. Quercetin regulates skeletal muscle fiber type switching via adiponectin signaling

Author

Dahui Liang, Xiaoling Chen, Hua Zhao, Guangmang Liu, Zhiqing Huang, and Gang Jia

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Gene Expression, Oxidative phosphorylation, Cell Line, Mice, 03 medical and health sciences, chemistry.chemical_compound, Lactate dehydrogenase, Internal medicine, Gene expression, medicine, Animals, heterocyclic compounds, Glycolysis, Mice, Inbred BALB C, Adiponectin, Chemistry, Myogenesis, 0402 animal and dairy science, Skeletal muscle, 04 agricultural and veterinary sciences, General Medicine, musculoskeletal system, 040201 dairy & animal science, Muscle Fibers, Slow-Twitch, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Dietary Supplements, Muscle Fibers, Fast-Twitch, Quercetin, Signal Transduction, Food Science
Abstract

This study aimed to investigate the role and underlying molecular mechanism of quercetin in regulating skeletal muscle fiber type transition. We found that dietary quercetin supplementation in mice significantly increased oxidative fiber-related gene expression, slow-twitch fiber percentage and succinic dehydrogenase (SDH) activity. By contrast, quercetin decreased lactate dehydrogenase (LDH) activity, fast MyHC protein expression, fast-twitch fiber percentage, and MyHC IIb mRNA expression. Furthermore, quercetin significantly increased serum adiponectin (AdipoQ) concentration, and the expression levels of AdipoQ and AdipoR1. However, inhibition of adiponectin signaling by AdipoR1 siRNA significantly attenuated the effects of quercetin on muscle fiber type-related gene expression, the percentages of slow MyHC-positive and fast MyHC-positive fibers, and metabolic enzyme activity in C2C12 myotubes. Together, our data indicated that quercetin could promote skeletal fiber switching from glycolytic type II to oxidative type I through AdipoQ signaling.

Published
2021

14. STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model

Author

Zai-Hua Zhao, Shi Zhao, Ting Li, Gong-Ping Liu, Xue-Feng Shen, Jian-Zhi Wang, Hua-Li Wan, Qun Wang, Bing-Ge Zhang, Qian Liu, and Xiao-Yue Hong

Subjects
Male, STAT3 Transcription Factor, Medicine (miscellaneous), tau Proteins, Hippocampal formation, Hippocampus, Receptors, N-Methyl-D-Aspartate, STAT3, Synapse, Mice, Cognition, synapse, Alzheimer Disease, Memory, medicine, Animals, Humans, Cognitive Dysfunction, STAT1, Phosphorylation, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Memory Disorders, Neuronal Plasticity, biology, Neurodegeneration, HEK 293 cells, medicine.disease, NMDAR, Mice, Inbred C57BL, Disease Models, Animal, HEK293 Cells, STAT1 Transcription Factor, Synapses, Synaptic plasticity, biology.protein, NMDA receptor, Tau, memory deficit, Neuroscience, Research Paper
Abstract

Background: Abnormal tau accumulation in the brain has a positively correlation with neurodegeneration and memory deterioration, but the mechanism underlying tau-associated synaptic and cognitive impairments remains unclear. Our previous work has found that human full length tau (hTau) accumulation activated signal transducer and activator of transcription-1 (STAT1) to suppress N-methyl-D-aspartate receptors (NMDARs) expression, followed by memory deficits. STAT3 also belongs to STAT protein family and is reported to involve in regulation of synaptic plasticity and cognition. Here, we investigated the role of STAT3 in the cognitive deficits induced by hTau accumulation. Methods: In vitro studies HEK293 cells were used. EMSA, Luciferase reporter assay, and Immunoprecipitation were applied to detect STAT3 activity. In vivo studies, AAV virus were injected into the hippocampal CA3 region of C57 mice. Western blotting, quantitative real-time polymerase chain reaction, and immunofluorescence were applied to examine the level of synaptic proteins. Electrophysiological analysis, behavioral testing and Golgi impregnation were used to determine synaptic plasticity and memory ability recovery after overexpressing STAT3 or non-acetylated STAT1. Results: Our results showed that hTau accumulation acetylated STAT1 to retain STAT3 in the cytoplasm by increasing the binding of STAT1 with STAT3, and thus inactivated STAT3. Overexpressing STAT3 or non-acetylated STAT1 ameliorated hTau-induced synaptic loss and memory deficits by increasing the expression of NMDARs. Conclusions: Taken together, our study indicates that hTau accumulation impaired synaptic plasticity through STAT3 inactivation induced suppression of NMDARs expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.

Published
2021

15. Screening of radiation gastrointestinal injury biomarkers in rat plasma by high-coverage targeted lipidomics

Author

Cong Xi, Hua Zhao, Hai-Xiang Liu, Jia-Qi Xiang, Xue Lu, Tian-Jing Cai, Shuang Li, Ling Gao, Xue-Lei Tian, Ke-Hui Liu, Mei Tian, and Qing-Jie Liu

Subjects
Male, Gamma Rays, Health, Toxicology and Mutagenesis, Clinical Biochemistry, Lipidomics, Animals, Biochemistry, Lipids, Biomarkers, Whole-Body Irradiation, Rats
Abstract

In the event of radiological accidents and cancer radiotherapies in the clinic, the gastrointestinal (GI) system is vulnerable to ionizing radiation and shows GI injury. Accessible biomarkers may provide means to predict, evaluate, and treat GI tissue damage. The current study investigated radiation GI injury biomarkers in rat plasma. High-coverage targeted lipidomics was employed to profile lipidome perturbations at 72 h after 0, 1, 2, 3, 5, and 8 Gy (60Co γ-rays at 1 Gy/min) total-body irradiation in male rat jejunum. The results were correlated with previous plasma screening outcomes. In total, 93 differential metabolites and 28 linear dose-responsive metabolites were screened in the jejunum. Moreover, 52 lipid species with significant differences both in jejunum and plasma were obtained. Three lipid species with linear dose-response relationship both in jejunum and plasma were put forth, which exhibited good to excellent sensitivity and specificity in triaging different exposure levels. The linear dose-effect relationship of lipid metabolites in the jejunum and the triage performance of radiation GI injury biomarkers in plasma were studied for the first time. The present study can provide insights into expanded biomarkers of IR-mediated GI injury and minimally invasive assays for evaluation.

Published
2022

16. Therapeutic strategies for retention of cranioplasty titanium mesh after mesh exposure

Author

Yao-Hua Zhao, Yu-Hong Feng, Hai-Tao Deng, Wei-Qi Huang, Li-Hong Xu, Xian-Ping Meng, and Xu-Gang Xie

Subjects
Adult, Male, Titanium, Skull, Middle Aged, Plastic Surgery Procedures, Surgical Mesh, Postoperative Complications, Humans, Surgery, Female, Neurology (clinical), Aged, Retrospective Studies
Abstract

Background Titanium mesh exposure after cranioplasty is a possible complication and is usually managed by mesh removal and flap transfer, but the advantages of the rigid prosthesis are then lost. This study aimed to present our experience with negative pressure wound therapy combined with soft tissue dilation for retaining the titanium mesh in patients with mesh exposure after cranioplasty. Methods This retrospective study included patients treated between 01/2016 and 05/2019 at the Jiangyin Hospital Affiliated to Southeast University School of Medicine. The wound was cleaned, and a cystic space was created for the tissue dilator, which was used with a self-designed negative pressure dressing. After the target dilation was achieved, the repair was conducted while retaining the titanium mesh. Results Eight patients were included (seven males and one female; 53.6 ± 8.8 (range, 43–65) years of age). The exposed mesh area ranged from 1 × 1 to 4 × 5.5 cm. The thinning scalp area around the exposed mesh ranged from 3.6 × 3.8 to 4 × 5.5 cm. Five patients had positive wound cultures and received sensitive antibiotics. The dilator embedding time was 20–28 days. The time of negative pressure wound therapy was 25–33 days. The hospital stay was 30–41 days. Primary wound healing was achieved in all eight patients. There were no signs of recurrence after 6–18 months of follow-up. The cranial CT scans were unremarkable. Conclusions Negative pressure wound therapy combined with soft tissue dilation for exposed titanium mesh after cranioplasty might help retain the titanium mesh.

Published
2022

17. Antiphospholipid Antibodies in Critically Ill Patients With COVID‐19

Author

Meng Xiao, Yongzhe Li, Jie Ma, Dong Wu, Jing Xie, Xuzhen Qin, Huan Chen, Jinglan Wang, Xin Ding, Wei Wu, Yongqiang Zhao, Shulan Zhang, Yu Chen, Peng Gao, Xian Wu, Yan Qin, Zhengyin Liu, Hongmin Zhang, Shuyang Zhang, Ran Tian, Xuefeng Sun, Taisheng Li, Fengchun Zhang, Yan Zhang, Wen Zhang, Dong Zhang, Hua Zhao, Xin Hou, Wei Cao, Huadong Zhu, Wei Jiang, Peng Xia, Minya Lu, Xiaowei Yan, Jing Zhao, Bin Du, Chunyao Wang, Xiang Zhou, and Yingchun Xu

Subjects
Adult, Male, Adolescent, Critical Illness, critically ill patients, Immunology, 030204 cardiovascular system & hematology, medicine.disease_cause, coagulopathy, Pathogenesis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, COVID‐19, immune system diseases, Antiphospholipid syndrome, medicine, Coagulopathy, Humans, Immunology and Allergy, neoplasms, Aged, Coronavirus, Aged, 80 and over, 030203 arthritis & rheumatology, biology, Cerebral infarction, business.industry, Brief Report, Incidence (epidemiology), antiphospholipid antibodies, COVID-19, Middle Aged, medicine.disease, Titer, Antibodies, Antiphospholipid, biology.protein, Female, Brief Reports, Antibody, business
Abstract

OBJECTIVE: Coagulopathy is one of the characteristics observed in critically ill patients with coronavirus disease 2019 (COVID-19). Antiphospholipid antibodies (aPLs) contribute to coagulopathy, though their role in COVID-19 remains unclear. This study was undertaken to determine the prevalence and characteristics of aPLs in patients with COVID-19. METHODS: Sera collected from 66 COVID-19 patients who were critically ill and 13 COVID-19 patients who were not critically ill were tested by chemiluminescence immunoassay for anticardiolipin antibodies (aCLs), anti-s2 -glycoprotein I (anti-s2 GPI) (IgG, IgM, and IgA), and IgG anti-s2 GPI-domain 1 (anti-s2 GPI-D1) and IgM and IgG anti-phosphatidylserine/prothrombin (anti-PS/PT) antibodies were detected in the serum by enzyme-linked immunosorbent assay. RESULTS: Of the 66 COVID-19 patients in critical condition, aPLs were detected in 31 (47% ). Antiphospholipid antibodies were not present among COVID-19 patients who were not in critical condition. The IgA anti-s2 GPI antibody was the most commonly observed aPL in patients with COVID-19 and was present in 28.8% (19 of 66) of the critically ill patients, followed by IgA aCLs (17 of 66, or 25.8%) and IgG anti-s2 GPI (12 of 66, or 18.2%). For multiple aPLs, IgA anti-s2 GPI + IgA aCLs was the most common antibody profile observed (15 of 66, or 22.7%), followed by IgA anti-s2 GPI + IgA aCL + IgG anti-s2 GPI (10 of 66, or 15.2%). Antiphospholipid antibodies emerge ~35-39 days after disease onset. A dynamic analysis of aPLs revealed 4 patterns based on the persistence or transient appearance of the aPLs. Patients with multiple aPLs had a significantly higher incidence of cerebral infarction compared to patients who were negative for aPLs (P = 0.023). CONCLUSION: Antiphospholipid antibodies were common in critically ill patients with COVID-19. Repeated testing demonstrating medium to high titers of aPLs and the number of aPL types a patient is positive for may help in identifying patients who are at risk of developing cerebral infarction. Antiphospholipid antibodies may be transient and disappear within a few weeks, but in genetically predisposed patients, COVID-19 may trigger the development of an autoimmune condition similar to the antiphospholipid syndrome (APS), referred to as "COVID-19-induced APS-like syndrome." Long-term follow-up of COVID-19 patients who are positive for aPLs would be of great importance in understanding the pathogenesis of this novel coronavirus.

Published
2020

18. Transplantation of neural stem cells preconditioned with high-mobility group box 1 facilitates functional recovery after spinal cord injury in rats

Author

Chen‑Xu Wang, Yu Xiang, Xiang Yin, Jian‑Hua Zhao, Xing‑Xing Chen, Xin Xue, Zong‑Feng Chen, Mingyong Liu, and Liang Zhang

Subjects
0301 basic medicine, Male, Cancer Research, Pathology, Biochemistry, Rats, Sprague-Dawley, Myelin, 0302 clinical medicine, Neural Stem Cells, Medicine, Axon, HMGB1 Protein, Spinal cord injury, Neurons, Cell Differentiation, Articles, differentiation, Neural stem cell, medicine.anatomical_structure, Oncology, Spinal Cord, 030220 oncology & carcinogenesis, Nissl body, symbols, Molecular Medicine, medicine.medical_specialty, Cell Survival, Motor Activity, Neuroprotection, 03 medical and health sciences, symbols.namesake, HMGB Proteins, Genetics, Animals, Molecular Biology, Spinal Cord Injuries, business.industry, Recovery of Function, Spinal cord, medicine.disease, spinal cord injury, Axons, Nerve Regeneration, Rats, Transplantation, ERK signaling pathway, high mobility group box-1, 030104 developmental biology, nervous system, business, Stem Cell Transplantation
Abstract

Spinal cord injury (SCI) is a devastating disorder that often results in temporary and/or permanent functional impairment below the injured level. To date, few satisfactory therapeutic strategies are available to treat SCI. Hence, exploring novel strategies for SCI is an essential public health concern. Cell transplantation therapy, which is associated with neuroprotection, immunomodulation, axon regeneration, neuronal relay formation and myelin regeneration, provides a promising therapeutic strategy for SCI. The neuronal stem cell (NSC) preconditioning method is an emerging approach, which facilitates NSC survival and neuronal differentiation after implantation. The aim of the present study was to develop a feasible candidate for cell‑based therapy following SCI in rats and to investigate the role of high mobility group box‑1 (HMGB1) in NSC activation. The results of the present study showed that transplantation of NSCs, preconditioned with 1 ng/ml HMGB1, facilitated functional improvement of injured spinal cords, as indicated by Basso, Beattie and Bresnahan mean scores, mechanical hypersensitivity and cold stimulation. Meanwhile, the histological examination of hematoxylin and eosin staining indicated that engraftment of HMGB1‑preconditioned NSCs resulted in decreased atrophy of the injured spinal cord. Meanwhile, the transplantation of HMGB1‑preconditioned NSCs resulted in an increased number of functional Nissl bodies in neurons, as detected by Nissl staining, and an increase in the number of βIII‑tubulin+ cells in the epicenter of injured spinal cords in rats with SCI. In addition, the results also demonstrated that 1 ng/ml HMGB1 promoted the differentiation of NSCs into neurons, and that the ERK signaling pathway played an important role in this process. In conclusion, the present data indicated that the preconditioning strategy with 1 ng/ml HMGB1 may present a feasible candidate for cell‑based therapy following SCI in rats, which may enlarge the scope of HMGB1 in NSC activation.

Published
2020

19. Leukocyte mitochondrial DNA copy number and built environment in Mexican Americans: a cross-sectional study

Author

Hua Zhao, Xueying Zhang, Jie Shen, Evan Leung, Wong Ho Chow, and Kai Zhang

Subjects
Adult, Male, Mitochondrial DNA, DNA Copy Number Variations, Cross-sectional study, lcsh:Medicine, Diseases, Biology, Logistic regression, DNA, Mitochondrial, Article, Odds, Mexican Americans, Leukocytes, Humans, Built Environment, lcsh:Science, Multidisciplinary, lcsh:R, Odds ratio, Middle Aged, Texas, Confidence interval, Cross-Sectional Studies, Risk factors, Population study, Female, lcsh:Q, Biomarkers, Demography, Cohort study
Abstract

Mitochondrial DNA (mtDNA) copy number in leukocytes has been regarded as a biomarker for various environmental exposures and chronic diseases. Our previous study showed that certain demographic factors (e.g. age, gender, BMI, etc.) significantly affect levels of leukocyte mtDNA copy number in Mexican Americans. However, the effect of the built environment on leukocyte mtDNA copy number has not been studied previously. In this cross-sectional study, we examined the association between multiple components of the built environment with leukocyte mtDNA copy number among 5,502 Mexican American adults enrolled in Mano-A-Mano, the Mexican American Cohort Study (MACS). Based on the median levels of mtDNA copy number, the study population was stratified into low mtDNA copy number group (

Published
2020

20. Effect of ambrisentan on echocardiographic and Doppler measures from patients in China with pulmonary arterial hypertension

Author

Yong Wang, Xiaofeng Zeng, Gang-Cheng Zhang, Zhi-Cheng Jing, Yong Huo, Qin-Hua Zhao, Jinming Liu, Fu-Hua Peng, Qiu-Shang Ji, Jian-Hui Li, Zai-Xin Yu, and Lu Zi

Subjects
Adult, Male, China, medicine.medical_specialty, Ambrisentan, Ventricular Dysfunction, Right, 030204 cardiovascular system & hematology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Humans, 030212 general & internal medicine, skin and connective tissue diseases, Retrospective Studies, Pulmonary Arterial Hypertension, Phenylpropionates, business.industry, General Medicine, Middle Aged, humanities, Pyridazines, body regions, medicine.anatomical_structure, Echocardiography, Ventricle, Ventricular Function, Right, symbols, Cardiology, Female, sense organs, Cardiology and Cardiovascular Medicine, business, Doppler effect, medicine.drug
Abstract

We retrospectively evaluated the echocardiographic data of ambrisentan-treated patients with pulmonary arterial hypertension (PAH) (NCT01808313).Change from baseline in right ventricle (RV) systolic function, right heart structure, and pulmonary artery systolic pressure (PASP) prognosis to Weeks 12 and 24 was evaluated by echocardiography.In the overall population, the mean tissue Doppler-derived tricuspid lateral annular systolic velocity (S') increased by 0.6 cm/s at both Weeks 12 (p 0.001) and 24 (p = 0.004) and tricuspid annular plane systolic excursion increased by 0.13 cm at Week 12 and 0.15 cm at Week 24 (both p 0.001). A marked decrease in transverse and longitudinal RV and RA diameter at Weeks 12 and 24 was observed. A significant decrease in diastolic eccentricity index at both Weeks 12 (-0.1; p = 0.02) and 24 (-0.1; p = 0.001). The decrease in PASP from baseline was significant at both Weeks 12 (-9.5 mmHg; p0.001) and 24 (-7.6 mmHg; p0.001), while a decrease in the estimated right atrium pressure was found to be significant at Week 24 (-0.8mmHg; p = 0.01).Significant improvements in a number of RV echocardiographic parameters were observed at Weeks 12 and 24 after ambrisentan treatment in patients with PAH.

Published
2020

21. A five-compartment model of age-specific transmissibility of SARS-CoV-2

Author

Ruo Yun Liu, Shi Xiong Hu, Yao Wang, Ze Yu Zhao, Tianmu Chen, Zhao Lei, Qing Qing Hu, Yuan Zhao Zhu, Yi Chen Chiang, Jing An Cui, Fang Xie, Meng Yang, Li Dong Gao, Li Luo, Ben Hua Zhao, Jia Rui, Ying Ying Su, Jia Li, Xing Chun Liu, Ling Yin, Qinglong Zhao, Shanshan Yu, Yanhua Su, and Jing Wen Xu

Subjects
Adult, Male, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Adolescent, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 030231 tropical medicine, Pneumonia, Viral, medicine.disease_cause, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Betacoronavirus, Young Adult, Age-specific dynamics, 0302 clinical medicine, Internal medicine, Epidemiology, medicine, Humans, lcsh:RC109-216, 030212 general & internal medicine, Young adult, Pandemics, Coronavirus, Aged, Models, Statistical, business.industry, Transmissibility, SARS-CoV-2, lcsh:Public aspects of medicine, Public Health, Environmental and Occupational Health, Age Factors, COVID-19, lcsh:RA1-1270, General Medicine, Middle Aged, Age specific, Transmissibility (vibration), Compartmental model, Infectious Diseases, Tropical medicine, Female, business, Coronavirus Infections, Research Article
Abstract

Background The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, also called 2019-nCoV) causes different morbidity risks to individuals in different age groups. This study attempts to quantify the age-specific transmissibility using a mathematical model. Methods An epidemiological model with five compartments (susceptible–exposed–symptomatic–asymptomatic–recovered/removed [SEIAR]) was developed based on observed transmission features. Coronavirus disease 2019 (COVID-19) cases were divided into four age groups: group 1, those ≤ 14 years old; group 2, those 15 to 44 years old; group 3, those 45 to 64 years old; and group 4, those ≥ 65 years old. The model was initially based on cases (including imported cases and secondary cases) collected in Hunan Province from January 5 to February 19, 2020. Another dataset, from Jilin Province, was used to test the model. Results The age-specific SEIAR model fitted the data well in each age group (P β43 = 7.71 × 10− 9; SAR43 = 3.86 × 10− 8), followed by group 3 to 4 (median: β34 = 3.07 × 10− 9; SAR34 = 1.53 × 10− 8), group 2 to 2 (median: β22 = 1.24 × 10− 9; SAR22 = 6.21 × 10− 9), and group 3 to 1 (median: β31 = 4.10 × 10− 10; SAR31 = 2.08 × 10− 9). The lowest transmissibility was from age group 3 to 3 (median: β33 = 1.64 × 10− 19; SAR33 = 8.19 × 10− 19), followed by group 4 to 4 (median: β44 = 3.66 × 10− 17; SAR44 = 1.83 × 10− 16), group 3 to 2 (median: β32 = 1.21 × 10− 16; SAR32 = 6.06 × 10− 16), and group 1 to 4 (median: β14 = 7.20 × 10− 14; SAR14 = 3.60 × 10− 13). In Jilin Province, the highest transmissibility occurred from age group 4 to 4 (median: β43 = 4.27 × 10− 8; SAR43 = 2.13 × 10− 7), followed by group 3 to 4 (median: β34 = 1.81 × 10− 8; SAR34 = 9.03 × 10− 8). Conclusions SARS-CoV-2 exhibits high transmissibility between middle-aged (45 to 64 years old) and elderly (≥ 65 years old) people. Children (≤ 14 years old) have very low susceptibility to COVID-19. This study will improve our understanding of the transmission feature of SARS-CoV-2 in different age groups and suggest the most prevention measures should be applied to middle-aged and elderly people.

Published
2020

22. Lipotoxic Hepatocyte‐Derived Exosomal MicroRNA 192‐5p Activates Macrophages Through Rictor/Akt/Forkhead Box Transcription Factor O1 Signaling in Nonalcoholic Fatty Liver Disease

Author

Qin Pan, Xiao-Lin Liu, Hai-Xia Cao, Feng-Zhi Xin, Huiping Zhou, Ze-Hua Zhao, Rui-Xu Yang, Jian-Gao Fan, and Jing Zeng

Subjects
Male, 0301 basic medicine, Macrophage polarization, FOXO1, Exosomes, Proinflammatory cytokine, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, medicine, Animals, Interleukin 6, Protein kinase B, Hepatology, biology, Chemistry, Forkhead Transcription Factors, Macrophage Activation, medicine.disease, Rats, MicroRNAs, Rapamycin-Insensitive Companion of mTOR Protein, 030104 developmental biology, Integrin alpha M, Hepatocytes, Cancer research, biology.protein, 030211 gastroenterology & hepatology, Tumor necrosis factor alpha, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

Background and aims Hepatic macrophages can be activated by many factors such as gut-derived bacterial components and factors released from damaged hepatocytes. Macrophage polarization toward a proinflammatory phenotype (M1) represents an important event in the disease progression of nonalcoholic fatty liver disease (NAFLD). However, the underlying molecular mechanisms remain incompletely understood. Exosomes have been identified as important mediators for cell-cell communication by transferring various biological components such as microRNAs (miRs), proteins, and lipids. The role of exosomes in crosstalk between hepatocytes and macrophages in disease progression of NAFLD is yet to be explored. Approach and results In the present study, we reported that lipotoxic injury-induced release of hepatocyte exosomes enriched with miR-192-5p played a critical role in the activation of M1 macrophages and hepatic inflammation. Serum miR-192-5p levels in patients with NAFLD positively correlated with hepatic inflammatory activity score and disease progression. Similarly, the serum miR-192-5p level and the number of M1 macrophages, as well as the expression levels of the hepatic proinflammatory mediators, were correlated with disease progression in high-fat high-cholesterol diet-fed rat models. Lipotoxic hepatocytes released more miR-192-5p-enriched exosomes than controls, which induced M1 macrophage (cluster of differentiation 11b-positive [CD11b+ ]/CD86+ ) activation and increase of inducible nitric oxide synthase, interleukin 6, and tumor necrosis factor alpha expression. Furthermore, hepatocyte-derived exosomal miR-192-5p inhibited the protein expression of the rapamycin-insensitive companion of mammalian target of rapamycin (Rictor), which further inhibited the phosphorylation levels of Akt and forkhead box transcription factor O1 (FoxO1) and resulted in activation of FoxO1 and subsequent induction of the inflammatory response. Conclusions Hepatocyte-derived exosomal miR-192-5p plays a critical role in the activation of proinflammatory macrophages and disease progression of NAFLD through modulating Rictor/Akt/FoxO1 signaling. Serum exosomal miR-192-5p represents a potential noninvasive biomarker and therapeutic target for nonalcoholic steatohepatitis.

Published
2020

23. Sex differences of hemodynamics during acute vasoreactivity testing to predict the outcomes of chronic thromboembolic pulmonary hypertension

Author

Yan-Zhe Yu, Rong Jiang, Ping Yuan, Chuan‐Yu Wang, Ci-Jun Luo, Weiping Xie, Yi-Lan Yang, Qin-Hua Zhao, Lan Wang, Jian Guo, Yuan Li, Jing He, Wen-Hui Wu, Hong-Ling Qiu, Jinling Li, Jinming Liu, and Su-Gang Gong

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, Right heart catheterization, Cardiac Catheterization, China, medicine.medical_specialty, Hypertension, Pulmonary, Vasodilator Agents, Hemodynamics, Independent predictor, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, Administration, Inhalation, Female patient, medicine, Humans, Immunology and Allergy, In patient, Iloprost, Pulmonary Wedge Pressure, 030212 general & internal medicine, Lung, Genetics (clinical), Aged, Sex Characteristics, Receiver operating characteristic, business.industry, Middle Aged, Prognosis, Progression-Free Survival, ROC Curve, 030228 respiratory system, Male patient, Chronic Disease, Cardiology, Regression Analysis, Female, Chronic thromboembolic pulmonary hypertension, Pulmonary Embolism, business
Abstract

BACKGROUND Acute vasoreactivity testing (AVT) which reflects the compliance of the pulmonary vascular bed has been proven to be of prognostic value. The purpose of the present study is to explore the sex differences of hemodynamics during the AVT and their impact on event-free survival in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS Eighty-six patients underwent a right heart catheterization and AVT at Shanghai Pulmonary Hospital from February 2009 to February 2018. Univariate and multiple stepwise regression analysis were performed to determine the predictors of independent event-free survival, and receiver operating characteristic curve was plotted to determine the cut-off value of independent parameters in CTEPH. RESULTS There were no significant differences in both demographics and hemodynamics between male and female patients with CTEPH. Except ΔPVR/PVR showed a significantly higher difference in female than male patients (P = 0.034). Male patients had higher mRAP of pre- and post-AVT than female patients in the event-free subgroup, while, female patients showed higher PVR of pre-AVT than male patients in the event subgroup (P

Published
2020

24. Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Author

Alison D. Murray, Anna L. Guyatt, Jing Hua Zhao, Eugene R. Bleecker, Matthias Wielscher, Frank Dudbridge, Martin D. Tobin, Veronique Vitart, Ida Surakka, Nadia N. Hansel, Ozren Polasek, Caroline Hayward, David P. Strachan, Per Bakke, Stefan Karrasch, Anubha Mahajan, James F. Wilson, Shona M. Kerr, Ruth Tal-Singer, James D. Crapo, Victoria E. Jackson, Jonathan Marten, Olli T. Raitakari, María Soler Artigas, Medea Imboden, Sungho Won, Beate Stubbe, Ulf Gyllensten, George R. Washko, Eleftheria Zeggini, David A. Lynch, Brian D. Hobbs, Matthew Moll, Mika Kähönen, Rajesh Rawal, Guy Brusselle, Ma'en Obeidat, Nicholas J. Wareham, Claudia Langenberg, Nicole Probst-Hensch, Peter K. Joshi, Blair H. Smith, Stefan Weiss, Woo Jin Kim, Kathleen C. Barnes, Sarah E. Harris, David J. Porteous, Stefan Enroth, Ian P. Hall, Alan L. James, Sina A. Gharib, Paul R. H. J. Timmers, Xingnan Li, Louise V. Wain, John E. Hokanson, Holger Schulz, Ralf Ewert, Ani Manichaikul, Lies Lahousse, Georg Homuth, R. Graham Barr, Scott T. Weiss, Phuwanat Sakornsakolpat, Sara R.A. Wijnant, Edwin K. Silverman, Christian Gieger, Jennie Hui, Andrew P. Morris, James P. Cook, Michael J. McGeachie, Dawn L. DeMeo, Nick Shrine, Traci M. Bartz, Amund Gulsvik, Deborah A. Meyers, Katherine A. Kentistou, Igor Rudan, Jian'an Luan, Ian J. Deary, Catherine John, Michael H. Cho, Lars Lind, Marjo-Riitta Järvelin, Ah Ra Do, Terho Lehtimäki, Stephen S. Rich, Bruce M. Psaty, Tampere University, Department of Clinical Physiology and Nuclear Medicine, Clinical Medicine, Department of Clinical Chemistry, Epidemiology, and Pulmonary Medicine

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, AMERICAN THORACIC SOCIETY, Vital Capacity, LOCI, Genome-wide association study, EMPHYSEMA, Cohort Studies, 03 medical and health sciences, FEV1/FVC ratio, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Risk Factors, Internal medicine, Forced Expiratory Volume, adult, case-control studies, cohort studies, female, forced expiratory volume, genome-wide association study, humans, male, middle aged, phenotype, pulmonary disease, chronic obstructive, risk factors, vital capacity, Medicine and Health Sciences, medicine, COPD, Humans, SMOKING-BEHAVIOR, 030212 general & internal medicine, GENOME-WIDE ASSOCIATION, FAMILIAL AGGREGATION, GENETIC EPIDEMIOLOGY, Framingham Risk Score, HERITABILITY, business.industry, Case-control study, Family aggregation, Odds ratio, Articles, Middle Aged, medicine.disease, respiratory tract diseases, LUNG-FUNCTION, Phenotype, 030228 respiratory system, Genetic epidemiology, Case-Control Studies, Female, 3111 Biomedicine, business, Genome-Wide Association Study
Abstract

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC 1

Published
2020

25. Population‐Based Study of Traffic‐Related Air Pollution and Obesity in Mexican Americans

Author

Kai Zhang, Wong Ho Chow, Casey P. Durand, Hua Zhao, Xueying Zhang, Moira Bixby, and Christine Markham

Subjects
Adult, Male, Traffic-Related Pollution, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Air pollution, Medicine (miscellaneous), 030209 endocrinology & metabolism, Mexican americans, medicine.disease_cause, Logistic regression, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Air Pollution, Mexican Americans, Prevalence, medicine, Humans, Obesity, 030212 general & internal medicine, Young adult, Aged, Aged, 80 and over, Air Pollutants, Nutrition and Dietetics, business.industry, Middle Aged, medicine.disease, Population based study, Cross-Sectional Studies, Geographic Information Systems, Female, Particulate Matter, business, Demography, Cohort study
Abstract

OBJECTIVE The purpose of this study was to assess the cross-sectional association between residential exposure to traffic-related air pollution and obesity in Mexican American adults. METHODS A total of 7,826 self-reported Mexican Americans aged 20 to 60 years old were selected from the baseline survey of the MD Anderson Mano-a-Mano Mexican American Cohort. Concentrations of traffic-related particulate matter with aerodynamic diameter

Published
2019

26. Comparing the diagnostic performance of radiotracers in prostate cancer biochemical recurrence: a systematic review and meta-analysis

Author

Weili Ma, Jiwei Mao, Jianfeng Yang, Ting Wang, and Zhen Hua Zhao

Subjects
Male, Positron Emission Tomography Computed Tomography, Humans, Prostatic Neoplasms, Radiology, Nuclear Medicine and imaging, Gallium Radioisotopes, General Medicine, Prostate-Specific Antigen, Neoplasm Recurrence, Local, Choline
Abstract

Objectives To systematically assess the early detection rate of biochemical prostate cancer recurrence using choline, fluciclovine, and PSMA. Methods Under the guidance of the Preferred Reporting Items for Systematic reviews and Meta-Analysis Diagnostic Test Accuracy guidelines, literature that assessed the detection rates (DRs) of choline, fluciclovine, and PSMA in prostate cancer biochemical recurrence was searched in PubMed and EMBASE databases for our systematic review from 2012 to July 15, 2021. In addition, the PSA-stratified performance of detection positivity was obtained to assess the DRs for various methods, including fluciclovine, PSMA, or choline PET/CT, with respect to biochemical recurrence based on different PSA levels. Results In total, 64 studies involving 11,173 patients met the inclusion criteria. Of the studies, 12, 7, and 48 focused on choline, fluciclovine, and PSMA, respectively. The pooled DRs were 24%, 37%, and 44%, respectively, for a PSA level less than 0.5 ng/mL (p < 0.001); 36%, 44%, and 60% for a PSA level of 0.5–0.99 ng/mL (p < 0.001); and 50%, 61%, and 80% for a PSA level of 1.0–1.99 ng/mL (p < 0.001). The DR with 18F-labeled PSMA was higher than that with 68Ga-labeled PSMA, and the DR was 58%, 72%, and 88% for PSA levels < 0.5 ng/mL, 0.5–0.9 ng/mL, and 1.0–1.99 ng/mL, respectively. Conclusion The DRs of PSMA-radiotracers were greater than those of choline-radiotracers and fluciclovine-radiotracers at the patient level. 18F-labeled PSMA achieved a higher DR than 68Ga-labeled PSMA. Key Points • The DRs of PSMA-radiotracers were greater than those of choline-radiotracers and fluciclovine-radiotracers at the patient level. •18F-labeled PSMA achieved a higher DR than68Ga-labeled PSMA.

Published
2021

27. Effect of zinc supplementation on growth performance, intestinal development, and intestinal barrier function in Pekin ducks with lipopolysaccharide challenge

Author

Yueqin Xie, Gang Jia, Min Wen, Jingyi Cai, Guangmang Liu, Hua Zhao, Gang Tian, and Xiaoling Chen

Subjects
Lipopolysaccharides, Male, medicine.medical_specialty, Lipopolysaccharide, Pekin duck, biology.animal_breed, chemistry.chemical_element, Zinc, SF1-1100, Proinflammatory cytokine, chemistry.chemical_compound, Internal medicine, IMMUNOLOGY, HEALTH AND DISEASE, intestinal inflammation, medicine, Animals, Intestinal Mucosa, Barrier function, growth performance, biology, zinc, General Medicine, medicine.disease, Intestinal epithelium, Animal culture, intestinal barrier, Endocrinology, Ducks, chemistry, Digestive enzyme, Dietary Supplements, Zinc deficiency, biology.protein, Animal Science and Zoology, Animal Nutritional Physiological Phenomena
Abstract

This study was conducted to investigate the influence of zinc (Zn) supplementation on growth performance, intestinal development and intestinal barrier function in Pekin ducks. A total of 480, one-day-old male Pekin ducks were divided into 6 groups with 8 replicates: 0 mg/kg Zn, 0 mg/kg Zn +0.5 mg/kg lipopolysaccharide (LPS), 30 mg/kg Zn, 30 mg/kg Zn +0.5 mg/kg LPS, 120 mg/kg Zn, 120 mg/kg Zn +0.5 mg/kg LPS. The duck primary intestinal epithelial cells (DIECs) were divided into 6 groups: D-Zn (Zinc deficiency, treated with 2 µmol/L zinc Chelator TPEN), A-Zn (Adequate Zinc, basal medium), H-Zn (High level of Zn, supplemented with 20 µmol/L Zn), D-Zn + 20 µg/mL LPS, A-Zn + 20 µg/mL LPS, H-Zn + 20 µg/mL LPS. The results were as follows: in vivo, with Zn supplementation of 120 mg/kg reduced LPS-induced decrease of growth performance and intestine damage (P < 0.05), and increased intestinal digestive enzyme activity of Pekin ducks (P < 0.05). In addition, Zn supplementation also attenuated LPS-induced intestinal epithelium permeability (P < 0.05), inhibited LPS-induced the expression of proinflammatory cytokines and apoptosis-related genes (P < 0.05), as well as reduced LPS-induced the intestinal stem cells mobilization of Pekin ducks (P < 0.05). In vitro, 20 µmol/L Zn inhibited LPS-induced expression of inflammatory factors and apoptosis-related genes (P < 0.05), promoted the expression of cytoprotection-related genes, and attenuated LPS-induced intestinal epithelium permeability in DIECs (P < 0.05). Mechanistically, 20 µmol/L Zn enhanced tight junction protein markers including CLDN-1, OCLD, and ZO-1 both at protein and mRNA levels (P < 0.05), and also increased the level of phosphorylation of TOR protein (P < 0.05) and activated the TOR signaling pathway. In conclusion, Zn improves growth performance, digestive enzyme activity, and intestinal barrier function of Pekin ducks. Importantly, Zn also reverses LPS-induced intestinal barrier damage via enhancing the expression of tight junction proteins and activating the TOR signaling pathway.

Published
2021

28. The Patterns of Complementary Feeding and Growth among 12 to 23 Month-Old Children in China

Author

Shuo, Wang, Yue, Mei, Zhong Hua, Ma, Wen Hua, Zhao, Xue Jun, Tang, Xue Hong, Pang, Qian, Zhang, Rui Li, Li, Yu Ying, Wang, and Tao, Xu

Subjects
Male, China, Cross-Sectional Studies, Humans, Infant, Female, Growth, Infant Nutritional Physiological Phenomena
Abstract

This study aimed to understand the characteristics of dietary patterns among children aged 12 to 23 months and discusses the relationship between dietary patterns and the growth of children.Cross-sectional data were selected from the National Nutrition and Health Systematic Survey for 0 to 18 year-old children in China (Four dietary patterns were identified among the childrenAlthough China is undergoing rapid urbanization and economic development, there is still a phenomenon of insufficient intake of protein-rich foods and dairy-based dietary patterns at the stage of complementary food introduced among children aged 12 to 23 months.

Published
2021

30. Land use mix and leukocyte telomere length in Mexican Americans

Author

Hua Zhao, Yuanqing Ye, Xifeng Wu, Wong-Ho Chow, Kai Zhang, David W. Chang, and Jie Shen

Subjects
Adult, Male, Aging, Science, Logistic regression, Article, Odds, Young Adult, Mexican Americans, Leukocytes, medicine, Humans, Built Environment, Cancer prevention, Multidisciplinary, business.industry, Telomere Homeostasis, Odds ratio, Middle Aged, Models, Theoretical, Telomere, medicine.disease, Obesity, Confidence interval, Environmental sciences, Environmental social sciences, Risk factors, Quartile, Medicine, Population study, Female, business, Biomarkers, Demography, Cohort study
Abstract

It has been well-known that built environment features influence the risk of chronic diseases. However, the existing data of its relationship with telomere length, a biomarker of biological aging, is still limited, with no study available for Mexican Americans. This study investigates the relationship between several factors of the built environment with leukocyte telomere length among 5,508 Mexican American adults enrolled in Mano-A-Mano, the Mexican American Cohort Study (MACS). Based on the quartile levels of telomere length, the study population was categorized into four groups, from the lowest (1st quartile) to the highest telomere length group (4th quartile). For individual built environment factors, their levels did not differ significantly across four groups. However, in the multinominal logistic regression analysis, increased Rundle’s land use mixture (LUM) and Frank’s LUM were found statistically significantly associated with increased odds of having high levels of telomere length (Rundle’s LUM: 2nd quartile: Odds ratio (OR)=1.26, 95% Confidence interval (CI): 1.07, 1.48; 3rd quartile: OR=1.25, 95% CI: 1.06, 1.46; 4th quartile: OR=1.19, 95% CI: 1.01, 1.41; Frank’s LUM: 2nd quartile: OR=1.34, 95% CI: 1.02, 2.63; 3rd quartile: OR=1.55, 95% CI: 1.04, 2.91; 4th quartile: OR=1.36, 95% CI: 1.05, 2.72, respectively). The associations for Rundle’s LUM remained significant after further adjusting other non-redundant built environment factors. Finally, in stratified analysis, we found the association between Rundle’s LUM and telomere length was more evident among younger individuals (

Published
2021

31. Anti-fatigue effect of quercetin on enhancing muscle function and antioxidant capacity

Author

Gang Jia, Dahui Liang, Guangmang Liu, Xiaoling Chen, Zhiqing Huang, and Hua Zhao

Subjects
Male, medicine.medical_specialty, Antioxidant, medicine.medical_treatment, Flavonoid, Biophysics, Antioxidants, Superoxide dismutase, chemistry.chemical_compound, Mice, Internal medicine, medicine, Animals, heterocyclic compounds, Muscle, Skeletal, Fatigue, Pharmacology, chemistry.chemical_classification, Mice, Inbred BALB C, Glycogen, biology, Glutathione peroxidase, Cell Biology, Malondialdehyde, Endocrinology, chemistry, Gluconeogenesis, biology.protein, Quercetin, Food Science
Abstract

The aim of this study was to evaluate the anti-fatigue effect of quercetin in mice. Three-week-old male BALB/c mice, fed with/without 0.005% quercetin for 6 weeks, were randomly divided into two experimental sets (loaded swimming and non-loading swimming tests). Our data indicated that dietary quercetin supplementation prolonged the exhaustive swimming time. In addition, lactic acid (LD) and blood urea nitrogen (BUN) levels, lactate dehydrogenase (LDH) and creatine kinase (CK) activities in serum were significantly decreased, while the levels of non-esterified free fatty acids (NEFA) in serum and the content of liver glycogen and muscle glycogen were significantly enhanced in dietary quercetin supplementation group. Furthermore, dietary quercetin supplementation significantly enhanced the glutathione peroxidase (GPx) and catalase (CAT) activities in serum, liver and gastrocnemius muscle and enhanced the total superoxide dismutase (T-SOD) activity in gastrocnemius muscle, but decreased the malondialdehyde (MDA) content and reactive oxygen species (ROS) level. Meanwhile, dietary quercetin supplementation affected the mRNA expression of regulators factors involved in muscle damage and inflammation, glucose metabolism and gluconeogenesis, muscle mitochondrial fatty acid β-oxidation and antioxidant related genes. Together, our data confirm that dietary quercetin supplementation can promote anti-fatigue capacity by promoting the antioxidant capacity and glycogen storage, as well as enhancing muscle function. PRACTICAL APPLICATIONS: Quercetin is a natural polyphenolic flavonoid substance. Here we confirm that quercetin has anti-fatigue activity. Our study indicates that quercetin may be used as natural anti-fatigue functional food or drugs.

Published
2021

32. Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Author

Labeau, Sonia O, Afonso, Elsa, Benbenishty, Julie, Blackwood, Bronagh, Boulanger, Carole, Brett, Stephen J, Calvino-Gunther, Silvia, Chaboyer, Wendy, Coyer, Fiona, Deschepper, Mieke, François, Guy, Honore, Patrick M, Jankovic, Radmilo, Khanna, Ashish K, Llaurado-Serra, Mireia, Lin, Frances, Rose, Louise, Rubulotta, Francesca, Saager, Leif, Williams, Ged, Blot, Stijn I, Dritan, Muzha, Antoni Margarit Ribas, Fernando, Lipovesty, Cecilia, Loudet, Fiona, Coyer, Philipp, Eller, Nafseen, Mostafa, Patrick, M Honoré, Vanesa Mercado Telleria, Jasmina, Smajic, Paula Cristina Nogueira, Khalid Mahmood Khan Nafees, Romuald, Hentchoya, Louise, Rose, Javiera, Soledad, Frances, Lin, Yenny, Cardenas, Amylkar Garay Reyes, Alan, Sustic, Meropi, Mpouzika, Tamas, Vymazal, Hanne Irene Jensen, Hernan, Aguirre-Bermeo, Liivi, Maddison, Maija, Valta, Silvia, Calvino-Gunther, Frank, Bloos, Faustina Excel Adipa, Vasilios, Koulouras, Judy, Enamorado, Zsuzsann, Ágoston, Hrönn, Birgisdóttir, Amit, Gupta, Mohan, Gurjar, Bram, Kilapong, Seyed Mohammadreza Hashemian, Ignacio, Martin-Loeches, Julie, Benbenishty, Andrea, Cortegiani, Kelly, Fletcher, Yoshiro, Hayashi, Wangari, Waweru-Siika, Khalid, Abidi, Sang-Min, Lee, Burhan, Hadri, Mihails, Dolgusevs, Fayez François Abillama, Tomas, Jovaisa, Cyril, Thix, Muhammed, Elhadi, Basri Mat Nor, Shanti, Ratnam, Mohd Zulfakar Mazlan, Sundaresan, Maiyalagan, Luis, Sánchez-Hurtado, Adrian, Belii, Mendsaikhan, Naranpurev, Prabha, Gautam, Dylan De Lange, Rachael, Parke, Rose Ekama Ilesanmi, Mirjana, Shosholcheva, Antonija, Petosic, Ranveig, Lind, Madiha Hashmi Ffarcsi, Javier, Bogarin, Aaron Mark Hernandez, Malgorzata, Mikaszewska-Sokolewicz, Bruno, Sousa, Dana, Tomescu, Dorel, Sandesc, Theogene, Twagirumugabe, Vitaly, Gusarov, Maie, Ebaid, Radmilo, Jankovic, Gari, Slobodianiuk, Andrea, Martonova, Rihard, Knafelj, Mervyn, Mer, Emilio, Maseda, Bernardo, Panka, Joerg, C Schefold, Eva, Joelsson-Alm, Konlawij, Trongtrakul, Lorna, Merritt-Charles, Lamia Ouanes Besbes, Yalım, Dikmen, Lesia, Zgrzheblovska, Mark, Fielding, Francesca, Rubulotta, Ashish, K Khanna, Leif, Saager, Ingrid von der Osten, Alban, Greca, Alma, Cani, Nordian, Xhindi, Genci, Hyska, Antonio Margarit Ribas, Susana, Pinto, Paulo, Alves, Romina, Esposito, Emanuel, Valgolio, John Thomas Sanchez Minope, Antonio, Abdala, Maria, Ayala, Silvina, Bravo, Ana, Bantar, Patricia, Delgado, Gustavo, Badariotti, Fernando, Lipovestky, Ana, Diaz, Pablo, Saul, Mariano, Setten, Alejandra, Aucapina, Ysica, Acosta, Victor, Gonzalez, Luis, Camputaro, Fernando, Baccaro, Robert, Villa, Marcela, Mastantuono, Emiliano, Dean, Oscar Fernández Rostello, Patricia, Brizuela, Julio Ricardo Bartoli, Matias, Guereschi, Cristian, Quiroga, Sofia, Putruele, Paula, Villegas, Veronica, Curilen, Ruben, Fernandez, Mariangeles Gabriela Nocheretti, Rosana Gabriela Escalante, Cecilia Inés Loudet, Silvia, Fernandez, Ana Laura Gonzalez, Gustavo Andres Alvarez, Federico, Iglesias, Silvia, Chaparro, Graciela, Zakalik, Gonzalo, Pagella, Matías, Baini, Pierina Arias Campos, Ignacio, Sabbag, Armando, Schmukler, Imelda Perdomo Fonseca, Gonzalo Martín Alvarez, Mario, Ramirez, Fernando, Tapia, Carlos Alejandro Bascary, Graciela Del Valle Gimenez, Fernando Pablo Bertoletti, Esteban, Milioto, Pablo Julio Maldonaldo Bonsignore, Maria Alejandra Fernandez, Julie, Smith, Tim, Chimunda, Lorraine, Thompson, Teena, Maguire, Wendy, Chaboyer, Stacey, Watts, Marion, Mitchell, Madeleine, Powell, India, Lye, Leanne, Parsons, Nerilee, Baker, Claire, Reynolds, Amy, Thompson, Kristy, Masters, Kellie, Sosnowski, Lynette, Morrison, Gavin, D Leslie, Ramanathan, Lakshmanan, Alexis, Tabah, Wendy, Brown, Sharon, McDowell-Skaines, Andrea, Mclucas, Chris, Smith, Mandy, Tallot, Sarah, Jones, Michelle, Barakat-Johnson, Thomas, Leong, Rand, Butcher, Kerrie, Martin, Philipp, Douschan, Dirk von Lewinski, René, Schmutz, Uta, Kolussi, Fatema, Salman, Zainab, Ateya, Koen De Decker, Niels Van Regenmortel, Anita, Jans, Patricia, Wijnands, Stefano, Coremans, Patrick, M Honore, David De Bels, Tanja, Depuydt, Caroline, Paillet, Luc-Marie, Jacquet, Walter, Swinnen, Francis, Hannes, Matthia, Mergeay, Stijn Van de Velde, Silvie, Allaert, Pieter, Hoste, Christophe, Borin, Sandrine, Balon, Vincent, Fraipont, Patrick, Biston, Nicolas De Schryver, Thierry, Dugernier, Ilse Van Cotthem, Angelica Olivetto de Almeida, Silvia Angelica Jorge, Delmiro, Becker, Raysa Cristina Schmidt, Evellyn, Oliveira, Aline, Ramalho, Eliane, Mazocoli, Audrey, Fioretti, Elaine, Barros, Leticia, Serpa, Suzana, Bianchini, Ticiane, Campanili, Taís, Pantaleao, Paulo Carlos Garcia, Ana Lucia Vitti Ronchini, Rayanne, Santos, Nurulhuda Binti, A Manap, Sean, Bagshaw, Dominic, Carney, Jon, Davidow, Ella, Rokosh, Andréa Maria Laizner, Samantha, Smith, Megan, Mcquirter, Betty Star Kampayana, René, Favre, Martin, Sills, Julie, Dallaire, Cathy, Becker, Sherissa, Microys, Bonnie, Bowes, Jennifer, Lajeunesse, Rishi, Ghosh, Jacqueline, Baptiste-Savoie, Rose, Raizman, Gabriel, Suen, Noushin, Taghavi, Orla, Smith, Clare, Fielding, Julieta, Canales, Pia, Molina, Javiera, Chaparro, Maria Idalia Sepulveda, Matias Jesús Flamm Zamorano, Pamela, Rocha, Ximena, Villanueva, Paola, Araya, Meneses, Dayan, Fernando, Avalos, Xiaohan, Li, Liu, Yu, Xinxia, Li, Xiaoyan, Chen, Zhixia, Jiang, Jing, Yang, Jingfang, Chen, Lei, Yang, Kefang, Wang, Jie, Gao, Xiuhua, Fang, Ronghua, Zhao, Xinhua, Xia, Hongmei, Liu, Jing, Li, Haiyan, Wang, Gen, Meng, Yanhong, Di, Damei, Wang, Rong Hua Zhao, Li Ping Hu, Peipei, Xu, Qing Feng Jiao, Hai Yun Wang, Chun Jie Xia, Yan, Liu, Mei, Ye, Yan, Wan, Wenmei, Wang, Yajun, Ding, Aiua, Ren, Yan, Gao, Qi, Li, Guifang, Du, Yanling, Shen, Yanming, Ding, Ning, Li, Cui, Yuan, Lei, Tan, Qiang, Lin, Hailing, Guo, Howe, Yan, Xiao, Xu, Wei, Zhang, Jinxian, Liang, Libing, Zhang, Eryun, Tian, Qian, Zhao, Lin, Insu, Jingwen, Dong, Yanmei, Gu, Ying, Liu, Lina, Zhao, Wei, Wang, Hongmei, Qiao, Lili, Tuo, Mengmeng, Lv, Jin Yu Zhu, Jifen, Zhu, Ying, Wei, Man, Liu, Yin, He, Jiyin, Cheng, Jin, Liu, Jia, Na, Dongfang, Wei, Qing, Li, Xiaoying, Wu, Huan, Duan, Dongliang, Lin, Qiong, Liang, Xiaofang, Luo, Yunfeng, Xiong, Rong Fen Huang, Jing, Fu, Tao, Zan, Man, Ye, Zeya, Shi, Yanfei, Long, Yang, Lei, Xiaodi, Liu, Chen, Yumei, Lingling, Wang, Yali, Zhang, Yan, Xu, Cheng, Wang, Zhijuan, Chengxia, Sun, Jinhui, Song, Yingli, Wang, Xiumei, Liu, Yupeng, Liu, Yuxia, Yuan, Qingping, Huang, Fengling, Yang, Yun, Wu, Xianping, Luo, Xiaowu, Bai, Hong, Zheng, Min, Song, Yue, Sun, Zhangshuangzi, Li, Feifei, Luo, Miao, Liu, Li Chuntang Li, Xinjian, Li, Guiping, Zhang, Lina, Xiao, Tingting, Yu, Guangyuan, Gao, Wei, Wei, Fanglan, Wang, Ting, Han, Tingting, Li, Zeng, Qi, Jing Mei Zeng, Yan, Long, Fuqun, Pan, Jing, Wang, Guoxue, He, Haiyan, Chen, Feifei, Zhang, Chao, Yu, Gao, Chunhua, Xiuying, Yao, Dongmei, Bai, Liu, Lu, Xuelian, Xu, Yan, Wang, Xuejuan, Liang, Zhang, Na, Aizhi, Zhang, Xiaochun, Hu, Hui, Zhang, Ruixia, Wang, Poon Shing Tak, Sung Wai Ho, Qun Xia Jiang, Xinran, Ding, Liu, Hong, Limei, Miao, Zhaoxia, Feng, Liping, Huang, Juan, Wu, Yuping, Wang, Jiye, Guo, Baoke, Zhang, Chaoqun, Ma, Han, Yu, Congcong, Liu, Min, Ding, Linlin, Luan, Jing, Zheng, Shanshan, Lv, Shumin, Jiang, Wenzhen, Cao, Xiujuan, Xue, Guangyan, Liu, Xiyan, Wei, Youru, Jiang, Zhiru, Yao, Gao, Li, Jinhua, Li, Wenwen, Zhao, Mei, Jiang, Junping, Hao, Jing, Zhang, Caiju, Song, Feifei, Chen, Shuhui, Wang, Lili, Hu, Deyan, Cao, Jianhong, Wan, Xiaomin, Wang, Hongyan, Shao, Zhenxia, Zhang, Xia, Cui, Jingyu, Liu, Lijuan, Zhao, Xingguo, Li, Limei, Fan, Ling, Zhang, Min, Yu, Biyan, Li, Chunxia, Li, Ling, Liu, Xuelian, Liu, Wenmin, Chen, Yan, Li, Zhang, Zhigang, Yuchen, Wu, Chenghau, Mu, Guoyan, Zhu, Fan, Yang, Qi, Bo, Ling, Li, Meili, Chen, Jing Hua Jiang, Hai, Yin, Xuelian, Pang, Yue Ying Gong, Shunzhu, Yang, Xiaoli, Yan, Xianhong, Zheng, Dehong, Lei, Lei, Lei, Yinhua, Guo, Lihong, Liu, Jing, Yu, Wei, Sun, Aiping, Bi, Weiwei, Li, Yang, Wu, Ji, Li, Dongshu, Ni, Zijing, Wu, Bing, Song, Qin, Fei, Yang, Xiaoyan, Qiong, Ran, Xixi, Li, Xueping, Jiao, Hua, Ji, Sun, Zhiping, Hong, Ma, Jianhong, Mu, Yanhua, Hao, Yin, Li, Ying, Wang, Caihong, Hui, Wenjie, Ju, Yuxia, Huo, Yuxia, Wang, Lei, Chen, Yan, Yan, Qingli, Zhao, Hongjuan, Chen, Guijun, Bao, Ying, Cao, Hong, Li, Hong, Zhang, Ying, Zhang, Lina, Xu, Jia, Guixiang, Ying, Li, Hui Min Zhao, Xia, Huang, Zhaoxing, Dai, Yanman, Jian, Hongsu, Zhang, Zhixia, Tian, Zu Qing Cao, Miao, Li, Yang, Liu, Fei, Ouyang, Fuying, Ma, Wangyan, Jin, Liuyan, Ge, Shifen, Wu, Weilian, Yuan, Tianfei, Chen, Guanxiu, Shi, Zhihong, Chen, Kewei, Liu, Xue, Lin, Yuemen, Ly, Sun, Lijuan, Xiao Fang Tian, Shuo, Wang, Zhangxia, Feng, Xiaozhe, Liu, Yunchun, Dong, Jundi, Zhang, Nie, Bocui, Guoxian, Wang, Yingjuan, Zhao, Xiaojun, Wu, Qiao, Yang, Rongjun Ling Hu, Xue Qin Li, Zhu Jun Yu, Yanlan, Yao, Xiaoqiong, Deng, Yan, Xiao, Yan, Xie, Yanping, Yang, Huai, Yang, Yuming, Zhou, Zhuqing, Li, Min, Xiao, Yongxia, Yang, Yani, Tian, Luz Marina Silva Gama, Juan Sebastian Hernandez, Nestor, Caicedo, Jorge, Marin, Maria-Elena, Ochoa, Monica, Gomez, José, Rojas-Suarez, Jeniffer, Gonzalez, Amylkar José Garay Reyes, Edwin, Chapeta, Estefania, Orozco, Ina, Filipović-Grčić, Anita, Vuković, Suzana, Pečenković, Aleksandar, Šuput, Gordana, Zivanovic-Posilovic, Armanda, Bozena, Nikolina, Udiljak, Morena, Milic, Renata Curic Radivojevic, Slobodan, Mihaljevic, Marijana, Matas, Dinko, Tonkovic, Hemena, Čuljak, Ivana, Herceg, Gordana, Pavlisa, Milena, Dobric, Tatjana, Beker, Višnja Nesek Adam, Tanja, Goranovic, Chrysanthos, Markoulias, Mina, Mathaios, Maria, Mylordou, Eleni, Achilleos, Pavlina, Kleanthous, Veronika, Kotanidi, Maria, Foka, Iwy, Charalabous, Anna, Alexandrou, Marios, Georgiou, Artemis, Patsalos, Sofia, Zepoy, Constantina, Constantinou, Petr, Piza, Tomas, Vymazal, Elisabeth, Wiborg, Louise, Bruhn, Karin, Kaasby, Karin Rehnholt Pedersen, Sanne, Mikkelsen, Marie, Collet, Anne, Langvad, Hanne, Andresen, Susanne, Fischer, Inger Ebbesen Kjærgård, Britta, Jepsen, Birthe, Husted, Morten, Bestle, Anne Marie Kodal, Tina Charlotte Bitsch Hansen, Anne Sofie Bomholt Pedersen, Tina Damgaar Thomsen, Anisette, Hoegenhaven, Mette, From, Tine Melgaard Frandsen, Grit, Henning, Anja, Hansen, Inger Abildgaard Bliksted, Luis Mario Tamayo, Pedro, Mogrovejo, Carolina, Palaez, Diego Rolando Morocho Tutillo, Cintia Valencia Hurtado, Maria Fernanda García, Diana, Alvarez, Fausto, Guerrero, Alexandra, Vasquez, Martin, Kütimets, Kadri, Tamme, Eneli, Anvelt, Lomangisi, Dlamini-Sserumaga, Carita, Löfqvist, Virpi, Lusenius, Outi, Kauppi, Jenni-Katarina, Sakki, Tarja, Tervo-Heikkinen, Ulla, Kesti, Merja, Merilainen, Elina, Karjula, Minna, Peltomaa, Auli, Palmu, Maarit, Ahtiala, Maija Anniina Valta, Hervé, Mentec, Gaëtan, Plantefève, Guillaume, Besch, Sébastien, Pili-Floury, Stanislas, Ledochowski, Marc Danguy des Déserts, Christophe, Giacardi, Cédric, Daubin, Audrey, Massard, Yann Le Guen, Agnès, Blanc, Simon, Mandaroux, Silvia Calvino Günther, Prune, Avogadro, Anthony, Radavidson, Jean, Turc, Sébastien, Jochmans, Hervé, Quintard, Laetitia, Boyer, Cédric, Bruel, François, Philippart, Philippe, Montravers, Enora, Atchade, Nadine, Flessel, Benoît, Chinardet, Léa, Soulisse, Cindy, Pillard, Delphine, Ngo, Benjamin, Bongiorno, Nathalie, Heitzler, Virginie, Souppart, Nathalie, Gautheret, Jean-Francois, Timsit, Fatiha, Essardy, Muriel, Fartoukh, Daisy, Mehay, Fabienne, Etourneau, Jean-Christophe, Farkas, Pascal, Beuret, Gabriel, Preda, Etienne De Montmollin, Vincent, Castelain, Ulrich, Jaschinski, Monika, Rothenfusser, Detlef, Kindgen-Milles, Thomas, Dimski, Christine, Fiedler, Tobias, Heinicke, Patrick, Meybohm, Tobias, Schulze, Marc, Bota, Sabrina, Pelz, Tobias, Odenthal, Martin, Christ, Kathrin, Bösl, Achilleas, Chovas, Sebastian, Stehr, Philipp, Simon, Sarah, Grotheer, Sebastian, Schüppel, Stefan, Schaller, Lea, Albrecht, Andeas, Stübner, Stephan, Graeser, Nina, Kolbe, Martina, Lausch, Anja, Diers, Ulf, Guenther, Reimer, Riessen, Martin, Roller, Irene Pearl Osei, Anita-Chrysolyte, Kusi-Appiah, Yakubu, H Yakubu, Belinda, Guadi-Gosh, Christos, Dragoumanis, Christos, Christofis, Nikolaos, Kazakos, Styliani, Bastani, Charalampos, Martinos, Vasileios, Bekos, Metaxia, Papanikolaou, Theonymfi, Papavasilopoulou, Anna, Efthymiou, Vasiliki, Chantziara, Anna, Kyriakoudi, Nikolaos, Kakaras, Chrisi, Diakaki, Aikaterini, Flevari, Charikleia, Nikolaou, Kounougeri, Katerina, Lamprini, Avramopoulou, Kyriaki, Tsikritsaki, Georgios, Gkiokas, Eirini, Pantiora, Chrysostomos, Katsenos, Eirini-Chysovalanto, Patsiou, Paraskevi, Alexandropoulou, Ioannis, Koutsodimitropoulos, Epaminontas, Farmakis, Konstantina, Nestora, Marinos, Chatzis, Eumorfia, Kondili, Stella, Soundoulounaki, Ourania, Mousafiri, Dimitra, Lepida, Antonia, Liarmakopoulou, Georgios, Papathanakos, Mrina, Oikonomou, Panagiotis, Ioannides, Dimitrios, Papadopoulos, Ioannis, Staikos, Maria, Stafylaraki, Bogdan, Raitsiou, Konstantinos, Mandis, Ifigenia, Ravani, Styliani, Kourelea, Aikaterini, Efthimiou, Giannoula, Thoma, Apostolos, Bakas, Konstantinos, Psarulis, Souzana, Anisoglou, Eirini, Papageorgiou, Evangelia, Michailidou, Thomai, Tholioti, Athena, Lavrentieva, Evdokia, Sourla, Anastasia, Spyropoulou, Nikolaos, Pantelas, Kristina Mariana Matei Stalika, Ioannis, Georgakas, Antigoni, Karathanou, Syragoula, Tsikriki, Aikaterini, Dimoula, Sofia, Kanakaki, Aristeidis, Vakalos, Konstantinos, Pagioulas, Judy Enamorado Enamorado, Gabor, Nardai, Fatime, Hawchar, Asbjorn, Blondal, Brynja, Rygvadottir, Rannveig, J Jonasdottir, Hrönn, Birgisdottir, Bhagyesh, Shah, Shuchi, Kaushik, Swagata, Tripathy, Mukta, Singh, Sonika, Agarwal, Manish, Gupta, Meraj, Ahmad, Kishore, Mangal, Vaibhav, Bhargava, Vilas, Kushare, Simant, Jha, Lakshay, Bhakhtiani, Manoj, Kamal, Arvind, Baronia, Ade, Susanti, Mayang Indah Lestari, Zulkifli, Zulkifli, Windu, Baskoro, Farid, Zand, Fatemeh, Zarei, Ata, Mahmoodpoor, Farshad, Heidari, Fateme, Jafaraghaee, Aidan, O'Shea, Fiona, O'Shea, Caroline, O'Donnell, Geraldine, Craig, Gerry, Fitzpatrick, Lisa, Dunne, Jennifer, Hastings, Brian, Marsh, Caitriona, Cody, Elizabeth, Campbell, Deirdre, Doyle, Michelle, Pacturanan, Christine, Sheehan, Annette, Carey, Charlotte, Carter, Regina, Mulvey, Damien O'Connell Rosemary Finn, Catherine, Motherway, Amy, Walsh, Jennifer, Kehoe, Shella, Delossantos, Jennifer, Lalor, Siobhan, O'Nuallain, Helena, Behan, Sandra, Mcpherson, Ailesh, Corcoran, Patricia, Gordon, Glenda, Rooney, Dassy, Levy, Mazal, Azencot, Vladimir, Gurevich, Alinoy, Lavy, Valentina, Bendelari, Romina, Marconi, Antonio, Barone, Chiara, Gatti, Andrea, Giampaoletti, Cinzia, Borgognoni, Davide Massimo Ghioldi, Arena, Raimondo, Giacomo, Castiglione, Anna Vita Bruno, Giorgia, Rubulotta, Antonella, Mo, Amalia, Corso, Salvatore, Girianni, Andrea, Bruni, Eugenio, Garofalo, Salvatore Maurizio Maggiore, Alessandro Di Risio, Italo, Calamai, Rosario, Spina, Savino, Spadaro, Carlo Alberto Volta, Antonella, Cotoia, Lucia, Mirabella, Laura, Maulicino, Giancarlo, Abregal, Maria, Donvito, Paolo, D'Ambrosio, Filipo, Binda, Ileana, Adamina, Alessandro, Galazzi, Alessandra, Negro, Rosanna, Vaschetto, Fabio, Capuzzi, Margherita, Boschetto, Lucia, Stivanello, Luciano, Bonaccorso, Chiara, Megna, Pasquale, Iozzo, Antonino, Rizzo, Giovanni, Scire, Maria Rosa Taibi, Francesca Paola Tranello, Antonio, Manzo, Lidia, Traina, Beatrice, Pastore, Attilio, Quaini, Gian Domenico Giusti, Gloria, Montaldi, Federica, Piergentili, Federica, Mancini, Simona, Casaioli, Francesco, Uccelli, Fabio, Guarracino, Adriana, Onelli, Valentina Di Gravio, Maria, Cossu, Oliva, Matrona, Monica, Rocco, Daniela, Alampi, Federica, Dellafiore, Flavia, Ranalli, Matteo, Bossolasco, Elisabetta, Brizio, Pina, Migliorino, Paolo, Cortellazi, Moris, Rosati, Francesco, D'Ambrosio, Catia, Quagliotto, Erik, Roman-Pognuz, Alberto, Peratoner, De Rosa, Silvia, Marina Alessandra Martin, Francesca De Sanctis, Paolo, Ciorba, Patrick, Toppin, Hyacinth, Harding-Goldson, Shunsuke, Taito, Nobuaki, Shime, Ryohey, Yamamoto, Fumiya, Kanda, Akemi, Hirao, Moritoki, Egi, Ayako, Noguchi, Satoru, Hashimoto, Umeda, Aya, Hideaki, Sakuramoto, Akira, Ohuchi, Jun, Kataoka, Kumi, Maruyama, Izumi, Nakayama, Yoshimasa, Nishime, Koji, Fujimoto, Kenji, Takahashi, Mayumi, Tsujimoto, Masako, Shimizu, Eunice, Tole, Malcolm, C Correia, Je Hyeong Kim, Sunghoon, Park, Kyung Chan Kim, Jonghyun, Baek, Jung-Min, Bae, So Young Park, Tai Sun Park, Heung Bum Lee, Seung Yong Park, Jisoo, Park, Lee, Yeon-Joo, Cho, Young-Jae, Sang-Miin, Lee, Kyeongman, Jeon, Seok Chan Kim, Jongmin, Lee, Hyun Keun Chee, Jin Won Huh, Yun Su Sim, Junghyun, Kim, Youjin, Chang, Jong-Joon, Ahn, Byung Ju Kang, Won-Yeon, Lee, Seok Jeong Lee, Nehat, Baftiu, Ivasr, Krastins, Sonia, Stiban, Michel El Feghaly, Elie, Gharios, Marie, Merheb, Mohamed, Benlamin, Ala, Khaled, Wesal Ali Belkhair, Majd, Tabib, Firas, Ashour, Ahmed, Elhadi, Osama Wanees Emhemid Tababa, Taha, Khaled, Soad Imhmed, R Alkhumsi, Abdualhamid, I Alshrif, Ahmed Ali Aboufray, Aya, Alabuzidi, Ahmed Ramadan Triki, Mala, Elgammudi, Hajer Ben Zahra, Enas, Soula, Maram Milud Said Al-Alawi, Hazem, Ahmed, Mohamed Abdurazzag Ali Ghula, Saulius, Vosylius, Lucie, Mouton, Touraj, Rastegar, Claude, Sertznig, Gilles, Martin, Christian, Theisen, Christian, Ferretti, Fränk, Gils, Marc, Gallion, Asmah, Zainudin, Laila Kamaliah Kamalul Bahrin, Shanti Rudra Deva, Azmin Huda Abdul Rahim, Sherliza, Wahab, W Nazaruddin, W Hassan, Wan Nasrudin Wan Ismail, Mohd Nazri Ali, Tien Meng Khoo, Noryani Mohd Samat, Jenny May Geok Tong, Nik Azman Nik Adib, Mohd Basri Mat Nor, Shanthi, Ratnam, Nahla, Ismail, Siti Rohayah Sulaiman, Kit Weng Foong, Anita, Alias, Ngu Pei Hua, Jorge Macias Zermeno, Daniel, Blanco, Karely, Duran, Claudia Lizbeth Lopez Nava, San Juan Roman Nandyelly, Luis Alejandro Sanchez-Hurtado, Brigitte, Tejeda-Huezo, Mario Del Moral Armengol, Luis Pedro Ambriz Nava, Jorge Guerra Herrera, Gilberto Felipe Vazquez de Anda, Humberto, Gallegos-Perez, Nancy, Hernandez-Sanchez, Lucia, Hernandez-Ponce, Luis, Gorordo-Delsol, Marcos, Hernandez-Romero, Saira, Gomez, Fernando, Molinar, Silvio, A Ñamendys-Silva, Juan, P Romero-Gonzalez, Daira, Gonzalez, Antonio, Landaverde, Miguel Ángel Sosa, Berenice, Navarro, José Ivan Rodriguez de Molina Serrano, Sergio Reyes Iburrigarro, Alejandro, Ibarra, Joaquin, Aguirre, Mayra, Martinez-Gonzalez, Nayeli Rocio Cañas Padilla, Ana Alícia Velarde Pineda, Missael Vladimir Espinoza Villafuerte, María Ocotlan Gonzalez Herrera, Battsetseg, Baasanjav, Abdelhamid, Hachimi, Mina, Elkhayari, Tarek, Dendane, Nisha Bhandari Subedi, Sabina Dhakal Pathak, Meena, Manandhar, Laura Van Gulik, Mark Van Den Brink, Peter Van Vliet, Benjamin, Gerretsen, Lettie Van Den Berg, Marina De Haan, Binny, Tuinstra, Paul, Kuijpers, Jennifer, Reijntjens, Jan Wytze Vermeijden, Martin, Rinket, Margijske, Vanroest, Auke, Reidinga, Bert, Loef, Willem, Dieperink, Marisa, Onrust, Tom, Dormans, Laura, Bormans, Matty, Koopmans, Rik, T Gerritsen, Arlette Van Den Elst, Mirjam, Evers, Oscar, Oiting, Rob, Wilting, Bart, Ramaker, Mark van der Kuil, Jan-Willem, Fijen, Lenneke, Haas, Jasper, Haringman, Lynette, Newby, Eileen, Gilder, Danielle, Hacking, Rica, Dagooc, Rima, Song, Hansjoerg, Waibel, Frances, Dawn, Jackie, Rapley, Llesley, Chadwick, Carmel, Chapman, Petra, Crone, Jonathan, Albrett, Peter, Marko, Jennifer, Goodson, Troy, Browne, Richard, Whitticase, Cheryl, Davidson, Harriet, Judd, Daniel, Owens, Tonia, Onyeka, Innocent, Ugwu, Rose, Ilesanmi, Prisca Olabisi Adejumo, Afolabi, Owojuyigbe, Anthony, Adenekan, Stella, Uba, Christiana, Chime, Deborah, Jibrin, Babangida John Sankey, Oyebola, Adekola, Simeon, Olanipekun, Mirjana, Shosolcheva, Vanja, Gievski, Andrijan, Kartalov, Filip, Naumovski, Biljana, Kuzmanovska, Angela, Trposak, Zaneta, Bogoevska-Miteva, Rodney, Rosalia, Brita Fosser Olsen, Britt, Sjobo, Karianne Dale Jensen, Drammen, Sykehus, Birgitte Fosser Johansen, Esben, Straede, Edda, Johansen, Inger Johanne Finnstrom, Annette, Toellefsen, Hege, Ostenjo, Hege, Bjorgen, Bjorn, Bratsberg, Elin, Kristoffersen, Elin Mari Skorstad, Siri, Hansen, Sylvi, Vullum, Gro Anne Lunde, Wenche, Arntsen, Mette, Lund, Gro Ringstad Akselsen, Kristina Reinertsen Monstad, Ane, Stenset, Hanne, Haugom, Bjoern, Monsen, Lisa, Høgvall, Siw, Trudvang, Britt, Galaaen, Siv Karin Malmin, Marit Hildegunn Andersen, Rita Foss Hargott, Yvonne, Andersen, Elin, Steffenak, Marit, Nyhus, Barbro, Meland, Madiha, Hashmi, Noelia, Rivas, Elizabeth, Maidana, Alberto de Jesús Ortiz, Dolly Mabel Bordon Cabral, Marcelo, Simi, Cesar, Aponte, Juan Carlos Rivas, Sirley, Gill, Amilcar, Garcia, Gloria, Alvarenga, Laura, Cespedes, Hugo, Perez, Maria Liz Moreira, Fidelina, Canete, Roberto, Gonzalez, Natalia, Monges, Mary, Coman, Marcelo, Pederzani, Natalia, Franco, Ferdinand, Aganon, Regina, Martinez, Debbie, Noblezada-Uy, Chris Gerome Ellazar, Franklin Dean Cerezo, Jose Emmanuel Palo, Cristal April Jane Aperocho, Michael, Isanan, Marta, Tubacka, Przemyslaw, Jasiewicz, Miroslaw, Czuczwar, Michal, Borys, Aleksandra, Gutysz-Wojnicka, Lidia, Glinka, Ryszard, Gawda, Jan, Bilawicz, Paula, Cabrita, João, Vieira, Margarida Ferreira Figueiredo, Cristiana Mota Pinheiro, Nelson, Antunes, Laura, Pedro, Fatima, Ferreira, Isabel, Parente, Maria, Varela, Fatima, Fernandes, Claudia, Martins, Abel, Viveiros, Raquel, Cavaco, Clara Santa Rita, Sofia, Dias, Ana Margarida Feranandes, Pedro, Silva, Catarina, Nunes, João, Cabral, Filpe, Pires, Hilaryano, Ferreira, Jacinta, Santos, Vitor Manuel Vaz Pinto, Bruno Miguel Bispo, Amelia, Ferreira, Elena, Molinos, Estevão, Lafuente, Ricardo, Gregorio, Humberto, Costa, Ângela, Lima, Susana, Ferreira, Vanda, Seromenho, Eulália, Luis, Idália, Valerio, Helena, Cesar, Ana, Tavares, Ahmed Subhy Alsheikhly, Saeed, Mahmood, Catalin Traian Guran, Alida, Moise, Daniela Carmen Filipescu, Mihail, Luchian, Mihai, Popescu, Monica Adriana Scutariu, Cristina, Petrisor, Natalia, Hagau, Ioana, Grigoras, Tatiana, Patrichi, Vitaly, Gusarev, Alexandra, Pivkina, Vladimir, Kulakov, Olga, Ignatenko, Julia, Kovaleva, Trina, Zhivotneva, Marina, Zhedaeva, Nikita, Matiushkov, Olga, Ershova, Natalya, Egorova, Victoria, Khoronenko, Danil, Baskakov, Dmitry, Sergeev, Michael, Piradov, Liudmila, Grishina, Marat, Magomedov, Evgeniy, Zuev, Uri, Gorokhovatsky, Anna, Leonova, Liudmila, Fadeeva, Vladislav, Belskiy, Dmitriy, Galishevskiy, Nadezhda, Zubareva, Maksim, Tribulev, Oksana, Zueva, Alexander, Kiselev, Nikolaj, Kamenshchikov, Ekaterina, Tokareva, Maxim, Petrushin, Irina, Starchenko, Isaac, Nshimyumuremyi, Jerome, Muhizi, Egide, Buregeya, Josue, Nzarora, Amer, Assiri, Maie Salem Ebaid, Ghaleb, Almekhlafi, Yasser, Mandourah, Jelena, Velickovic, Dejan, Veličković, Bojan, Jovanovic, Adi, Hadzibegovic, Branislava, Stefanovic, Vanja, Misic, Vesna, Bumbasirevic, Marija, Rajković, Milena, Stojanovic, Srđan, Gavrilovic, Maja, Stanojević, Aktham, Yaghi, Anton, Turčan, Peter, Firment, Garri, Slobodianiuk, Daria, Rabarova, Danca, Lančaričová, Janko, Vlaovic, Matjaž, Groznik, Milica, Lukic, Janja, Perme, Maja, Sostaric, Nejc, Umek, Tomislav, Mirkovic, Simon, Dolenc, Misa, Fister, Nika, Zorko, Andrej, Markota, Nomhle Princess Yeni, Phumele, Jali, Shelley, Schmollgruber, Muhommed Ridwaan Syed, Nivisha, Parag, Robert, Wise, Maria, Galiana, José Alejandro Navarro, Ana María De Pablo, Patricia, Albert, Pilar, Martinez, Yolanda, Mendiara, Barbara, Garcia, Ana Alabart Llinas, Marilyn, Riveiro, Elisabet, Gallart, Alba, Riera, Miquel, Sanz, Swagotika, Salo, Miguel Angel Gimenez Lajara, Montserrat Venturas Nieto, Rosa, Garcia, José Manuel Garcia Pena, Maria Carmen Gorgolas, Maria Aranzazu Isasi, Rafael, Sierra, Federico, Gordo, Isabel, Conejo, Vicent, Salvà-Costa, Carolina, Garzón-Tovar, Sara, Lospitao, Rafael, Gonzalez, Pedro, Gutierrez, Mercè, Girona, Jordi, Adamuz, Pablo Garcia Olivares, José Peral Gutierrez de Ceballos, Celia, Tirado, Irene De Wit, Ana Belén Curto Polo, Maria Del Mar Diaz Salcedo, Javier, Ripolles-Melchor, Eugenio, Martinez-Hurtado, Jorge Duerto Alvarez, María Luisa Bravo Arcas, Juan Ignacio Torres Gonzalez, Ana Belén Sánchez de la Ventana, Pablo Lopez-Arcas Calleja, Raquel Garcia Alvarez, Purificacion Sanchez Zamora, Alvaro Ortega Guerrero, Rosario, Cosano, Jonathan, Perez-Vacas, Margarita, Campos-Perez, Emma Moreno Barreiro, Losune Cano Sanchez, Monica Garcia Diaz, Raquel, Jimenez, Lorena Del Rio Cabajo, Daniel Sancho Muriel, Helena Fernandez Alonso, Ana Wensell Fernández, Isabel Santín Piñan, Guillermo Muñiz Albaiceta, Maria Cristina Iglesias Fernandez, Francisco Javier Saenz Abos, Pablo, Monedero, Ramon Molina Chueca, Lydia Gallego Aguirre, Silvia Call Manosa, Carmen Partera Luque, Neus, Calpe, Monica Recio Losilla, Meritxell Tapia Fores, Olga, Farre, Oscar, Fernandez, M Del Rosario Villar Redondo, Donaldo, S Arteta Arteta, Maria Angeles Hurtado Sanchez, Cristina Paños Espinosa, Laura Martinez Reyes, Laura Claramunt Domenech, Carmen Velasco Guillén, Josep Trenado Alvarez, Mercedes Del Cotillo, Jesus Emilio Barrueco-Francioni, Belen Burgos Conde, Maria Pilar Sogues Blanco, Maria Luisa Blasco, Ana Isabel Clement, Clara, Hurtado, Luz Coronado Sanz, David, Perez-Torres, Estefanía, Prol-Silva, Jorge, Pereira, Iván Areán González, Anastasio Espejo Cano, Cesar Rodriguez Nuñez, Inmaculada Lorenzo Fernadez, Alejandra Azahara Marguello Fernandez, Rosa Del Bosque Diez, Badiola, Hilario, Begoña, Zalba-Etayo, Ana, Pascual-Bielsa, Preveen, Banwarie, Dick, Nahar, Alisha van Axel, Naraindath, N Boedjawan, Erika Backlund Jansson, Ann-Sofie, Malvemyr, Lotta, Johansson, Ulla, Sandberg, Catarina, Tingsvik, Gunilla, Mattsson, Gun, Löf, Martin, Spångfors, Mona, Ringdal, Sebastian, Geijer, Lotti, Orvelius, Mia, Hylen, Caroline, Lagerhäll, Eva, Åkerman, Viveca Hamback Hellkvist, Ulrica, Mickelsson, Ewa, Wahlbom, Ing-Marie, Larsson, Ewa, Wallin, Filippo, Boroli, Solenne, Ory, Margaret Lynn Jong, Alexander, Dullenkopf, Martin, Lang, Yvan, Fleury, Marianne, Maus, Nawfel, Ben-Hamouda, Anne, Fishman, Mei Yu Hsu, Shu Chuan Chang, Konlawij, Trongtratul, Chaiwut, Sawawiboon, Sunthiti, Morakul, Bodin, Khwannimit, Keevan, Singh, Dale, Ventour, Dianne, Figaro-Barclay, Sasha, Sankar-Maharaj, Mhamed Sami Mebazaa, Salma, Kamoun, Souheil, Elatrous, Lamia, Besbes, Fekri, Abroug, Walid, Naija, Youssef Zied Elhechmi, Walid, Sellami, Zied, Hajjej, Takoua, Merhabene, Imen, Talik, Ozlem Ozkan Kuscu, Ozcengiz, Dilek, Avşar, Zerman, Hayriye Cankar Dal, Sema, Turan, Semih, Aydemir, Hakan, Yilmaz, Duygu Kayar Calili, Seval, İzdes, Melike, Cengiz, Ayça, Gümüş, Banu, Taşdemir, Ali, Kağnıcı, Mustafa, Ay, Serap Avcı Ay, Gulbahar, Caliskan, Turkay, Akbas, Abidin Oner Balbay, Serdar, Efe, Volkan, Inal, Gülseren, Elay, Pınar, Karabacak, Boğaç, Özserezli, Evren, Şentürk, Oktay, Demirkiran, Suha, Bozbay, Elif, Erdogan, Mustafa, Akker, Nebia, Peker, Asu, Ozgultekin, Sibel Ocak Serin, Can, Turan, Gulsah, Karaoren, Senay, Goksu, Sait, Karakurt, Huseyin, Arikan, Fethi, Gül, İsmail, Cinel, Iskender, Kara, Hasan Nabi Undar, Yesim Serife Bayraktar, Jale Bengi Çelik, Murat Emre Tokur, Demet Tok Aydin, İsmail, Yildiz, Beysim, Özcan, Başar, Erdivanli, Ahmet, Eroglu, Devrim, Akdağ, Nurdan, Ünlü, Adonis, Dungca, Ashwaq, Ali, Bindu, Thankamma, Paul Eric Reyes, Sini, John, Ajitha, Rajendran, Fatima Kasem El Ahmad, Kathleen Ann Smiley, Susanna, Hojden, Mia Thorning Miller, Vishnu Das Sasidharan Nair, Maria Gracia San Antonio, Khaled Al Qawasmeh, Sabah Abu Shawish, Hilary, Twiggs, Ines, Rosado, Volodymyr, Babych, Faye, Morren, Charlotte, Young, Nicola, Vaughan-Jones, Stephanie, Harris, Karen, Burns, Carmel, Georgiev, Rosina, Shayamano, Ian, Kerslake, Peter, Creber, Ana, Vochin, Catherine, O'Brien, Paul, Caddell, Samantha, Hagan, Mandy, Hughes, Tomasz, Torlinski, James, Sherwin, Santhana, Kannan, Amber, Markham, Richard, Lebon, Jason, Cupitt, Julius, Cranshaw, Nigel, White, Victoria, Marriott, Wendy, Milner, Casiano Barrera Groba, Joao, Azoia, Petra, Polgarova, Shaly, George, Ritoo, Kapoor, Ceri, Lynch, Nathalie, Fox, Karen, Cranmer, Natalie, Fox, Thomas, Llewellym, Kelly, Matthews, Louise, Maltby, Jowena, Ibao, Karen, Boulton, Rachel, Jarman, Karen, Baxter, Ashok Sundai Raj, Arif, Moghal, Joanne, White, Suzanne, Barrowcliffe, Mark, Pulletz, Vaarisan, Ganeshalingam, Rosaleen, Baruah, Carole, Boulanger, Helen, Baker, Justin, Woods, Poe Poe Ei, Vongayi, Ogbeide, Paul, Hayden, Jennifer, Hughes, Madhu, Balasubramanian, Armorel, Salberg, Rajnish, Saha, Dagmar, Holmquist, Claire, Derbyshire, Neil, Smith, Elizabeth, Stones, Jane, Ademokun, Monica, Popescu, Maria Schofield Legorburo, Samantha, North, Carole, Brett, Helen, Jaundoo, Jayne, Craig, Simon, Whiteley, Clare, Howcroft, Liz, Wilby, Peter, Delve, David, Shaw, Karen, Williams, Ingeborg, D Welters, Jane, Mcmullen, Stephen, Brett, Leah, Flores, Treiza, Trueman-Dawkins, Mae, Templeton, John, Adams, Catherine, Smith, John, Prowle, Heather, Byers, Andrea, Mcdonnell, Bernd Oliver Rose, Rosie, Reece-Anthony, Luis, Mendes, Marcela, Vizcaychipi, Rhian, Bull, Grace, Lacaden, Eleanor, Santiago, Carlos Castro Delgado, Sarah, Farnell-Ward, Elaine, Thorpe, Justine, Somerville, Anne, Williams, Donna, Cummings, Helen, Derrick, Sarah, Brumwell, Claire, Randell, Nicola, Mccann, Emma, Aves, Gillian, Berry, Tamas, Szakmany, Una, Gunter, Paul, Pulak, Nikki, Sarkar, Kerry, Wright, Vitor, Gomes, Jones, Jo, Ruth, Palfrey, Julie, Camsooksai, Abby, Lewis, Antony, Eneas, Ascanio, Tridente, Louise, Barr, Beverley, Thomas, Emma, Parkin, Daniel, Horner, Christian, Frey, Suzanne, Bench, Rachel, Baumber, Phil, Broadhurst, Matthew, Jackson, Lynne, Williams, Michele, Clark, Jonathan, Paddle, Sarah, Bean, Sarah, Buckley, Christopher, Palfreeman, Sophie, Liu, Nicola, Allison, Ben, Attwood, Penny, Parsons, Victoria, Houghton, Sarah Jane Turner, David, Higgins, Egidija, Bielskute, Nicola, Horrigan, Reni, Jacob, Karen, Habgood, Ahmed, Zaki, Amy, Collins, Jenny, Lord, Charalice, Ramiro, Agnieszka, Kubisz-Pudelko, Michelle, Kotze, Helen, Williams, Ihor, Iovenko, Alexander, Tsarev, Arturo, Briva, Gabriela, Mendez, Lena, Napolitano, Magnus, Teig, Jarone, Lee, Gabriel Enrique Rodriguez, Talia, Ben-Jacob, Christopher, Potestio, Timothy, Eng, Dea, Mahanes, Ashish, Khanna, Abhijit, Duggal, Masakatsu, Nananmori, Manuel, Lois, Anna, Diaz, Kunal, Karamchandani, Cheryl, Bealer, Cindy, Barefield, Dorothy, Terry, Pauline, Fivecoat, Olakunle, Idowu, Juan, Cata, Tara, Clesi, Jessica, Peterson, Kevin, Hatton, Jasdeep, Dhaliwal, Dorothee, Mueller, Jing, Tao, Ashley Szabo Eltorai, Stephen, M Pastores, Natalie, Remor, Janel, Salazar, Diane, Barkas, Aaron, Joffe, Christopher, Barnes, Carrie, Sona, Marilyn, Schallom, Jack, Short, Javier, Lorenzo, Ingrid Von Der Osten, Marta, Borkowska, Mireia, Llaurado-Serra, Liesbet, Demarré, Vincianne, Pleitinckx, Cynthia, Xing, Anne-Sophie, Debue, Stefan, Goller, Elsa, Afonso, Gusarov, V, Eugeniya, Larina, Llaurado-Serra, M, Yalim, Dikmen, DecubICUs Study Team, European Society of Intensive Care Medicine (ESICM) Trials Group Collaborators, Muzha, D., Ribas, A.M., Lipovesty, F., Loudet, C., Coyer, F., Eller, P., Mostafa, N., Honoré, P.M., Telleria, V.M., Smajic, J., Nogueira, P.C., Nafees, KMK, Hentchoya, R., Rose, L., Soledad, J., Lin, F., Cardenas, Y., Reyes, A.G., Sustic, A., Mpouzika, M., Vymazal, T., Jensen, H.I., Aguirre-Bermeo, H., Maddison, L., Valta, M., Calvino-Gunther, S., Bloos, F., Adipa, F.E., Koulouras, V., Enamorado, J., Ágoston, Z., Birgisdóttir, H., Gupta, A., Gurjar, M., Kilapong, B., Hashemian, S.M., Martin-Loeches, I., Benbenishty, J., Cortegiani, A., Fletcher, K., Hayashi, Y., Waweru-Siika, W., Abidi, K., Lee, S.M., Hadri, B., Dolgusevs, M., Abillama, F.F., Jovaisa, T., Thix, C., Elhadi, M., Nor, B.M., Ratnam, S., Mazlan, M.Z., Maiyalagan, S., Sánchez-Hurtado, L., Belii, A., Naranpurev, M., Gautam, P., De Lange, D., Parke, R., Ilesanmi, R.E., Shosholcheva, M., Petosic, A., Lind, R., Ffarcsi, M.H., Bogarin, J., Hernandez, A.M., Mikaszewska-Sokolewicz, M., Sousa, B., Tomescu, D., Sandesc, D., Twagirumugabe, T., Gusarov, V., Ebaid, M., Jankovic, R., Slobodianiuk, G., Martonova, A., Knafelj, R., Mer, M., Maseda, E., Panka, B., Schefold, J.C., Joelsson-Alm, E., Trongtrakul, K., Merritt-Charles, L., Besbes, L.O., Dikmen, Y., Zgrzheblovska, L., Fielding, M., Rubulotta, F., Khanna, A.K., Saager, L., von der Osten, I., Greca, A., Cani, A., Xhindi, N., Hyska, G., Pinto, S., Alves, P., Esposito, R., Valgolio, E., Minope, JTS, Abdala, A., Ayala, M., Bravo, S., Bantar, A., Delgado, P., Badariotti, G., Lipovestky, F., Diaz, A., Saul, P., Setten, M., Aucapina, A., Acosta, Y., Gonzalez, V., Camputaro, L., Baccaro, F., Villa, R., Mastantuono, M., Dean, E., Rostello, O.F., Brizuela, P., Bartoli, J.R., Guereschi, M., Quiroga, C., Putruele, S., Villegas, P., Curilen, V., Fernandez, R., Nocheretti, M.G., Escalante, R.G., Loudet, C.I., Fernandez, S., Gonzalez, A.L., Alvarez, G.A., Iglesias, F., Chaparro, S., Zakalik, G., Pagella, G., Baini, M., Campos, P.A., Sabbag, I., Schmukler, A., Fonseca, I.P., Alvarez, G.M., Ramirez, M., Tapia, F., Bascary, C.A., Del Valle Gimenez, G., Bertoletti, F.P., Milioto, E., Bonsignore, PJM, Fernandez, M.A., Smith, J., Chimunda, T., Thompson, L., Maguire, T., Chaboyer, W., Watts, S., Mitchell, M., Powell, M., Lye, I., Parsons, L., Baker, N., Reynolds, C., Thompson, A., Masters, K., Sosnowski, K., Morrison, L., Leslie, G.D., Lakshmanan, R., Tabah, A., Brown, W., McDowell-Skaines, S., McLucas, A., Smith, C., Tallot, M., Jones, S., Barakat-Johnson, M., Leong, T., Butcher, R., Martin, K., Douschan, P., von Lewinski, D., Schmutz, R., Kolussi, U., Salman, F., Ateya, Z., De Decker, K., Van Regenmortel, N., Jans, A., Wijnands, P., Coremans, S., Honore, P.M., De Bels, D., Depuydt, T., Paillet, C., Jacquet, L.M., Swinnen, W., Hannes, F., Mergeay, M., Van de Velde, S., Allaert, S., Hoste, P., Borin, C., Balon, S., Fraipont, V., Biston, P., De Schryver, N., Dugernier, T., Van Cotthem, I., de Almeida, A.O., Jorge, S.A., Becker, D., Schmidt, R.C., Oliveira, E., Ramalho, A., Mazocoli, E., Fioretti, A., Barros, E., Serpa, L., Bianchini, S., Campanili, T., Pantaleao, T., Garcia, P.C., Ronchini, ALV, Santos, R., Manap, NBA, Bagshaw, S., Carney, D., Davidow, J., Rokosh, E., Laizner, A.M., Smith, S., McQuirter, M., Kampayana, B.S., Favre, R., Sills, M., Dallaire, J., Becker, C., Microys, S., Bowes, B., Lajeunesse, J., Ghosh, R., Baptiste-Savoie, J., Raizman, R., Suen, G., Taghavi, N., Smith, O., Fielding, C., Canales, J., Molina, P., Chaparro, J., Sepulveda, M.I., Zamorano, MJF, Rocha, P., Villanueva, X., Araya, P., Dayan, M., Avalos, F., Li, X., Liu, Y., Chen, X., Jiang, Z., Yang, J., Chen, J., Yang, L., Wang, K., Gao, J., Fang, X., Zhao, R., Xia, X., Liu, H., Li, J., Wang, H., Meng, G., Di, Y., Wang, D., Zhao, R.H., Hu, L.P., Peipei, X., Jiao, Q.F., Wang, H.Y., Xia, C.J., Ye, M., Wan, Y., Wang, W., Ding, Y., Ren, A., Gao, Y., Li, Q., Du, G., Shen, Y., Li, N., Yuan, C., Tan, L., Lin, Q., Guo, H., Yan, H., Xu, X., Zhang, W., Liang, J., Zhang, L., Tian, E., Zhao, Q., InSu, L., Dong, J., Gu, Y., Zhao, L., Qiao, H., Tuo, L., Lv, M., Zhu, J.Y., Zhu, J., Wei, Y., Liu, M., He, Y., Cheng, J., Liu, J., Jia, N., Wei, D., Wu, X., Duan, H., Lin, D., Liang, Q., Luo, X., Xiong, Y., Huang, R.F., Fu, J., Zan, T., Shi, Z., Long, Y., Lei, Y., Liu, X., Yumei, C., Wang, L., Zhang, Y., Xu, Y., Cheng, X., Zhijuan, W., Sun, C., Song, J., Wang, Y., Yuan, Y., Huang, Q., Yang, F., Wu, Y., Bai, X., Zheng, H., Song, M., Sun, Y., Li, Z., Luo, F., Li, L.C., Zhang, G., Xiao, L., Yu, T., Gao, G., Wei, W., Wang, F., Han, T., Li, T., Zeng, Q., Zeng, J.M., Pan, F., Wang, J., He, G., Chen, H., Zhang, F., Chao, Y., Chunhua, G., Yao, X., Bai, D., Liu, L., Liang, X., Zhang, N., Zhang, A., Hu, X., Zhang, H., Wang, R., Tak, P.S., Ho, S.W., Jiang, Q.X., Ding, X., Hong, L., Miao, L., Feng, Z., Huang, L., Wu, J., Guo, J., Zhang, B., Ma, C., Han, Y., Liu, C., Ding, M., Luan, L., Zheng, J., Lv, S., Jiang, S., Cao, W., Xue, X., Liu, G., Wei, X., Jiang, Y., Yao, Z., Gao, L., Zhao, W., Jiang, M., Hao, J., Zhang, J., Song, C., Chen, F., Wang, S., Hu, L., Cao, D., Wan, J., Wang, X., Shao, H., Zhang, Z., Cui, X., Fan, L., Yu, M., Li, B., Li, C., Chen, W., Li, Y., Zhigang, Z., Yuchen, W., Mu, C., Zhu, G., Bo, Q., Li, L., Chen, M., Jiang, J.H., Yin, H., Pang, X., Gong, Y.Y., Yang, S., Yan, X., Zheng, X., Lei, D., Lei, L., Guo, Y., Yu, J., Sun, W., Bi, A., Li, W., Ni, D., Wu, Z., Song, B., Fei, Q., Xiaoyan, Y., Ran, Q., Xixi, L., Jiao, X., Ji, H., Zhiping, S., Hong, M., Jianhong, M., Hao, Y., Yin, L., Hui, C., Ju, W., Huo, Y., Chen, L., Yan, Y., Bao, G., Cao, Y., Xu, L., Guixiang, J., Zhao, H.M., Huang, X., Dai, Z., Jian, Y., Tian, Z., Cao, Z.Q., Li, M., Ouyang, F., Ma, F., Jin, W., Ge, L., Wu, S., Yuan, W., Chen, T., Shi, G., Chen, Z., Liu, K., Lin, X., Yuemen, L., Lijuan, S., Tian, X.F., Dong, Y., Bocui, N., Wang, G., Zhao, Y., Yang, Q., Hu, R.L., Li, X.Q., Yu, Z.J., Yao, Y., Deng, X., Xiao, Y., Xie, Y., Yang, Y., Yang, H., Zhou, Y., Xiao, M., Tian, Y., Gama, LMS, Hernandez, J.S., Caicedo, N., Marin, J., Ochoa, M.E., Gomez, M., Rojas-Suarez, J., Gonzalez, J., Reyes, AJG, Chapeta, E., Orozco, E., Filipović-Grčić, I., Vuković, A., Pečenković, S., Šuput, A., Zivanovic-Posilovic, G., Bozena, A., Udiljak, N., Milic, M., Radivojevic, R.C., Mihaljevic, S., Matas, M., Tonkovic, D., Čuljak, H., Herceg, I., Pavlisa, G., Dobric, M., Beker, T., Adam, V.N., Goranovic, T., Markoulias, C., Mathaios, M., Mylordou, M., Achilleos, E., Kleanthous, P., Kotanidi, V., Foka, M., Charalabous, I., Alexandrou, A., Georgiou, M., Patsalos, A., Zepoy, S., Constantinou, C., Piza, P., Wiborg, E., Bruhn, L., Kaasby, K., Pedersen, K.R., Mikkelsen, S., Collet, M., Langvad, A., Andresen, H., Fischer, S., Kjærgård, I.E., Jepsen, B., Husted, B., Bestle, M., Kodal, A.M., Hansen, TCB, Pedersen, ASB, Thomsen, T.D., Hoegenhaven, A., From, M., Frandsen, T.M., Henning, G., Hansen, A., Bliksted, I.A., Tamayo, L.M., Mogrovejo, P., Palaez, C., Tutillo, DRM, Hurtado, C.V., García, M.F., Alvarez, D., Guerrero, F., Vasquez, A., Kütimets, M., Tamme, K., Anvelt, E., Dlamini-Sserumaga, L., Löfqvist, C., Lusenius, V., Kauppi, O., Sakki, J.K., Tervo-Heikkinen, T., Kesti, U., Merilainen, M., Karjula, E., Peltomaa, M., Palmu, A., Ahtiala, M., Valta, M.A., Mentec, H., Plantefève, G., Besch, G., Pili-Floury, S., Ledochowski, S., Déserts, MDD, Giacardi, C., Daubin, C., Massard, A., Le Guen, Y., Blanc, A., Mandaroux, S., Günther, S.C., Avogadro, P., Radavidson, A., Turc, J., Jochmans, S., Quintard, H., Boyer, L., Bruel, C., Philippart, F., Montravers, P., Atchade, E., Flessel, N., Chinardet, B., Soulisse, L., Pillard, C., Ngo, D., Bongiorno, B., Heitzler, N., Souppart, V., Gautheret, N., Timsit, J.F., Essardy, F., Fartoukh, M., Mehay, D., Etourneau, F., Farkas, J.C., Beuret, P., Preda, G., De Montmollin, E., Castelain, V., Jaschinski, U., Rothenfusser, M., Kindgen-Milles, D., Dimski, T., Fiedler, C., Heinicke, T., Meybohm, P., Schulze, T., Bota, M., Pelz, S., Odenthal, T., Christ, M., Bösl, K., Chovas, A., Stehr, S., Simon, P., Grotheer, S., Schüppel, S., Schaller, S., Albrecht, L., Stübner, A., Graeser, S., Kolbe, N., Lausch, M., Diers, A., Guenther, U., Riessen, R., Roller, M., Osei, I.P., Kusi-Appiah, A.C., Yakubu, Y.H., Guadi-Gosh, B., Dragoumanis, C., Christofis, C., Kazakos, N., Bastani, S., Martinos, C., Bekos, V., Papanikolaou, M., Papavasilopoulou, T., Efthymiou, A., Chantziara, V., Kyriakoudi, A., Kakaras, N., Diakaki, C., Flevari, A., Nikolaou, C., Katerina, K., Avramopoulou, L., Tsikritsaki, K., Gkiokas, G., Pantiora, E., Katsenos, C., Patsiou, E.C., Alexandropoulou, P., Koutsodimitropoulos, I., Farmakis, E., Nestora, K., Chatzis, M., Kondili, E., Soundoulounaki, S., Mousafiri, O., Lepida, D., Liarmakopoulou, A., Papathanakos, G., Oikonomou, M., Ioannides, P., Papadopoulos, D., Staikos, I., Stafylaraki, M., Raitsiou, B., Mandis, K., Ravani, I., Kourelea, S., Efthimiou, A., Thoma, G., Bakas, A., Psarulis, K., Anisoglou, S., Papageorgiou, E., Michailidou, E., Tholioti, T., Lavrentieva, A., Sourla, E., Spyropoulou, A., Pantelas, N., Stalika, KMM, Georgakas, I., Karathanou, A., Tsikriki, S., Dimoula, A., Kanakaki, S., Vakalos, A., Pagioulas, K., Enamorado, J.E., Nardai, G., Hawchar, F., Blondal, A., Rygvadottir, B., Jonasdottir, R.J., Birgisdottir, H., Shah, B., Kaushik, S., Tripathy, S., Singh, M., Agarwal, S., Gupta, M., Ahmad, M., Mangal, K., Bhargava, V., Kushare, V., Jha, S., Bhakhtiani, L., Kamal, M., Baronia, A., Susanti, A., Lestari, M.I., Zulkifli, Z., Baskoro, W., Zand, F., Zarei, F., Mahmoodpoor, A., Heidari, F., Jafaraghaee, F., O'Shea, A., O'Shea, F., O'Donnell, C., Craig, G., Fitzpatrick, G., Dunne, L., Hastings, J., Marsh, B., Cody, C., Campbell, E., Doyle, D., Pacturanan, M., Sheehan, C., Carey, A., Carter, C., Mulvey, R., Finn, DOR, Motherway, C., Walsh, A., Kehoe, J., Delossantos, S., Lalor, J., O'Nuallain, S., Behan, H., McPherson, S., Corcoran, A., Gordon, P., Rooney, G., Levy, D., Azencot, M., Gurevich, V., Lavy, A., Bendelari, V., Marconi, R., Barone, A., Gatti, C., Giampaoletti, A., Borgognoni, C., Ghioldi, D.M., Raimondo, A., Castiglione, G., Bruno, A.V., Rubulotta, G., Mo, A., Corso, A., Girianni, S., Bruni, A., Garofalo, E., Maggiore, S.M., Di Risio, A., Calamai, I., Spina, R., Spadaro, S., Volta, C.A., Cotoia, A., Mirabella, L., Maulicino, L., Abregal, G., Donvito, M., D'Ambrosio, P., Binda, F., Adamina, I., Galazzi, A., Negro, A., Vaschetto, R., Capuzzi, F., Boschetto, M., Stivanello, L., Bonaccorso, L., Megna, C., Iozzo, P., Rizzo, A., Scire, G., Taibi, M.R., Tranello, F.P., Manzo, A., Traina, L., Pastore, B., Quaini, A., Giusti, G.D., Montaldi, G., Piergentili, F., Mancini, F., Casaioli, S., Uccelli, F., Guarracino, F., Onelli, A., Di Gravio, V., Cossu, M., Matrona, O., Rocco, M., Alampi, D., Dellafiore, F., Ranalli, F., Bossolasco, M., Brizio, E., Migliorino, P., Cortellazi, P., Rosati, M., D'Ambrosio, F., Quagliotto, C., Roman-Pognuz, E., Peratoner, A., De Rosa, S., Martin, M.A., De Sanctis, F., Ciorba, P., Toppin, P., Harding-Goldson, H., Taito, S., Shime, N., Yamamoto, R., Kanda, F., Hirao, A., Egi, M., Noguchi, A., Hashimoto, S., Aya, U., Sakuramoto, H., Ohuchi, A., Kataoka, J., Maruyama, K., Nakayama, I., Nishime, Y., Fujimoto, K., Takahashi, K., Tsujimoto, M., Shimizu, M., Tole, E., Correia, M.C., Kim, J.H., Park, S., Kim, K.C., Baek, J., Bae, J.M., Park, S.Y., Park, T.S., Lee, H.B., Park, J., Yeon-Joo, L., Young-Jae, C., Jeon, K., Kim, S.C., Lee, J., Chee, H.K., Huh, J.W., Sim, Y.S., Kim, J., Chang, Y., Ahn, J.J., Kang, B.J., Lee, W.Y., Lee, S.J., Baftiu, N., Krastins, I., Stiban, S., Feghaly, M.E., Gharios, E., Merheb, M., Benlamin, M., Khaled, A., Belkhair, W.A., Tabib, M., Ashour, F., Elhadi, A., Tababa, OWE, Khaled, T., Alkhumsi, SIR, Alshrif, A.I., Aboufray, A.A., Alabuzidi, A., Triki, A.R., Elgammudi, M., Zahra, H.B., Soula, E., Al-Alawi, MMS, Ahmed, H., Ghula, MAA, Vosylius, S., Mouton, L., Rastegar, T., Sertznig, C., Martin, G., Theisen, C., Ferretti, C., Gils, F., Gallion, M., Zainudin, A., Bahrin, LKK, Deva, S.R., Rahim, AHA, Wahab, S., Hassan, WNW, Ismail, WNW, Ali, M.N., Khoo, T.M., Samat, N.M., Tong, JMG, Adib, NAN, Nor, MBM, Ismail, N., Sulaiman, S.R., Foong, K.W., Alias, A., Hua, N.P., Zermeno, J.M., Blanco, D., Duran, K., Nava, CLL, Nandyelly, SJR, Sanchez-Hurtado, L.A., Tejeda-Huezo, B., Del Moral Armengol, M., Nava, LPA, Herrera, J.G., de Anda, GFV, Gallegos-Perez, H., Hernandez-Sanchez, N., Hernandez-Ponce, L., Gorordo-Delsol, L., Hernandez-Romero, M., Gomez, S., Molinar, F., Ñamendys-Silva, S.A., Romero-Gonzalez, J.P., Gonzalez, D., Landaverde, A., Sosa, M.Á., Navarro, B., de Molina Serrano, JIR, Iburrigarro, S.R., Ibarra, A., Aguirre, J., Martinez-Gonzalez, M., Padilla, NRC, Pineda, AAV, Villafuerte, MVE, Herrera, MOG, Baasanjav, B., Hachimi, A., Elkhayari, M., Dendane, T., Subedi, N.B., Pathak, S.D., Manandhar, M., Van Gulik, L., Van Den Brink, M., Van Vliet, P., Gerretsen, B., Van Den Berg, L., De Haan, M., Tuinstra, B., Kuijpers, P., Reijntjens, J., Vermeijden, J.W., Rinket, M., Vanroest, M., Reidinga, A., Loef, B., Dieperink, W., Onrust, M., Dormans, T., Bormans, L., Koopmans, M., Gerritsen, R.T., Van Den Elst, A., Evers, M., Oiting, O., Wilting, R., Ramaker, B., van der Kuil, M., Fijen, J.W., Haas, L., Haringman, J., Newby, L., Gilder, E., Hacking, D., Dagooc, R., Song, R., Waibel, H., Dawn, F., Rapley, J., Chadwick, L., Chapman, C., Crone, P., Albrett, J., Marko, P., Goodson, J., Browne, T., Whitticase, R., Davidson, C., Judd, H., Owens, D., Onyeka, T., Ugwu, I., Ilesanmi, R., Adejumo, P.O., Owojuyigbe, A., Adenekan, A., Uba, S., Chime, C., Jibrin, D., Sankey, B.J., Adekola, O., Olanipekun, S., Shosolcheva, M., Gievski, V., Kartalov, A., Naumovski, F., Kuzmanovska, B., Trposak, A., Bogoevska-Miteva, Z., Rosalia, R., Olsen, B.F., Sjobo, B., Jensen, K.D., Sykehus, D., Johansen, B.F., Straede, E., Johansen, E., Finnstrom, I.J., Toellefsen, A., Ostenjo, H., Bjorgen, H., Bratsberg, B., Kristoffersen, E., Skorstad, E.M., Hansen, S., Vullum, S., Lunde, G.A., Arntsen, W., Lund, M., Akselsen, G.R., Monstad, K.R., Stenset, A., Haugom, H., Monsen, B., Høgvall, L., Trudvang, S., Galaaen, B., Malmin, S.K., Andersen, M.H., Hargott, R.F., Andersen, Y., Steffenak, E., Nyhus, M., Meland, B., Hashmi, M., Rivas, N., Maidana, E., de Jesús Ortiz, A., Cabral, DMB, Simi, M., Aponte, C., Rivas, J.C., Gill, S., Garcia, A., Alvarenga, G., Cespedes, L., Perez, H., Moreira, M.L., Canete, F., Gonzalez, R., Monges, N., Coman, M., Pederzani, M., Franco, N., Aganon, F., Martinez, R., Noblezada-Uy, D., Ellazar, C.G., Cerezo, F.D., Palo, J.E., Aperocho, CAJ, Isanan, M., Tubacka, M., Jasiewicz, P., Czuczwar, M., Borys, M., Gutysz-Wojnicka, A., Glinka, L., Gawda, R., Bilawicz, J., Cabrita, P., Vieira, J., Figueiredo, M.F., Pinheiro, C.M., Antunes, N., Pedro, L., Ferreira, F., Parente, I., Varela, M., Fernandes, 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Kushare V., Jha S., Bhakhtiani L., Kamal M., Baronia A., Susanti A., Lestari M.I., Zulkifli Z., Baskoro W., Zand F., Zarei F., Mahmoodpoor A., Heidari F., Jafaraghaee F., O'Shea A., O'Shea F., O'Donnell C., Craig G., Fitzpatrick G., Dunne L., Hastings J., Marsh B., Cody C., Campbell E., Doyle D., Pacturanan M., Sheehan C., Carey A., Carter C., Mulvey R., Finn D.O.C.R., Motherway C., Walsh A., Kehoe J., Delossantos S., Lalor J., O'Nuallain S., Behan H., McPherson S., Corcoran A., Gordon P., Rooney G., Levy D., Azencot M., Gurevich V., Lavy A., Bendelari V., Marconi R., Barone A., Gatti C., Giampaoletti A., Borgognoni C., Ghioldi D.M., Raimondo A., Castiglione G., Bruno A.V., Rubulotta G., Mo A., Corso A., Girianni S., Bruni A., Garofalo E., Maggiore S.M., Di Risio A., Calamai I., Spina R., Spadaro S., Volta C.A., Cotoia A., Mirabella L., Maulicino L., Abregal G., Donvito M., D'Ambrosio P., Binda F., Adamina I., Galazzi A., Negro A., Vaschetto R., Capuzzi F., Boschetto M., Stivanello L., Bonaccorso L., Megna C., Iozzo P., Rizzo A., Scire G., Taibi M.R., Tranello F.P., Manzo A., Traina L., Pastore B., Quaini A., Giusti G.D., Montaldi G., Piergentili F., Mancini F., Casaioli S., Uccelli F., Guarracino F., Onelli A., Di Gravio V., Cossu M., Matrona O., Rocco M., Alampi D., Dellafiore F., Ranalli F., Bossolasco M., Brizio E., Migliorino P., Cortellazi P., Rosati M., D'Ambrosio F., Quagliotto C., Roman-Pognuz E., Peratoner A., De Rosa S., Martin M.A., De Sanctis F., Ciorba P., Toppin P., Harding-Goldson H., Taito S., Shime N., Yamamoto R., Kanda F., Hirao A., Egi M., Noguchi A., Hashimoto S., Aya U., Sakuramoto H., Ohuchi A., Kataoka J., Maruyama K., Nakayama I., Nishime Y., Fujimoto K., Takahashi K., Tsujimoto M., Shimizu M., Tole E., Correia M.C., Kim J.H., Park S., Kim K.C., Baek J., Bae J.-M., Park S.Y., Park T.S., Lee H.B., Park J., Yeon-Joo L., Young-Jae C., Jeon K., Kim S.C., Lee J., Chee H.K., Huh J.W., Sim Y.S., Kim J., Chang Y., Ahn J.-J., Kang B.J., Lee W.-Y., Lee S.J., Baftiu N., Krastins I., Stiban S., Feghaly M.E., Gharios E., Merheb M., Benlamin M., Khaled A., Belkhair W.A., Tabib M., Ashour F., Elhadi A., Tababa O.W.E., Khaled T., Alkhumsi S.I.R., Alshrif A.I., Aboufray A.A., Alabuzidi A., Triki A.R., Elgammudi M., Zahra H.B., Soula E., Al-Alawi M.M.S., Ahmed H., Ghula M.A.A., Vosylius S., Mouton L., Rastegar T., Sertznig C., Martin G., Theisen C., Ferretti C., Gils F., Gallion M., Zainudin A., Bahrin L.K.K., Deva S.R., Rahim A.H.A., Wahab S., Hassan W.N.W., Ismail W.N.W., Ali M.N., Khoo T.M., Samat N.M., Tong J.M.G., Adib N.A.N., Nor M.B.M., Ismail N., Sulaiman S.R., Foong K.W., Alias A., Hua N.P., Zermeno J.M., Blanco D., Duran K., Nava C.L.L., Nandyelly S.J.R., Sanchez-Hurtado L.A., Tejeda-Huezo B., Del Moral Armengol M., Nava L.P.A., Herrera J.G., de Anda G.F.V., Gallegos-Perez H., Hernandez-Sanchez N., Hernandez-Ponce L., Gorordo-Delsol L., Hernandez-Romero M., Gomez S., Molinar F., Namendys-Silva S.A., Romero-Gonzalez J.P., Gonzalez D., Landaverde A., Sosa M.A., Navarro B., de Molina Serrano J.I.R., Iburrigarro S.R., Ibarra A., Aguirre J., Martinez-Gonzalez M., Padilla N.R.C., Pineda A.A.V., Villafuerte M.V.E., Herrera M.O.G., Baasanjav B., Hachimi A., Elkhayari M., Dendane T., Subedi N.B., Pathak S.D., Manandhar M., Van Gulik L., Van Den Brink M., Van Vliet P., Gerretsen B., Van Den Berg L., De Haan M., Tuinstra B., Kuijpers P., Reijntjens J., Vermeijden J.W., Rinket M., Vanroest M., Reidinga A., Loef B., Dieperink W., Onrust M., Dormans T., Bormans L., Koopmans M., Gerritsen R.T., Van Den Elst A., Evers M., Oiting O., Wilting R., Ramaker B., van der Kuil M., Fijen J.-W., Haas L., De Lange D., Haringman J., Newby L., Gilder E., Hacking D., Dagooc R., Song R., Waibel H., Dawn F., Rapley J., Chadwick L., Chapman C., Crone P., Albrett J., Marko P., Goodson J., Browne T., Whitticase R., Davidson C., Judd H., Owens D., Onyeka T., Ugwu I., Ilesanmi R., Adejumo P.O., Owojuyigbe A., Adenekan A., Uba S., Chime C., Jibrin D., Sankey B.J., Adekola O., Olanipekun S., Shosolcheva M., Gievski V., Kartalov A., Naumovski F., Kuzmanovska B., Trposak A., Bogoevska-Miteva Z., Rosalia R., Olsen B.F., Sjobo B., Jensen K.D., Sykehus D., Johansen B.F., Straede E., Johansen E., Finnstrom I.J., Toellefsen A., Ostenjo H., Bjorgen H., Bratsberg B., Kristoffersen E., Skorstad E.M., Hansen S., Vullum S., Lunde G.A., Arntsen W., Lund M., Akselsen G.R., Monstad K.R., Stenset A., Haugom H., Monsen B., Hogvall L., Trudvang S., Galaaen B., Malmin S.K., Andersen M.H., Hargott R.F., Andersen Y., Steffenak E., Nyhus M., Meland B., Hashmi M., Rivas N., Maidana E., de Jesus Ortiz A., Cabral D.M.B., Simi M., Aponte C., Rivas J.C., Gill S., Garcia A., Alvarenga G., Cespedes L., Perez H., Moreira M.L., Canete F., Gonzalez R., Monges N., Coman M., Pederzani M., Franco N., Aganon F., Martinez R., Noblezada-Uy D., Ellazar C.G., Cerezo F.D., Palo J.E., Aperocho C.A.J., Isanan M., Tubacka M., Jasiewicz P., Czuczwar M., Borys M., Gutysz-Wojnicka A., Glinka L., Gawda R., Bilawicz J., Cabrita P., Vieira J., Figueiredo M.F., Pinheiro C.M., Antunes N., Pedro L., Ferreira F., Parente I., Varela M., Fernandes F., Martins C., Viveiros A., Cavaco R., Rita C.S., Dias S., Feranandes A.M., Silva P., Nunes C., Cabral J., Pires F., Ferreira H., Santos J., Pinto V.M.V., Bispo B.M., Ferreira A., Molinos E., Lafuente E., Gregorio R., Costa H., Lima A., Ferreira S., Seromenho V., Luis E., Valerio I., Cesar H., Tavares A., Alsheikhly A.S., Mahmood S., Guran C.T., Moise A., Filipescu D.C., Luchian M., Popescu M., Scutariu M.A., Petrisor C., Hagau N., Grigoras I., Patrichi T., Gusarev V., Pivkina A., Kulakov V., Ignatenko O., Kovaleva J., Zhivotneva T., Zhedaeva M., Matiushkov N., Ershova O., Egorova N., Khoronenko V., Baskakov D., Sergeev D., Piradov M., Grishina L., Magomedov M., Zuev E., Gorokhovatsky U., Leonova A., Fadeeva L., Belskiy V., Galishevskiy D., Zubareva N., Tribulev M., Zueva O., Kiselev A., Kamenshchikov N., Tokareva E., Petrushin M., Starchenko I., Nshimyumuremyi I., Muhizi J., Buregeya E., Nzarora J., Assiri A., Ebaid M.S., Almekhlafi G., Mandourah Y., Velickovic J., Velickovic D., Jovanovic B., Hadzibegovic A., Stefanovic B., Misic V., Bumbasirevic V., Rajkovic M., Stojanovic M., Gavrilovic S., Stanojevic M., Yaghi A., Turcan A., Firment P., Rabarova D., Lancaricova D., Vlaovic J., Groznik M., Lukic M., Perme J., Sostaric M., Umek N., Mirkovic T., Dolenc S., Fister M., Zorko N., Markota A., Yeni N.P., Jali P., Schmollgruber S., Syed M.R., Parag N., Wise R., Galiana M., Navarro J.A., De Pablo A.M., Albert P., Martinez P., Mendiara Y., Garcia B., Llinas A.A., Riveiro M., Gallart E., Riera A., Sanz M., Salo S., Lajara M.A.G., Nieto M.V., Garcia R., Pena J.M.G., Gorgolas M.C., Isasi M.A., Sierra R., Gordo F., Conejo I., Salva-Costa V., Garzon-Tovar C., Lospitao S., Gutierrez P., Girona M., Adamuz J., Olivares P.G., de Ceballos J.P.G., Tirado C., De Wit I., Polo A.B.C., del Mar Diaz Salcedo M., Ripolles-Melchor J., Martinez-Hurtado E., Alvarez J.D., Arcas M.L.B., Gonzalez J.I.T., de la Ventana A.B.S., Calleja P.L.-A., Alvarez R.G., Zamora P.S., Guerrero A.O., Cosano R., Perez-Vacas J., Campos-Perez M., Barreiro E.M., Sanchez L.C., Diaz M.G., Jimenez R., Del Rio Cabajo L., Muriel D.S., Alonso H.F., Fernandez A.W., Pinan I.S., Albaiceta G.M., Fernandez M.C.I., Abos F.J.S., Monedero P., Chueca R.M., Aguirre L.G., Manosa S.C., Luque C.P., Calpe N., Losilla M.R., Fores M.T., Farre O., Fernandez O., del Rosario Villar Redondo M., Arteta Arteta D.S., Sanchez M.A.H., Espinosa C.P., Reyes L.M., Domenech L.C., Guillen C.V., Alvarez J.T., del Cotillo M., Barrueco-Francioni J.E., Conde B.B., Blanco M.P.S., Blasco M.L., Clement A.I., Hurtado C., Sanz L.C., Perez-Torres D., Prol-Silva E., Pereira J., Gonzalez I.A., Cano A.E., Nunez C.R., Fernadez I.L., Fernandez A.A.M., Del Bosque Diez R., Hilario B., Zalba-Etayo B., Pascual-Bielsa A., Banwarie P., Nahar D., van Axel A., Boedjawan N.N., Jansson E.B., Malvemyr A.-S., Johansson L., Sandberg U., Tingsvik C., Mattsson G., Lof G., Spangfors M., Ringdal M., Geijer S., Orvelius L., Hylen M., Lagerhall C., Akerman E., Hellkvist V.H., Mickelsson U., Wahlbom E., Larsson I.-M., Wallin E., Boroli F., Ory S., Jong M.L., Dullenkopf A., Lang M., Fleury Y., Maus M., Ben-Hamouda N., Fishman A., Hsu M.Y., Chang S.C., Trongtratul K., Sawawiboon C., Morakul S., Khwannimit B., Singh K., Ventour D., Figaro-Barclay D., Sankar-Maharaj S., Mebazaa M.S., Kamoun S., Elatrous S., Besbes L., Abroug F., Naija W., Elhechmi Y.Z., Sellami W., Hajjej Z., Merhabene T., Talik I., Kuscu O.O., Dilek O., Zerman A., Dal H.C., Turan S., Aydemir S., Yilmaz H., Calili D.K., Izdes S., Cengiz M., Gumus A., Tasdemir B., Kagnici A., Ay M., Ay S.A., Caliskan G., Akbas T., Balbay A.O., Efe S., Inal V., Elay G., Karabacak P., Ozserezli B., Senturk E., Demirkiran O., Bozbay S., Erdogan E., Akker M., Peker N., Ozgultekin A., Serin S.O., Turan C., Karaoren G., Goksu S., Karakurt S., Arikan H., Gul F., Cinel I., Kara I., Undar H.N., Bayraktar Y.S., Celik J.B., Tokur M.E., Aydin D.T., Yildiz I., Ozcan B., Erdivanli B., Eroglu A., Akdag D., Unlu N., Dungca A., Ali A., Thankamma B., Reyes P.E., John S., Rajendran A., Ahmad F.K.E., Smiley K.A., Hojden S., Miller M.T., Das Sasidharan Nair V., Antonio M.G.S., Qawasmeh K.A., Shawish S.A., Twiggs H., Rosado I., Babych V., Morren F., Young C., Vaughan-Jones N., Harris S., Burns K., Georgiev C., Shayamano R., Kerslake I., Creber P., Vochin A., O'Brien C., Caddell P., Hagan S., Hughes M., Torlinski T., Sherwin J., Kannan S., Markham A., Lebon R., Cupitt J., Cranshaw J., White N., Marriott V., Milner W., Groba C.B., Azoia J., Polgarova P., George S., Kapoor R., Lynch C., Fox N., Cranmer K., Llewellym T., Matthews K., Maltby L., Ibao J., Boulton K., Jarman R., Baxter K., Raj A.S., Moghal A., White J., Barrowcliffe S., Pulletz M., Ganeshalingam V., Baruah R., Baker H., Woods J., Ei P.P., Ogbeide V., Hayden P., Hughes J., Balasubramanian M., Salberg A., Saha R., Holmquist D., Derbyshire C., Smith N., Stones E., Ademokun J., Legorburo M.S., North S., Brett C., Jaundoo H., Craig J., Whiteley S., Howcroft C., Wilby L., Delve P., Shaw D., Williams K., Welters I.D., McMullen J., Brett S., Flores L., Trueman-Dawkins T., Templeton M., Adams J., Prowle J., Byers H., McDonnell A., Rose B.O., Reece-Anthony R., Mendes L., Vizcaychipi M., Bull R., Lacaden G., Santiago E., Delgado C.C., Farnell-Ward S., Thorpe E., Somerville J., Williams A., Cummings D., Derrick H., Brumwell S., Randell C., McCann N., Aves E., Berry G., Szakmany T., Gunter U., Pulak P., Sarkar N., Wright K., Gomes V., Jones J., Palfrey R., Camsooksai J., Lewis A., Eneas A., Tridente A., Barr L., Thomas B., Parkin E., Horner D., Frey C., Bench S., Baumber R., Broadhurst P., Jackson M., Williams L., Clark M., Paddle J., Bean S., Buckley S., Palfreeman C., Liu S., Allison N., Attwood B., Parsons P., Houghton V., Turner S.J., Higgins D., Bielskute E., Horrigan N., Jacob R., Habgood K., Zaki A., Collins A., Lord J., Ramiro C., Kubisz-Pudelko A., Kotze M., Williams H., Iovenko I., Tsarev A., Briva A., Mendez G., Napolitano L., Teig M., Rodriguez G.E., Ben-Jacob T., Potestio C., Eng T., Mahanes D., Khanna A., Duggal A., Nananmori M., Lois M., Karamchandani K., Bealer C., Barefield C., Terry D., Fivecoat P., Idowu O., Cata J., Clesi T., Peterson J., Hatton K., Dhaliwal J., Mueller D., Tao J., Eltorai A.S., Pastores S.M., Remor N., Salazar J., Barkas D., Joffe A., Barnes C., Sona C., Schallom M., Short J., Lorenzo J., Von Der Osten I., Borkowska M., Demarre L., Pleitinckx V., Xing C., Debue A.-S., Goller S., Larina E., Labeau, S. O., Blackwood, B., Brett, S. J., Deschepper, M., Francois, G., Honore, P. M., Khanna, A. K., Williams, G., Blot, S. I., Ribas, A. M., Telleria, V. M., Nogueira, P. C., Nafees, K. M. K., Reyes, A. G., Jensen, H. I., Adipa, F. E., Agoston, Z., Hashemian, S. M., Lee, S. -M., Abillama, F. F., Nor, B. M., Mazlan, M. Z., Sanchez-Hurtado, L., De lange, D., Ilesanmi, R. E., Ffarcsi, M. H., Hernandez, A. M., Schefold, J. C., Besbes, L. O., Minope, J. T. S., Rostello, O. F., Bartoli, J. R., Nocheretti, M. G., Escalante, R. G., Loudet, C. I., Gonzalez, A. L., Alvarez, G. A., Campos, P. A., Fonseca, I. P., Alvarez, G. M., Bascary, C. A., del Valle Gimenez, G., Bertoletti, F. P., Bonsignore, P. J. M., Fernandez, M. A., Leslie, G. D., Mclucas, A., Jacquet, L. -M., de Almeida, A. O., Jorge, S. A., Schmidt, R. C., Garcia, P. C., Ronchini, A. L. V., Manap, N. B. A., Laizner, A. M., Mcquirter, M., Kampayana, B. S., Sepulveda, M. I., Zamorano, M. J. F., Zhao, R. H., Hu, L. P., Jiao, Q. F., Wang, H. Y., Xia, C. J., Insu, L., Zhu, J. Y., Zhu, J. F., Huang, R. F., Wang, L. L., Song, J. H., Liu, X. M., Li, Z. S., Li, L. C., Zeng, J. M., Hu, X. C., Wang, R. X., Tak, P. S., Ho, S. W., Jiang, Q. X., Huang, L. P., Liu, X. L., Jiang, J. H., Gong, Y. Y., Lei, D. H., Bi, A. P., Zhao, H. M., Cao, Z. Q., Wu, S. F., Tian, X. F., Feng, Z. X., Liu, X. Z., Jiang, Z. X., Wang, G. X., Hu, R. L., Li, X. Q., Yu, Z. J., Yang, Y. X., Gama, L. M. S., Hernandez, J. S., Ochoa, M. -E., Reyes, A. J. G., Filipovic-Grcic, I., Vukovic, A., Pecenkovic, S., Suput, A., Radivojevic, R. C., Culjak, H., Adam, V. N., Pedersen, K. R., Kjaergard, I. E., Kodal, A. M., Hansen, T. C. B., Pedersen, A. S. B., Thomsen, T. D., Frandsen, T. M., Bliksted, I. A., Tamayo, L. M., Tutillo, D. R. M., Hurtado, C. V., Garcia, M. F., Kutimets, M., Lofqvist, C., Sakki, J. -K., Valta, M. A., Plantefeve, G., Deserts, M. D., Gunther, S. C., Timsit, J. -F., Farkas, J. -C., Bosl, K., Schuppel, S., Stubner, A., Osei, I. P., Kusi-Appiah, A. -C., Yakubu, Y. H., Patsiou, E. -C., Stalika, K. M. M., Enamorado, J. E., Jonasdottir, R. J., Lestari, M. I., Finn, D. O. C. R., Mcpherson, S., Ghioldi, D. M., Bruno, A. V., Maggiore, S. M., Volta, C. A., Taibi, M. R., Tranello, F. P., Giusti, G. D., Martin, M. A., Correia, M. C., Kim, J. H., Kim, K. C., Bae, J. -M., Park, S. Y., Park, T. S., Lee, H. B., Kim, S. C., Chee, H. K., Huh, J. W., Sim, Y. S., Ahn, J. -J., Kang, B. J., Lee, W. -Y., Lee, S. J., Feghaly, M. E., Belkhair, W. A., Tababa, O. W. E., Alkhumsi, S. I. R., Alshrif, A. I., Aboufray, A. A., Triki, A. R., Zahra, H. B., Al-Alawi, M. M. S., Ghula, M. A. A., Bahrin, L. K. K., Deva, S. R., Rahim, A. H. A., Hassan, W. N. W., Ismail, W. N. W., Ali, M. N., Khoo, T. M., Samat, N. M., Tong, J. M. G., Adib, N. A. N., Nor, M. B. M., Sulaiman, S. R., Foong, K. W., Hua, N. P., Zermeno, J. M., Nava, C. L. L., Nandyelly, S. J. R., Sanchez-Hurtado, L. A., Nava, L. P. A., Herrera, J. G., de Anda, G. F. V., Namendys-Silva, S. A., Romero-Gonzalez, J. P., Sosa, M. A., de Molina Serrano, J. I. R., Iburrigarro, S. R., Padilla, N. R. C., Pineda, A. A. V., Villafuerte, M. V. E., Herrera, M. O. G., Subedi, N. B., Pathak, S. D., Vermeijden, J. W., Gerritsen, R. T., Fijen, J. -W., Adejumo, P. O., Sankey, B. J., Olsen, B. F., Jensen, K. D., Johansen, B. F., Finnstrom, I. J., Skorstad, E. M., Lunde, G. A., Akselsen, G. R., Monstad, K. R., Hogvall, L., Malmin, S. K., Andersen, M. H., Hargott, R. F., de Jesus Ortiz, A., Cabral, D. M. B., Rivas, J. C., Moreira, M. L., Ellazar, C. G., Cerezo, F. D., Palo, J. E., Aperocho, C. A. J., Figueiredo, M. F., Pinheiro, C. M., Rita, C. S., Feranandes, A. M., Pinto, V. M. V., Bispo, B. M., Lima, A., Alsheikhly, A. S., Guran, C. T., Filipescu, D. C., Scutariu, M. A., Ebaid, M. S., Velickovic, D., Rajkovic, M., Stanojevic, M., Turcan, A., Lancaricova, D., Yeni, N. P., Syed, M. R., Navarro, J. A., De Pablo, A. M., Llinas, A. A., Lajara, M. A. G., Nieto, M. V., Pena, J. M. G., Gorgolas, M. C., Isasi, M. A., Salva-Costa, V., Garzon-Tovar, C., Olivares, P. G., de Ceballos, J. P. G., Polo, A. B. C., del Mar Diaz Salcedo, M., Alvarez, J. D., Arcas, M. L. B., Gonzalez, J. I. T., de la Ventana, A. B. S., Calleja, P. L. -A., Alvarez, R. G., Zamora, P. S., Guerrero, A. O., Barreiro, E. M., Sanchez, L. C., Diaz, M. G., Muriel, D. S., Alonso, H. F., Fernandez, A. W., Pinan, I. S., Albaiceta, G. M., Fernandez, M. C. I., Abos, F. J. S., Chueca, R. M., Aguirre, L. G., Manosa, S. C., Luque, C. P., Losilla, M. R., Fores, M. T., del Rosario Villar Redondo, M., Arteta Arteta, D. S., Sanchez, M. A. H., Espinosa, C. P., Reyes, L. M., Domenech, L. C., Guillen, C. V., Alvarez, J. T., del Cotillo, M., Barrueco-Francioni, J. E., Conde, B. B., Blanco, M. P. S., Blasco, M. L., Clement, A. I., Sanz, L. C., Gonzalez, I. A., Cano, A. E., Nunez, C. R., Fernadez, I. L., Fernandez, A. A. M., Boedjawan, N. N., Jansson, E. B., Malvemyr, A. -S., Lof, G., Spangfors, M., Lagerhall, C., Akerman, E., Hellkvist, V. H., Larsson, I. -M., Jong, M. L., Hsu, M. Y., Chang, S. C., Mebazaa, M. S., Elhechmi, Y. Z., Kuscu, O. O., Dal, H. C., Calili, D. K., Izdes, S., Gumus, A., Tasdemir, B., Kagnici, A., Ay, S. A., Balbay, A. O., Ozserezli, B., Senturk, E., Serin, S. O., Gul, F., Cinel, I., Undar, H. N., Bayraktar, Y. S., Celik, J. B., Tokur, M. E., Aydin, D. T., Yildiz, I., Ozcan, B., Akdag, D., Unlu, N., Reyes, P. E., Ahmad, F. K. E., Smiley, K. A., Miller, M. T., Antonio, M. G. S., Qawasmeh, K. A., Shawish, S. A., Groba, C. B., Raj, A. S., Ei, P. P., Legorburo, M. S., Welters, I. D., Mcmullen, J., Mcdonnell, A., Rose, B. O., Delgado, C. C., Mccann, N., Turner, S. J., Rodriguez, G. E., Eltorai, A. S., Pastores, S. M., Demarre, L., and Debue, A. -S.

Subjects
Male, Original, medicine.medical_treatment, artificial, Critical Care and Intensive Care Medicine, Medical and Health Sciences, Pressure ulcer, law.invention, Decubitus epidemiology, ICU, Morbidity, Mortality, Outcome, Pressure injury, Risk factors, Adult, Aged, Hospital Mortality, Humans, Patient Discharge, Prevalence, Risk Factors, Intensive Care Units, Respiration, Artificial, 0302 clinical medicine, decubitus epidemiology, pressure injury, pressure ulcer, outcome, risk factors, morbidity, mortality, law, Medicine and Health Sciences, adults, Medicine, Simplified Acute Physiology Score, icu, ziekenhuissterfte, Immunodeficiency, intensive care, European Society of Intensive Care Medicine (ESICM) Trials Group Collaborators, mannen, volwassenen, COST, Intensive care unit, STATE, ULCERS, Underweight, medicine.symptom, Life Sciences & Biomedicine, Human, medicine.medical_specialty, risicofactoren, Decubitus epidemiology, ICU, Pressure injury, Pressure ulcer, Outcome, Risk factors, Morbidity, Mortality, pressure injuries, Intensive Care Unit, prevalentie, NO, 1117 Public Health and Health Services, DecubICUs Study Team, 03 medical and health sciences, Critical Care Medicine, Anesthesiology, General & Internal Medicine, Health Sciences, ouderen, Mechanical ventilation, Science & Technology, business.industry, decubitus, Risk Factor, 030208 emergency & critical care medicine, 1103 Clinical Sciences, Odds ratio, medicine.disease, Emergency & Critical Care Medicine, Confidence interval, 030228 respiratory system, Emergency medicine, kunstmatige ademhaling, RISK-FACTORS, business, respiration
Abstract

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347, Funder: Flemish Society for Critical Care Nurses, Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score < 19, ICU stay > 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat.

Published
2021
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33. A Blood-based Polyamine Signature Associated With MEN1 Duodenopancreatic Neuroendocrine Tumor Progression

Author

Rachel S van Leeuwaarde, Hua Zhao, Ehsan Irajizad, Carolina R.C. Pieterman, Johannes F. Fahrmann, Hansini Krishna, Eunice Murage, Jody Vykoukal, Gerlof D. Valk, Jennifer B. Dennison, Lee S. Weinstein, Jaydira Del Rivero, Amanda R. Wasylishen, James Welch, Guillermina Lozano, Samir M. Hanash, Menno R. Vriens, Mary Walter, Daniel M. Halperin, R. R. Wu, Nancy D. Perrier, Sunita K. Agarwal, Jenny E Blau, Kim Anh Do, Mark J C van Treijen, Naris Nilubol, and Christine B. Peterson

Subjects
Adult, Male, Oncology, medicine.medical_specialty, polyamines, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Neuroendocrine tumors, Biochemistry, Young Adult, chemistry.chemical_compound, Endocrinology, Duodenal Neoplasms, Men1 fl/fl Pdx1-Cre Tg mice, Commentaries, Internal medicine, Biomarkers, Tumor, Multiple Endocrine Neoplasia Type 1, Humans, Medicine, MEN1, Online Only Articles, Multiple endocrine neoplasia, Aged, Retrospective Studies, dpNETs, business.industry, Biochemistry (medical), Disease progression, Cancer, Middle Aged, Prognosis, medicine.disease, United States, Pancreatic Neoplasms, Neuroendocrine Tumors, chemistry, Tumor progression, Case-Control Studies, Disease Progression, Biomarker (medicine), Female, Polyamine, business, AcademicSubjects/MED00250, Follow-Up Studies
Abstract

Context Duodenopancreatic neuroendocrine tumors (dpNETs) frequently occur in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic dpNET is the primary cause of disease-related mortality. There is a need for biomarkers that can identify patients with MEN1-related dpNETs that are at high risk of developing distant metastasis. Polyamines have tumor-promoting roles in several cancer types. Objective We hypothesized that MEN1-dpNET–related disease progression is associated with elevated levels of circulating polyamines. Methods Through an international collaboration between The University of Texas MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht, plasma polyamine levels were assessed using mass spectrometry in 84 patients with MEN1 (20 with distant metastatic dpNETs [patients] and 64 with either indolent dpNETs or no dpNETs [controls]). A mouse model of MEN1-pNET, Men1fl/flPdx1-CreTg, was used to test time-dependent changes in plasma polyamines associated with disease progression. Results A 3-marker plasma polyamine signature (3MP: N-acetylputrescine, acetylspermidine, and diacetylspermidine) distinguished patients with metastatic dpNETs from controls in an initial set of plasmas from the 3 participating centers. The fixed 3MP yielded an area under the curve of 0.84 (95% CI, 0.62-1.00) with 66.7% sensitivity at 95% specificity for distinguishing patients from controls in an independent test set from MDACC. In Men1fl/flPdx1-CreTg mice, the 3MP was elevated early and remained high during disease progression. Conclusion Our findings provide a basis for prospective testing of blood-based polyamines as a potential means for monitoring patients with MEN1 for harboring or developing aggressive disease.

Published
2021

34. Chaperonin‐containing tailless complex polypeptide 1 subunit 6A correlates with increased World Health Organization grade, less isocitrate dehydrogenase mutation, and deteriorative survival of astrocytoma patients

Author

Peng Fu, Peng Lv, Fangcheng Zhang, Wo-Hua Zhao, Yueyun Hu, Xiaobing Jiang, and Hongyang Zhao

Subjects
Male, Microbiology (medical), overall survival, Protein subunit, Clinical Biochemistry, Astrocytoma, CCT6A, World Health Organization, medicine.disease_cause, isocitrate dehydrogenase mutation, law.invention, World Health Organization grade, law, Biomarkers, Tumor, medicine, Humans, Immunology and Allergy, Research Articles, Polymerase chain reaction, Retrospective Studies, Mutation, Messenger RNA, business.industry, Biochemistry (medical), Public Health, Environmental and Occupational Health, Hematology, Middle Aged, Prognosis, medicine.disease, Isocitrate Dehydrogenase, Survival Rate, Medical Laboratory Technology, Isocitrate dehydrogenase, Cancer research, Immunohistochemistry, Female, chaperonin‐containing tailless complex polypeptide 1 subunit 6A, business, Chaperonin Containing TCP-1, Follow-Up Studies, Research Article
Abstract

Objective Chaperonin‐containing tailless complex polypeptide 1 subunit 6A (CCT6A) is reported to be an efficient prognostic biomarker in various cancers, but it is rarely reported in astrocytoma. Thus, this study aimed to evaluate the expression of CCT6A and its correlation with disease features and prognosis in astrocytoma patients. Methods Totally, 198 astrocytoma patients who received surgery treatment were enrolled. CCT6A protein expression was determined in the tumor tissues fixed in formalin and embedded in paraffin (FFEP) by immunohistochemistry (IHC) assay. In addition, 133 out of 198 astrocytoma patients had fresh tumor tissues frozen in the liquid nitrogen for the determination of CCT6A mRNA expression by reverse transcription‐quantitative polymerase chain reaction. Results Sixty‐nine (34.8%), 70 (35.4%), 46 (23.2%), and 13 (6.6%) astrocytoma patients had the CCT6A immunohistochemistry (IHC) score of 0–3, 4–6, 7–9, and 10–12, respectively. CCT6A protein expression was correlated with increased World Health Organization (WHO) grade (P 0.05). Moreover, CCT6A protein high and CCT6A mRNA high were related to shorter accumulating overall survival (OS; both P, Chaperonin‐containing tailless complex polypeptide 1 subunit 6A (CCT6A) is reported to be an efficient prognostic biomarker in various cancers, but it is rarely reported in astrocytoma. Thus, this study aimed to evaluate the expression of CCT6A and its correlation with disease features and prognosis in astrocytoma patients. Totally, 198 astrocytoma patients who received surgery treatment were enrolled. CCT6A protein expression was determined in the tumor tissues fixed in formalin and embedded in paraffin (FFEP) by immunohistochemistry (IHC) assay. In addition, 133 out of 198 astrocytoma patients had fresh tumor tissues frozen in the liquid nitrogen for the determination of CCT6A mRNA expression by reverse transcription‐quantitative polymerase chain reaction. Sixty‐nine (34.8%), 70 (35.4%), 46 (23.2%), and 13 (6.6%) astrocytoma patients had the CCT6A immunohistochemistry (IHC) score of 0–3, 4–6, 7–9, and 10–12, respectively. CCT6A protein expression was correlated with increased World Health Organization (WHO) grade (P 0.05). Moreover, CCT6A protein high and CCT6A mRNA high were related to shorter accumulating overall survival (OS; both P

Published
2021

35. Thalidomide Reduces Activation of Murine Pancreatic Stellate Cells by Inhibiting the TGF-β/Smad Pathway

Author

Peng, Lv, Zhen-Hua, Zhao, Li-Juan, Fan, Jian, Zhang, Pei, Jiang, Qing-Shun, Meng, and Xiu-Guo, Li

Subjects
Male, Mice, Inbred C57BL, Mice, Transforming Growth Factor beta, Pancreatic Stellate Cells, Animals, Angiogenesis Inhibitors, Smad3 Protein, Actins, Collagen Type I, Signal Transduction, Smad7 Protein, Thalidomide
Abstract

The aim of this study was to investigate the effects and mechanism of thalidomide on pancreatic stellate cell (PSC) activation in mice and to find the optimal timing of thalidomide administration.PSCs, isolated from mouse pancreas tissue, were divided into five groups with specific treatments: (A) control PSCs (PSC), (B) PSCs induced by TGF-β1 (PSC+TGF-β1), (C) PSCs induced by TGF-β1 followed by thalidomide (PSC+TGF-β1+Thalidomide), (D) PSCs receiving TGF-β1 and thalidomide simultaneously (PSC+(TGF-β1+Thalidomide)), and (E) PSCs treated with thalidomide only (PSC+Thalidomide). We measured the effects of thalidomide on PSC activation by detecting the expression of α-SMA, collagen type I, and the TGF-β/Smad pathway through quantitative real-time PCR and Western blot analysis.Compared with TGF-β1 alone, thalidomide significantly inhibited PSC activation by reducing α-SMA expression (Thalidomide could repress PSC activation and alleviate fibrosis by regulating the TGF-β/Smad pathway. Preventive use of thalidomide had maximum effect, and there was no evidence for the reversal of the activation of quiescent PSCs.

Published
2021

36. Inhibitor of apoptosis‐stimulating p53 protein protects against inflammatory bowel disease in mice models by inhibiting the nuclear factor kappa B signaling

Author

Hua Zhao, Dongju Long, Shalong Wang, Hongliang Yao, Lianwen Yuan, Yuhong Jiang, Kuijie Liu, Ke Qian, Qianqian Jin, and Yong Kuang

Subjects
0301 basic medicine, Adult, Male, Chemokine, Colon, Immunology, Anti-Inflammatory Agents, Inflammation, Apoptosis, Inhibitor of apoptosis, Inflammatory bowel disease, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, medicine, Immunology and Allergy, Animals, Humans, Colitis, biology, business.industry, Tumor Necrosis Factor-alpha, Dextran Sulfate, NF-kappa B, NF-κB, Middle Aged, medicine.disease, Inflammatory Bowel Diseases, digestive system diseases, Mice, Inbred C57BL, CXCL2, Disease Models, Animal, 030104 developmental biology, chemistry, Trinitrobenzenesulfonic Acid, Cancer research, biology.protein, Cytokines, Tumor necrosis factor alpha, medicine.symptom, ORIGINAL ARTICLES, Tumor Suppressor Protein p53, business, 030215 immunology, Signal Transduction
Abstract

Summary Drugs and therapies available for the treatment of inflammatory bowel disease (IBD) are not satisfactory. Our previous study has established the inhibitor of apoptosis-stimulating p53 protein (iASPP) as an oncogenic regulator in colorectal cancer by forming a regulatory axis or feedback loop with miR-124, p53, or p63. As iASPP could target and inhibit nuclear factor kappa B (NF-κB) activation, in this study the role and mechanism of iASPP in IBD was investigated. The aberrant up-regulation of iASPP in IBD was subsequently confirmed, based on online data sets, clinical sample examinations and 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and dextran sulfate sodium (DSS)-induced colitis mice models. TNBS or DSS stimulation successfully induced colon shortness, body weight loss, mice colon oxidative stress and inflammation. In both types of colitis mice models, iASPP over-expression improved, whereas iASPP knockdown aggravated TNBS or DSS stimulation-caused colon shortness, body weight loss and mice colon oxidative stress and inflammation. Meanwhile, in both types of colitis mice models, iASPP over-expression inhibited p65 phosphorylation and decreased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, C-X-C motif chemokine ligand (CXCL)1 and CXCL2 in mice colons, whereas iASPP knockdown exerted opposite effects.

Published
2021

37. Cavotricuspid isthmus ablation using ablation index in typical right atrial flutter

Author

Zhi-hong Han, Yunlong Wang, Tao Zhang, Hua Zhao, Yongquan Wu, Ye Wang, Xuejun Ren, and Zhuo Liang

Subjects
Male, Cavotricuspid isthmus, Time Factors, Inguinal hematoma, medicine.medical_treatment, Action Potentials, Vena Cava, Inferior, 030204 cardiovascular system & hematology, Single Center, Right atrial, Pulmonary vein, 03 medical and health sciences, Pseudoaneurysm, 0302 clinical medicine, Heart Rate, Recurrence, Risk Factors, Physiology (medical), medicine, Humans, 030212 general & internal medicine, Aged, Retrospective Studies, business.industry, Middle Aged, medicine.disease, Ablation, Treatment Outcome, Atrial Flutter, Catheter Ablation, Feasibility Studies, Female, Tricuspid Valve, Cardiology and Cardiovascular Medicine, Nuclear medicine, business, Atrial flutter
Abstract

Background Ablation index (AI) has been evaluated as guidance quality marker for pulmonary vein isolation, but not for linear ablation of the cavotricuspid isthmus (CTI) for typical right atrial flutter (AFL). We thus studied the feasibility and effectiveness of AI-guided CTI for AFL. Methods Procedural and 6-month outcomes of ablation for AFL were retrospectively compared between consecutive patients undergoing either AI-guided ablation of CTI (n = 43; AI target of 500 for anterior 2/3 segments and 400 for posterior 1/3 segments) or contact force (CF)-guided ablation (n = 42) at a single center. Each Visitag dataset from all patients in each group was analyzed. Results AI guidance vs CF guidance was associated with: higher first-pass conduction block of CTI (93.0% vs 76.2%, P = .03) with similar ablation time; similar acute spontaneous CTI reconnection 2.3% vs 9.5%, P = .343); fewer radiofrequency (RF) applications (10.1 ± 2.8 vs 11.5 ± 3.0, P = .031) needed to achieve CTI directional block; significantly higher mean ablation time, impedance drop, force time integral and AI and similar mean CF and power of each VisiTag point. One inguinal hematoma and one pseudoaneurysm developed in the AI and CF groups, respectively. Recurrent AFL was recorded in two (4.7%) AI-group patients and four (9.5%) CF-group patients (P = .650). Conclusion AI-guided ablation of CTI line for AFL appears feasible and effective with similar ablation time, fewer RF applications, a higher rate of first-pass conduction block, and no additional complications.

Published
2019

38. Apatinib Combined with Local Irradiation Leads to Systemic Tumor Control via Reversal of Immunosuppressive Tumor Microenvironment in Lung Cancer

Author

Chenxi Hu, Xiao-wei Geng, Yong Liu, Lijun Liang, Youyou Xia, Lei Wang, Guoqing Gu, Feng-hua Zhao, Jiayan Fei, Yiliyar Ahongjiang, Ting Chen, Jie Dong, Xiaodong Jiang, Yixuan Wen, and Kaiyuan Hui

Subjects
0301 basic medicine, PD-L1, Male, Cancer Research, Lung Neoplasms, Pyridines, medicine.medical_treatment, Abscopal effect, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Anti-angiogenesis, Carcinoma, medicine, Tumor Microenvironment, Animals, Humans, Apatinib, Lung cancer, Protein Kinase Inhibitors, Tumor microenvironment, biology, business.industry, medicine.disease, Primary tumor, Combined Modality Therapy, Radiation therapy, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Original Article, Female, Stereotactic ablative radiotherapy, business
Abstract

PurposeThis study aimed to investigate the potential systemic antitumor effects of stereotactic ablative radiotherapy (SABR) and apatinib (a novel vascular endothelial growth factor receptor 2 inhibitor) via reversing the immunosuppressive tumor microenvironment for lung carcinoma.Materials and MethodsLewis lung cancer cells were injected into C57BL/6 mice in the left hindlimb (primary tumor; irradiated) and in the right flank (secondary tumor; nonirradiated). When both tumors grew to the touchable size, mice were randomly divided into eight treatment groups. These groups received normal saline or three distinct doses of apatinib (50 mg/kg, 150 mg/kg, and 200 mg/kg) daily for 7 days, in combination with a single dose of 15 Gy radiotherapy or not to the primary tumor. The further tumor growth/regression of mice were followed and observed.ResultsFor the single 15 Gy modality, tumor growth delay could only be observed at the primary tumor. When combining SABR and apatinib 200 mg/kg, significant retardation of both primary and secondary tumor growth could be observed, indicated an abscopal effect was induced. Mechanism analysis suggested that programmed death-ligand 1 expression increased with SABR was counteract by additional apatinib therapy. Furthermore, when apatinib was combined with SABR, the composition of immune cells could be changed. More importantly, this two-pronged approach evoked tumor antigen–specific immune responses and the mice were resistant to another tumor rechallenge, finally, long-term survival was improved.ConclusionOur results suggested that the tumor microenvironment could be managed with apatinib, which was effective in eliciting an abscopal effect induced by SABR.

Published
2019

39. Development and validation of a UPLC-MS/MS method for quantification of doxofylline and its metabolites in human plasma

Author

Mingqing Mao, Ling Yang, Xiao-Hua Zhao, Hui Jia, Lina Fang, and Shuyue Xia

Subjects
Adult, Male, Spectrometry, Mass, Electrospray Ionization, Formic acid, Electrospray ionization, Clinical Biochemistry, Pharmaceutical Science, Mass spectrometry, 01 natural sciences, High-performance liquid chromatography, Analytical Chemistry, chemistry.chemical_compound, Theophylline, Tandem Mass Spectrometry, Drug Discovery, Humans, Protein precipitation, Infusions, Intravenous, Chromatography, High Pressure Liquid, Spectroscopy, Doxofylline, Chromatography, 010405 organic chemistry, 010401 analytical chemistry, Selected reaction monitoring, Reproducibility of Results, Healthy Volunteers, 0104 chemical sciences, Triple quadrupole mass spectrometer, chemistry, Calibration, Female
Abstract

A sensitive and specific ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneous determination of doxofylline and its two metabolites in human plasma. After protein precipitation with methanol, the chromatographic separation was carried out on an ACQUITY UPLC HSS T3 column, with acetonitrile and 0.1% formic acid in water as mobile phase at a flow rate of 0.30 mL·min−1. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source, with target quantitative ion pairs of m/z 267.0→181.1 for doxofylline, 239.0→181.1 for theophylline-7-acetic acid and 225.1→181.1 for etofylline. The calibration curve was linear over the range of 2–3000 ng·mL−1 (r > 0.99). The LLOQ was evaluated to be 2 ng·mL−1. The method described herein allowed simultaneous determination of the three analytes for the first time and was successfully applied to the pharmacokinetic study of doxofylline and its metabolites after intravenous administration in healthy volunteers.

Published
2019

40. The Hepatoprotective Effects of Zinc Glycine on Liver Injury in Meat Duck Through Alleviating Hepatic Lipid Deposition and Inflammation

Author

Bing Wu, Hua Zhao, Ting Yang, Zhengyu Zhang, Guangmang Liu, Jingyi Cai, Yaqi Chang, Xiaoling Chen, Yunhan Zhang, Gang Jia, Min Wen, and Gang Tian

Subjects
Male, medicine.medical_specialty, Apolipoprotein B, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Glycine, Peroxisome proliferator-activated receptor, chemistry.chemical_element, Zinc, 010501 environmental sciences, Protective Agents, 01 natural sciences, Biochemistry, Inorganic Chemistry, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, medicine, Animals, 0105 earth and related environmental sciences, Inflammation, chemistry.chemical_classification, Liver injury, 0303 health sciences, biology, Triglyceride, 030302 biochemistry & molecular biology, Biochemistry (medical), Fatty acid, General Medicine, Lipid Metabolism, medicine.disease, Fatty acid synthase, Ducks, Endocrinology, Liver, chemistry, Dietary Supplements, Zinc deficiency, biology.protein
Abstract

Dietary zinc status was recently approved to exert a powerful influence on liver health, and zinc deficiency results in hepatic injury caused by fat deposition, inflammation, and oxidant stress, but the effect of zinc on hepatic lipid metabolism and liver injury in meat duck has not been well defined. To determine the hepatoprotective effects of graded zinc glycine in meat ducks. A total of 384 1-day-old male meat ducks were subjected to 5 weeks feeding program with three experimental diets: (1) low-zinc diet, (2) adequate-zinc diet, and (3) high-zinc diet. Blood and liver samples were collected for biochemical analysis, gene expression analysis, and histopathological study. Diet with low zinc increased hepatic lipid content and triglyceride concentration. Meat ducks fed low-zinc diet exhibited considerably increased serum alanine aminotransferase (ALT) activity than birds fed other diets among all groups (P < 0.05). Low zinc administration also notably induced hepatocyte apoptosis and stimulated hepatic inflammatory gene expression. Adequate or high zinc supplementation increased hepatic zinc level, reduced hepatic lipid deposition and hepatosomatic indices through suppressing the expression of lipogenic genes including fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) (P < 0.05), and upregulated the mRNA expression of both fatty acid secretion and β-oxidation, including carnitine palmitoyltransferase 1a (Cpt1a), peroxisome proliferator-activated receptor (PPAR)α, and apolipoprotein B (ApoB) (P < 0.05). Dietary zinc addition also declined hepatic mRNA expression of interleukin (IL)-1β and IL-6 (P < 0.05). Furthermore, diets with adequate or high zinc significantly decreased serum ALT activity and hepatocyte apoptosis. These data revealed that supplementing adequate- or high-zinc glycine efficiently protects liver injury by attenuating lipid deposition and hepatic inflammation.

Published
2019

41. Clinical outcomes and prognostic factors in patients with no less than three distant organ system metastases from differentiated thyroid carcinoma

Author

Jian-Wen Sun, Xiao-Yue Chen, Xin-Yun Zhang, Jin-Hua Zhao, Yang Wang, Zhong-Ling Qiu, and Quan-Yong Luo

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Lung Neoplasms, Multivariate analysis, Endocrinology, Diabetes and Metabolism, Bone Neoplasms, 030209 endocrinology & metabolism, Adenocarcinoma, Iodine Radioisotopes, Thyroid carcinoma, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Diabetes mellitus, Overall survival, Humans, Medicine, Avidity, In patient, Thyroid Neoplasms, Organ system, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Proportional hazards model, Middle Aged, Prognosis, medicine.disease, Survival Rate, Treatment Outcome, 030220 oncology & carcinogenesis, Female, business
Abstract

For patients with differentiated thyroid carcinoma (DTC), distant metastases are commonly identified in the lungs and bones. However, they are relatively rare in other distant organs, such as the liver, kidneys, or brain. The aim of the current study was to describe the clinical outcomes and evaluate the prognostic factors of patients with no less than three different distant organ system metastases from DTC. This study retrospectively identified 717 patients diagnosed with DTC with distant metastases between January 2005 and December 2017. Patient response to radioactive iodine (RAI) therapy was monitored by changes in serum thyroglobulin levels and imaging changes. Five-year and 10-year overall survival (OS) rates were calculated by the Kaplan–Meier methods and Cox proportional hazards. Among the 717 participants, 37 (5.16%) patients had no less than three different distant organ system metastases from DTC. Five-year and 10-year OS were 45.9% and 37.8% in patients with three or more distant organ system metastases while 74.5% and 64.9% in individuals with one or two distant organ system metastases, respectively. RAI avidity and RAIR-DTC were main independent prognostic factors influencing the clinical outcomes for both groups of patients. The presence of 3 or more different distant organ system metastases was the only independent prognostic factors for 10-year OS by multivariate analysis. Patients with no less than three distant organ system metastases from DTC had poor prognosis. RAI avidity and RAIR-DTC were main factors influencing overall survival for patients with distant metastases from DTC in both groups.

Published
2019

42. Prognostic significance of locally invaded sites and tissue types in patients with nasal extranodal natural-killer/T-cell lymphoma: a single-center retrospective analysis

Author

Ge-Hong Dong, Yong Li, Ji-Yong Dong, Xue Li, Hong-Fei Wan, Lei Yang, Jing-Wen Wang, Li-Ping Gong, Yi-Hua Zhao, Hong Zhang, Zi-Fen Gao, Hong-Gang Liu, and Ning-Ning Wang

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Lymphoma, Facial Muscles, lcsh:Medicine, Kaplan-Meier Estimate, Single Center, Gastroenterology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, International Prognostic Index, T-cell, Internal medicine, Positron Emission Tomography Computed Tomography, medicine, Humans, Aged, Retrospective Studies, business.industry, Hazard ratio, lcsh:R, Soft tissue, Brain, General Medicine, Original Articles, Cheek, Middle Aged, medicine.disease, Prognosis, Invasiveness, Log-rank test, Killer Cells, Natural, Lymphoma, Extranodal NK-T-Cell, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Maxilla, Multivariate Analysis, Natural killer cells, Neoplasm, Female, business, 030217 neurology & neurosurgery
Abstract

Background: Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, is an aggressive entity within the World Health Organization classification of lymphoid tumors. The International Prognostic Index is reported to be prognostically meaningful for ENKTL, but lacks discriminatory power for stage I/II ENKTL with extensive local invasion. This study aimed to evaluate the prognostic effects of local invasion by site and tissue type in patients with ENKTL. Methods: We retrospectively analyzed data of 86 patients who were diagnosed with ENKTL by the Department of Pathology of Beijing Tongren Hospital from June 2002 to April 2016, and ascertained tumor infiltration of adjacent structures (AS), bone, and soft tissue for each patient, using physical findings and imaging scans. We used univariate and multivariate analysis to assess the association of each involved tissue or site with patients’ overall survival (OS). Results: Of the 86 patients, 71(82.6%) experienced invasion of AS, 22(25.6%) of soft tissue, and 26(30.2%) had bone involvement. Overall, patients with AS involvement did not show significantly shorter survival than those without AS involvement (Log rank χ2 = 1.177, P = 0.278); however, patients who had involved eyeballs or brains showed significantly lower 2-year OS rates than those without eyeball involvement (Log rank χ2 = 4.105, P = 0.043) or brain involvement (Log rank χ2 = 7.126, P = 0.008). Patients with involved local soft tissue or bones, respectively, showed lower 2-year OS rates than those without involved local soft tissue (Log rank χ2 = 10.390, P = 0.001) or bones (Log rank χ2 = 8.993, P = 0.003). Multivariate analysis showed that involvement of the cheek or facial muscles (hazard ratio, HR = 5.471, 95% confidence interval [CI]: 1.466–20.416, P = 0.011) and the maxilla bone (HR = 6.120, 95% CI: 1.517–24.694, P = 0.011) were significantly independent predictors of lower 2-year OS rates. Conclusions: Imaging can accurately detect ENKTL invasion of AS, soft tissue, and bone. Involvement of local soft tissue or bone was significantly associated with lower 2-year OS rates. Involvements of the cheek or facial muscle, as well as maxilla bone, are independent predictors of lower 2-year OS rates in ENKTL patients. Key words: Lymphoma; Natural killer cells; T-cell; Neoplasm; Invasiveness; Prognosis

Published
2019

43. Social support as a mediator between depression and quality of life in Chinese community-dwelling older adults with chronic disease

Author

Ling-Na Kong, Yu Yao, Qing-Hua Zhao, and Ping Hu

Subjects
Male, Gerontology, China, 03 medical and health sciences, Social support, 0302 clinical medicine, Mediator, Asian People, Quality of life, Negatively associated, Surveys and Questionnaires, Chinese community, Humans, Medicine, 030212 general & internal medicine, Depression (differential diagnoses), Aged, Depression, business.industry, Social Support, Mental health, humanities, Cross-Sectional Studies, Mental Health, Chronic disease, Chronic Disease, Quality of Life, Female, Independent Living, business, 030217 neurology & neurosurgery
Abstract

The older adults with chronic disease usually show poor mental health and experience low quality of life (QOL). This study aimed to examine the mediating role of social support in the relationship between depression and QOL in community-dwelling older adults with chronic disease. A total of 387 Chinese older adults aged 60 or above with chronic disease were included in this cross-sectional study. Social support was negatively associated with depression and positively associated with physical component scale (PCS) and mental component scale (MCS). Depression and social support were all predictors of PCS and MCS. Mediation analysis suggested that social support partially mediated the impact of depression on PCS and MCS. Understanding the mediating role of social support might be beneficial in reducing the adverse impact of depression on QOL in community-dwelling older adults with chronic disease.

Published
2019

44. Small molecule IVQ, as a prodrug of gluconeogenesis inhibitor QVO, efficiently ameliorates glucose homeostasis in type 2 diabetic mice

Author

Gaihong Wang, Yuan Ruan, Xiao-wei Guan, Yinan Zhang, Jun Guo, Jing Jiang, Fei Ma, Ji-Ming Ye, Yong-hua Zhao, Xu Shen, Tong Zhao, Tingting Zhou, Lihong Hu, Jing Chen, Jin Ren, and Qiu-ying Yan

Subjects
Male, 0301 basic medicine, Indoles, Enzyme Activators, AMP-Activated Protein Kinases, Pharmacology, Article, Diabetes Mellitus, Experimental, Electron Transport Complex III, 03 medical and health sciences, 0302 clinical medicine, In vivo, Animals, Hypoglycemic Agents, Glucose homeostasis, Prodrugs, Pharmacology (medical), Enzyme Inhibitors, Protein kinase A, Electron Transport Complex I, Chemistry, Kinase, Gluconeogenesis, AMPK, General Medicine, Prodrug, Mitochondria, Mice, Inbred C57BL, 030104 developmental biology, Diabetes Mellitus, Type 2, Liver, 030220 oncology & carcinogenesis, Glucose-6-Phosphatase, Hepatocytes, Quinolines, Phosphoenolpyruvate Carboxykinase (GTP), Signal transduction, Signal Transduction
Abstract

Gluconeogenesis is a major source of hyperglycemia in patients with type 2 diabetes mellitus (T2DM), thus targeting gluconeogenesis to suppress glucose production is a promising strategy for anti-T2DM drug discovery. In our preliminary in vitro studies, we found that a small-molecule (E)-3-(2-(quinoline-4-yl)vinyl)-1H-indol-6-ol (QVO) inhibited the hepatic glucose production (HGP) in primary hepatocytes. We further revealed that QVO suppressed hepatic gluconeogenesis involving calmodulin-dependent protein kinase kinase β- and liver kinase B1-adenosine monophosphate-activated protein kinase (AMPK) pathways as well as AMPK-independent mitochondrial function-related signaling pathway. To evaluate QVO’s anti-T2DM activity in vivo, which was impeded by the complicated synthesis route of QVO with a low yield, we designed and synthesized 4-[2-(1H-indol-3-yl)vinyl]quinoline (IVQ) as a prodrug with easier synthesis route and higher yield. IVQ did not inhibit the HGP in primary hepatocytes in vitro. Pharmacokinetic studies demonstrated that IVQ was quickly converted to QVO in mice and rats following administration. In both db/db and ob/ob mice, oral administration of IVQ hydrochloride (IVQ-HCl) (23 and 46 mg/kg every day, for 5 weeks) ameliorated hyperglycemia, and suppressed hepatic gluconeogenesis and activated AMPK signaling pathway in the liver tissues. Furthermore, IVQ caused neither cardiovascular system dysfunction nor genotoxicity. The good druggability of IVQ has highlighted its potential in the treatment of T2DM and the prodrug design for anti-T2DM drug development.

Published
2019

45. Associations between the built environment and body mass index in the Mexican American Mano A Mano Cohort

Author

Xueying Zhang, Christine Markham, Hua Zhao, Wong Ho Chow, Casey P. Durand, and Kai Zhang

Subjects
Adult, Male, Generalized linear model, Environmental Engineering, 010504 meteorology & atmospheric sciences, Population, 010501 environmental sciences, Logistic regression, 01 natural sciences, Body Mass Index, Cohort Studies, Young Adult, Residence Characteristics, Mexican Americans, Prevalence, medicine, Humans, Environmental Chemistry, Obesity, Built Environment, education, Waste Management and Disposal, Built environment, 0105 earth and related environmental sciences, education.field_of_study, Odds ratio, Middle Aged, medicine.disease, Texas, Pollution, Cross-Sectional Studies, Geography, Cohort, Female, Body mass index, Demography
Abstract

Background Obesity is highly prevalent in Mexican American adults. Studies on the role of the built environment in relation to obesity among this population are scarce. Objectives To investigate cross-sectional associations between multiple components of the built environment, and Body Mass Index (BMI) as well as obesity status among Mexican American adults enrolled in the Mano a Mano Cohort (MAC) study in Houston, Texas. Methods We calculated BMI from measured height and weight among 9534 Mexican American adults (aged 20–60) who participated in the baseline survey during 2008–2013. Several metrics of exposure to the built environment (physical activity environment, land use, and food environment) were generated using Geographic Information System and Google Maps based on participants' residential address. Generalized linear regression and logistic regression models were used to estimate associations between exposure to the built environment, a continuous BMI variable and categorical BMI variables ( Results Among all built environment exposure variables investigated, road density (total road length per km2) [0.21 (0.06, 0.36) as coefficient (95% CI)], intersection density (intersection links per km2) [0.74 (0.21, 1.28)], networked distance (km) [−0.29 (−0.47, −0.10)], and walking time (mins) [−0.02 (−0.04, −0.01)] to the nearest parks had statistically significantly linear associations with BMI. Those variables were found to have statistically significant associations with BMI ≥ 35 in logistic regression models, the odds ratio was 1.08 (1.02, 1.14) for road density, 1.31 (1.07, 1.60) for intersection density, 0.91 (0.85, 0.98) for networked distance, and 0.99 (0.99, 1.00) for walking time. None of the built environment exposure variables were found to be associated with BMI ≥ 30. Conclusions Living in areas with high density of roads exhibited significant associations with increased BMI, in particular BMI ≥ 35, among enrolled Mexican American adults in the MAC study.

Published
2019

46. The Zuo Jin Wan Formula increases chemosensitivity of human primary gastric cancer cells by AKT mediated mitochondrial translocation of cofilin-1

Author

Jian Sun, Tao Jie, Dan-Dan Wang, Si Cai, Xiao-Hua Zhao, Qiu-Xue Wu, Zhen-Hua Ni, Meng-Yao Sun, Qing-Feng Tang, and Jian-Yue Sun

Subjects
Adult, Cofilin 1, Male, endocrine system diseases, Apoptosis, 01 natural sciences, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Stomach Neoplasms, Drug Discovery, Tumor Cells, Cultured, medicine, Humans, Protein kinase B, Aged, Cell Proliferation, Aged, 80 and over, Cisplatin, medicine.diagnostic_test, 010405 organic chemistry, Cell growth, Chemistry, General Medicine, Middle Aged, Mitochondria, 0104 chemical sciences, Blot, Proto-Oncogene Proteins c-bcl-2, Complementary and alternative medicine, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Female, Proto-Oncogene Proteins c-akt, Immortalised cell line, Drugs, Chinese Herbal, medicine.drug
Abstract

Resistance to cisplatin (DDP)-based chemotherapy is a major cause of treatment failure in human gastric cancer (GC). It is necessary to identify the drugs to re-sensitize GC cells to DDP. In our previous research, Zuo Jin Wan Formula (ZJW) has been proved could increase the mitochondrial apoptosis via cofilin-1 in a immortalized cell line, SGC-7901/DDP. Due to the immortalized cells may still difficult highly recapitulate the important molecular events in vivo, primary GC cells model derived from clinical patient was constructed in the present study to further evaluate the effect of ZJW and the underlying molecular mechanism. Immunofluorescent staining was used to indentify primary cultured human GC cells. Western blotting was carried out to detect the protein expression. Cell Counting Kit-8 (CCK-8) was used to evaluate cell proliferation. Flow cytometry analysis was performed to assess cell apoptosis. ZJW inhibited proliferation and induced apoptosis in primary DDP-resistant GC cells. Notably, the apoptosis in GC cells was mediated by inducing cofilin-1 mitochondrial translocation, down-regulating Bcl-2 and up-regulating Bax expression. Surprisingly, the level of p-AKT protein was higher in DDP-resistant GC cells than that of the DDP-sensitive GC cells, and the activation of AKT could attenuate ZJW-induced sensitivity to DDP. These data revealed that ZJW can increase the chemosensitivity in DDP-resistant primary GC cells by inducing mitochondrial apoptosis and AKT inactivation. The combining chemotherapy with ZJW may be an effective therapeutic strategy for GC chemoresistance patients.

Published
2019

47. Clinical Significance of Serum Type III Interferons in Patients with Gastric Cancer

Author

Ting Liu, Hua Zhao, Nan Dong, Yawen Zheng, Peng Zhang, Xiubao Ren, and Lili Yang

Subjects
Adult, Aged, 80 and over, Male, business.industry, Immunology, Cancer, Cell Biology, Middle Aged, medicine.disease, Interferon Lambda, Stomach Neoplasms, Interferon, Virology, Cancer research, Humans, Biomarker (medicine), Medicine, Female, In patient, Clinical significance, Interferons, business, Aged, medicine.drug
Abstract

Type III interferon (IFN) is a newly established IFN that shows roles different from those of type I and II IFNs. However, the effect of type III IFN on the prognosis of patients with gastric cancer (GC) is controversial. This study aimed to investigate the effects of serum IFN-α, IFN-β, IFN-γ, IFN-λ1, and IFN-λ2/3 levels on the survival of patients with GC. LEGENDplex bead-based immunoassays were used to analyze the serum IFN-α, IFN-β, IFN-γ, IFN-λ1, and IFN-λ2/3 levels in patients with GC and healthy volunteers. Flow cytometry was used to test the IFN concentrations. Compared with the healthy controls, the patients with GC had significantly decreased serum IFN-α, IFN-γ, and IFN-λ1 levels, but significantly increased serum IFN-λ2/3 level. Analysis of the serum IFN concentrations and clinical parameters of the patients with GC showed significant correlations of serum IFN-α, IFN-β, IFN-γ, and IFN-λ2/3 levels with clinical stages. Serum IFN-λ1 levels significantly correlated with tumor location, histopathology, and lymph node involvement. Serum IFN-λ2/3 levels significantly correlated with lymph node involvement and distant metastasis. In addition, serum IFN-α, IFN-β, and IFN-γ levels significantly correlated with clinical stage and lymph node metastasis. Serum IFN-β and IFN-γ levels also significantly correlated with Lauren classification. Furthermore, the patients with stage IV GC exhibited significantly lower IFN-λ2/3 levels and higher IFN-α, IFN-β, and IFN-γ levels than the patients with stage I-III GC. The univariate analysis revealed that tumor sizes of5 cm, higher clinical stage, and high IFN-λ2/3 level were significantly associated with poor prognosis. This study shows the relationship between serum IFN level and GC progression. High serum IFN-λ2/3 levels were associated with poor prognosis and could be a novel biomarker for evaluating GC progression and predicting the outcomes of nonmetastatic GC.

Published
2019

48. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

Author

Phuwanat Sakornsakolpat, James F. Wilson, María Soler Artigas, Beate Stubbe, Nicholas J. Wareham, James D. Crapo, Victoria E. Jackson, Eleftheria Zeggini, Olga G. Troyanskaya, Medea Imboden, A. Mesut Erzurumluoglu, Adam S. Butterworth, Carl A. Melbourne, Ian Sayers, Lars Lind, Stefan Weiss, Margaret M. Parker, Timmers Prhj, Edwin K. Silverman, John C. Whittaker, Ian P. Hall, Ozren Polasek, Mika Kähönen, Katherine A. Fawcett, Anna Hansell, Liming Li, David J. Porteous, Louise V. Wain, Robert A. Scott, Richard Packer, Richard J. Allen, Robin G Walters, Anna L. Guyatt, Terho Lehtimäki, Nicole Probst-Hensch, Shona M. Kerr, Christian Gieger, Matthias Wielscher, Rajesh Rawal, Jing Hua Zhao, John E. Hokanson, Holger Schulz, Nicola F. Reeve, Claudia Langenberg, Ke Hao, Corry-Anke Brandsma, Megan L. Paynton, Vitart, Dmitry Prokopenko, Jennie Hui, Eugene R. Bleecker, Ma'en Obeidat, John Danesh, Ralf Ewert, Benjamin B. Sun, Frank Dudbridge, Jian Zhou, Brian D. Hobbs, Blair H. Smith, Don D. Sin, Dawn L. DeMeo, Joseph C. Maranville, Ida Surakka, Alison Catherine Murray, Nicholas Locantore, Katherine A. Kentistou, Terri H. Beaty, Igor Rudan, Kuang Lin, Amund Gulsvik, Ian J. Deary, Ruth Tal-Singer, Kijoung Song, David C. Nickle, Michael H. Cho, Jian'an Luan, Joshua D. Hoffman, Georg Homuth, Zhengming Chen, Dandi Qiao, Heiko Runz, Per Bakke, Chiara Batini, Caroline Hayward, Stefan Karrasch, Alan James, Andrew P. Morris, Prescott G. Woodruff, Laura M Yerges Armstrong, David Sparrow, Ulf Gyllensten, James P. Cook, Jonathan Marten, Olli T. Raitakari, Nick Shrine, Deborah A. Meyers, Tobin, Ruth Boxall, Marjo-Riitta Järvelin, David P. Strachan, Sarah E. Harris, Philippe Joubert, Stefan Enroth, Xingnan Li, van den Berge M, Anubha Mahajan, Yohan Bossé, Peter K. Joshi, Shrine, Nick [0000-0003-3641-4371], Guyatt, Anna L [0000-0003-1860-6337], Hobbs, Brian D [0000-0001-9564-0745], Sakornsakolpat, Phuwanat [0000-0002-4308-0974], Obeidat, Ma'en [0000-0002-5443-2752], Weiss, Stefan [0000-0002-3553-4315], Kentistou, Katherine A [0000-0002-5816-664X], Sun, Benjamin B [0000-0001-6347-2281], Enroth, Stefan [0000-0002-5056-9137], Vitart, Veronique [0000-0002-4991-3797], Allen, Richard J [0000-0002-8450-3056], Beaty, Terri H [0000-0002-7644-1705], Bossé, Yohan [0000-0002-3067-3711], Joshi, Peter K [0000-0002-6361-5059], Mahajan, Anubha [0000-0001-5585-3420], Murray, Alison [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Sayers, Ian [0000-0001-5601-5410], Smith, Blair H [0000-0002-5362-9430], Tal-Singer, Ruth [0000-0002-5275-8062], Timmers, Paul RHJ [0000-0002-5197-1267], Troyanskaya, Olga G [0000-0002-5676-5737], Rudan, Igor [0000-0001-6993-6884], Wilson, James F [0000-0001-5751-9178], Zeggini, Eleftheria [0000-0003-4238-659X], Hayward, Caroline [0000-0002-9405-9550], Morris, Andrew P [0000-0002-6805-6014], Butterworth, Adam S [0000-0002-6915-9015], Walters, Robin G [0000-0002-9179-0321], Cho, Michael H [0000-0002-4907-1657], Strachan, David P [0000-0001-7854-1366], Tobin, Martin D [0000-0002-3596-7874], Wain, Louise V [0000-0003-4951-1867], Apollo - University of Cambridge Repository, Institute for Molecular Medicine Finland, Groningen Research Institute for Asthma and COPD (GRIAC), UNIVERSITY OF OULU, and Commission of the European Communities

Subjects
Male, Smoking/genetics, LOCI, Genome-wide association study, VARIANTS, Bioinformatics, Genome-wide association studies, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, GWAS, GENOME-WIDE ASSOCIATION, HERITABILITY, COPD, Lung, 11 Medical and Health Sciences, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Genetic Predisposition to Disease/genetics, Smoking, 1184 Genetics, developmental biology, physiology, Middle Aged, Polymorphism, Single Nucleotide/genetics, 3. Good health, medicine.anatomical_structure, Meta-analysis, Genome-Wide Association Study/methods, Medical genetics, Female, Life Sciences & Biomedicine, medicine.medical_specialty, Understanding Society Scientific Group, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetics, medicine, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Genetic association, Aged, Respiratory tract diseases, Science & Technology, Case-control study, Lung/physiopathology, 06 Biological Sciences, medicine.disease, Pulmonary Disease, Chronic Obstructive/genetics, respiratory tract diseases, Case-Control Studies, 3111 Biomedicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD., Editorial summary: A genome-wide association study in over 400,000 individuals identifies 139 new signals for lung function. These variants can predict chronic obstructive pulmonary disease in independent, trans-ethnic cohorts.

Published
2019

49. Effects of Dietary Supplementation of Recombinant Plectasin on Growth Performance, Intestinal Health and Innate Immunity Response in Broilers

Author

Li Hua Zhao, Lihong Zhao, Qiu Gang Ma, Zhi Qiang Zhang, Jing Zhang, Cheng Ji, Yong Peng Guo, Dan Dan Sun, and Jing Lin Ma

Subjects
Male, 0301 basic medicine, Aerobic bacteria, 030106 microbiology, Population, Enramycin, Ileum, Biology, Microbiology, Jejunum, 03 medical and health sciences, chemistry.chemical_compound, Cecum, Animal science, medicine, Animals, Animal Husbandry, education, Molecular Biology, education.field_of_study, Plectasin, Malondialdehyde, Recombinant Proteins, Gastrointestinal Microbiome, Intestines, 030104 developmental biology, medicine.anatomical_structure, chemistry, Dietary Supplements, Molecular Medicine, Animal Nutritional Physiological Phenomena, Peptides, Chickens, medicine.drug
Abstract

The present study was conducted to evaluate the effects of dietary supplementation of recombinant plectasin (Ple) on the growth performance, intestinal health, and serum immune parameters in broilers. A total of 288 1-day-old male broilers (Arbor Acres) were randomly allotted to four dietary treatments including the basal diet (NC) and basal diet supplemented with 10 mg enramycin/kg (PC), 100 mg Ple/kg (LPle), and 200 mg Ple/kg (HPle) diets. The results indicated Ple increased (P

Published
2019

50. Anti-PD-1 Antibody SHR-1210 Combined with Apatinib for Advanced Hepatocellular Carcinoma, Gastric, or Esophagogastric Junction Cancer: An Open-label, Dose Escalation and Expansion Study

Author

Gairong Zhang, Yun Zhang, Yao Yue Zhang, Xin Yi, Zhiyuan Hu, Ru Jia, Jianming Xu, Jian Jun Zou, Chun Xia Chen, Chuan Hua Zhao, Chun Yan Yue, Lianpeng Chang, Quan Ren Wang, Rongrui Liu, and Yan Wang

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Carcinoma, Hepatocellular, Esophageal Neoplasms, Combination therapy, Pyridines, Antibodies, Monoclonal, Humanized, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, Antineoplastic Agents, Immunological, 0302 clinical medicine, Stomach Neoplasms, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Carcinoma, Humans, Apatinib, Molecular Targeted Therapy, Adverse effect, Aged, business.industry, Liver Neoplasms, Cancer, Middle Aged, Prognosis, medicine.disease, Treatment Outcome, 030104 developmental biology, Oncology, Tolerability, chemistry, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Toxicity, Female, Esophagogastric Junction, business, Biomarkers
Abstract

Purpose: This study assessed the safety and efficacy of SHR-1210 (anti-PD-1 antibody) and apatinib (VEGFR2 inhibitor) as combination therapy in patients with advanced hepatocellular carcinoma (HCC), gastric, or esophagogastric junction cancer (GC/EGJC). Patients and Methods: This was an open-label, dose-escalation (phase Ia) and expansion study (phase Ib). In phase Ia, patients (n = 15) received SHR-1210 200 mg every 2 weeks and apatinib 125–500 mg once daily until unacceptable toxicity or disease progression. In phase Ib, patients (n = 28) received apatinib at the phase Ia–identified recommended phase II dose (RP2D) plus SHR-1210. The primary objectives were safety and tolerability and RP2D determination. Results: At data cutoff, 43 patients were enrolled. In phase Ia, four dose-limiting toxicity events were observed (26.7%): one grade 3 lipase elevation (6.7%) in the apatinib 250 mg cohort and three grade 3 pneumonitis events (20%) in the apatinib 500 mg cohort. The maximum tolerated RP2D for apatinib was 250 mg. Of the 33 patients treated with the R2PD combination, 20 (60.6%) experienced a grade ≥3 treatment-related adverse event; adverse events in ≥10% of patients were hypertension (15.2%) and increased aspartate aminotransferase (15.2%). The objective response rate in 39 evaluable patients was 30.8% (95% CI: 17.0%–47.6%). Eight of 16 evaluable HCC patients achieved a partial response (50.0%, 95% CI: 24.7%–75.4%). Conclusions: SHR-1210 and apatinib combination therapy demonstrated manageable toxicity in patients with HCC and GC/EGJC at recommended single-agent doses of both drugs. The RP2D for apatinib as combination therapy was 250 mg, which showed encouraging clinical activity in patients with advanced HCC.

Published
2019

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