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1. Single-cell genomics and regulatory networks for 388 human brains.

Author

Emani, Prashant, Liu, Jason, Clarke, Declan, Jensen, Matthew, Warrell, Jonathan, Gupta, Chirag, Meng, Ran, Lee, Che Yu, Xu, Siwei, Dursun, Cagatay, Lou, Shaoke, Chen, Yuhang, Chu, Zhiyuan, Galeev, Timur, Hwang, Ahyeon, Li, Yunyang, Ni, Pengyu, Zhou, Xiao, Bakken, Trygve, Bendl, Jaroslav, Bicks, Lucy, Chatterjee, Tanima, Cheng, Lijun, Cheng, Yuyan, Dai, Yi, Duan, Ziheng, Flaherty, Mary, Fullard, John, Gancz, Michael, Garrido-Martín, Diego, Gaynor-Gillett, Sophia, Grundman, Jennifer, Hawken, Natalie, Henry, Ella, Hoffman, Gabriel, Huang, Ao, Jiang, Yunzhe, Jin, Ting, Jorstad, Nikolas, Kawaguchi, Riki, Khullar, Saniya, Liu, Jianyin, Liu, Junhao, Liu, Shuang, Ma, Shaojie, Margolis, Michael, Mazariegos, Samantha, Moore, Jill, Moran, Jennifer, Nguyen, Eric, Phalke, Nishigandha, Pjanic, Milos, Pratt, Henry, Quintero, Diana, Rajagopalan, Ananya, Riesenmy, Tiernon, Shedd, Nicole, Shi, Manman, Spector, Megan, Terwilliger, Rosemarie, Travaglini, Kyle, Wamsley, Brie, Wang, Gaoyuan, Xia, Yan, Xiao, Shaohua, Yang, Andrew, Zheng, Suchen, Gandal, Michael, Lee, Donghoon, Lein, Ed, Roussos, Panos, Sestan, Nenad, Weng, Zhiping, White, Kevin, Won, Hyejung, Girgenti, Matthew, Zhang, Jing, Wang, Daifeng, Geschwind, Daniel, and Gerstein, Mark

Subjects
Humans, Aging, Brain, Cell Communication, Chromatin, Gene Regulatory Networks, Genomics, Mental Disorders, Prefrontal Cortex, Quantitative Trait Loci, Single-Cell Analysis
Abstract

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

Published
2024

2. Lipid-anchored proteasomes control membrane protein homeostasis.

Author

Zhang, Ruizhu, Pan, Shuxian, Zheng, Suya, Liao, Qingqing, Jiang, Zhaodi, Wang, Dixian, Li, Xuemei, Hu, Ao, Li, Xinran, Zhu, Yezhang, Shen, Xiaoqi, Lei, Jing, Zhong, Siming, Zhang, Xiaomei, Huang, Lingyun, Wang, Xiaorong, Huang, Lan, Shen, Li, Song, Bao-Liang, Zhao, Jing-Wei, Wang, Zhiping, Yang, Bing, and Guo, Xing

Subjects
Humans, Animals, Mice, Proteasome Endopeptidase Complex, Membrane Proteins, Proteostasis, Endoplasmic Reticulum-Associated Degradation, Mice, Nude, Lipids
Abstract

Protein degradation in eukaryotic cells is mainly carried out by the 26S proteasome, a macromolecular complex not only present in the cytosol and nucleus but also associated with various membranes. How proteasomes are anchored to the membrane and the biological meaning thereof have been largely unknown in higher organisms. Here, we show that N-myristoylation of the Rpt2 subunit is a general mechanism for proteasome-membrane interaction. Loss of this modification in the Rpt2-G2A mutant cells leads to profound changes in the membrane-associated proteome, perturbs the endomembrane system, and undermines critical cellular processes such as cell adhesion, endoplasmic reticulum-associated degradation and membrane protein trafficking. Rpt2G2A/G2A homozygous mutation is embryonic lethal in mice and is sufficient to abolish tumor growth in a nude mice xenograft model. These findings have defined an evolutionarily conserved mechanism for maintaining membrane protein homeostasis and underscored the significance of compartmentalized protein degradation by myristoyl-anchored proteasomes in health and disease.

Published
2023

3. Cross-stage neural pattern similarity in the hippocampus predicts false memory derived from post-event inaccurate information

Author

Shao, Xuhao, Li, Ao, Chen, Chuansheng, Loftus, Elizabeth F, and Zhu, Bi

Subjects
Biological Psychology, Information and Computing Sciences, Psychology, Behavioral and Social Science, Clinical Research, Basic Behavioral and Social Science, Neurosciences, Neurological, Mental health, Humans, Memory, Hippocampus, Cerebral Cortex, Prefrontal Cortex, Communication, Magnetic Resonance Imaging, Brain Mapping, Mental Recall, false memory, misinformation, fMRI, hippocampus, encoding, retrieval
Abstract

The misinformation effect occurs when people's memory of an event is altered by subsequent inaccurate information. No study has systematically tested theories about the dynamics of human hippocampal representations during the three stages of misinformation-induced false memory. This study replicates behavioral results of the misinformation effect, and investigates the cross-stage pattern similarity in the hippocampus and cortex using functional magnetic resonance imaging. Results show item-specific hippocampal pattern similarity between original-event and post-event stages. During the memory-test stage, hippocampal representations of original information are weakened for true memory, whereas hippocampal representations of misinformation compete with original information to create false memory. When false memory occurs, this conflict is resolved by the lateral prefrontal cortex. Individuals' memory traces of post-event information in the hippocampus predict false memory, whereas original information in the lateral parietal cortex predicts true memory. These findings support the multiple-trace model, and emphasize the reconstructive nature of human memory.

Published
2023

4. Stiff matrix induces exosome secretion to promote tumour growth.

Author

Wu, Bin, Liu, Di-Ao, Guan, Lei, Myint, Phyoe, Chin, LiKang, Dang, Hien, Xu, Ye, Ren, Jinqi, Li, Ting, Yu, Ziyan, Jabban, Sophie, Mills, Gordon, Nukpezah, Jonathan, Chen, Youhai, Furth, Emma, Gimotty, Phyllis, Wells, Rebecca, Weaver, Valerie, Radhakrishnan, Ravi, Wang, Xin, and Guo, Wei

Subjects
Humans, Exosomes, Proteomics, Neoplasms, Extracellular Matrix, Signal Transduction, Tumor Microenvironment
Abstract

Tissue fibrosis and extracellular matrix (ECM) stiffening promote tumour progression. The mechanisms by which ECM regulates its contacting cells have been extensively studied. However, how stiffness influences intercellular communications in the microenvironment for tumour progression remains unknown. Here we report that stiff ECM stimulates the release of exosomes from cancer cells. We delineate a molecular pathway that links stiff ECM to activation of Akt, which in turn promotes GTP loading to Rab8 that drives exosome secretion. We further show that exosomes generated from cells grown on stiff ECM effectively promote tumour growth. Proteomic analysis revealed that the Notch signalling pathway is activated in cells treated with exosomes derived from tumour cells grown on stiff ECM, consistent with our gene expression analysis of liver tissues from patients. Our study reveals a molecular mechanism that regulates exosome secretion and provides insight into how mechanical properties of the ECM control the tumour microenvironment for tumour growth.

Published
2023

5. Acoustofluidic assembly of primary tumor-derived organotypic cell clusters for rapid evaluation of cancer immunotherapy.

Author

Wu, Zhuhao, Ao, Zheng, Cai, Hongwei, Li, Xiang, Chen, Bin, Tu, Honglei, Wang, Yijie, Lu, Rongze, Gu, Mingxia, Cheng, Liang, Lu, Xin, and Guo, Feng

Subjects
Acoustofluidics, Cancer immunotherapy, Cancer models, Cell clusters, Microfluidics, Humans, Female, Breast Neoplasms, Immunotherapy
Abstract

Cancer immunotherapy shows promising potential for treating breast cancer. While patients may have heterogeneous treatment responses for adjuvant therapy, it is challenging to predict an individual patients response to cancer immunotherapy. Here, we report primary tumor-derived organotypic cell clusters (POCCs) for rapid and reliable evaluation of cancer immunotherapy. By using a label-free, contactless, and highly biocompatible acoustofluidic method, hundreds of cell clusters could be assembled from patient primary breast tumor dissociation within 2 min. Through the incorporation of time-lapse living cell imaging, the POCCs could faithfully recapitulate the cancer-immune interaction dynamics as well as their response to checkpoint inhibitors. Superior to current tumor organoids that usually take more than two weeks to develop, the POCCs can be established and used for evaluation of cancer immunotherapy within 12 h. The POCCs can preserve the cell components from the primary tumor due to the short culture time. Moreover, the POCCs can be assembled with uniform fabricate size and cell composition and served as an open platform for manipulating cell composition and ratio under controlled treatment conditions with a short turnaround time. Thus, we provide a new method to identify potentially immunogenic breast tumors and test immunotherapy, promoting personalized cancer therapy.

Published
2023

6. EMG-Driven Musculoskeletal Model Calibration With Wrapping Surface Personalization.

Author

Ao, Di, Li, Geng, Shourijeh, Mohammad, Fregly, Benjamin, and Patten, Carolynn

Subjects
Humans, Electromyography, Muscle, Skeletal, Calibration, Models, Biological, Hip Joint, Biomechanical Phenomena
Abstract

Muscle forces and joint moments estimated by electromyography (EMG)-driven musculoskeletal models are sensitive to the wrapping surface geometry defining muscle-tendon lengths and moment arms. Despite this sensitivity, wrapping surface properties are typically not personalized to subject movement data. This study developed a novel method for personalizing OpenSim cylindrical wrapping surfaces during EMG-driven model calibration. To avoid the high computational cost of repeated OpenSim muscle analyses, the method uses two-level polynomial surrogate models. Outer-level models specify time-varying muscle-tendon lengths and moment arms as functions of joint angles, while inner-level models specify time-invariant outer-level polynomial coefficients as functions of wrapping surface parameters. To evaluate the method, we used walking data collected from two individuals post-stroke and performed four variations of EMG-driven lower extremity model calibration: 1) no calibration of scaled generic wrapping surfaces (NGA), 2) calibration of outer-level polynomial coefficients for all muscles (SGA), 3) calibration of outer-level polynomial coefficients only for muscles with wrapping surfaces (LSGA), and 4) calibration of cylindrical wrapping surface parameters for muscles with wrapping surfaces (PGA). On average compared to NGA, SGA reduced lower extremity joint moment matching errors by 31%, LSGA by 24%, and PGA by 12%, with the largest reductions occurring at the hip. Furthermore, PGA reduced peak hip joint contact force by 47% bodyweight, which was the most consistent with published in vivo measurements. The proposed method for EMG-driven model calibration with wrapping surface personalization produces physically realistic OpenSim models that reduce joint moment matching errors while improving prediction of hip joint contact force.

Published
2023

7. CRISPRi screens in human iPSC-derived astrocytes elucidate regulators of distinct inflammatory reactive states

Author

Leng, Kun, Rose, Indigo VL, Kim, Hyosung, Xia, Wenlong, Romero-Fernandez, Wilber, Rooney, Brendan, Koontz, Mark, Li, Emmy, Ao, Yan, Wang, Shinong, Krawczyk, Mitchell, TCW, Julia, Goate, Alison, Zhang, Ye, Ullian, Erik M, Sofroniew, Michael V, Fancy, Stephen PJ, Schrag, Matthew S, Lippmann, Ethan S, and Kampmann, Martin

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Brain Disorders, Stem Cell Research, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Humans, Astrocytes, Induced Pluripotent Stem Cells, Signal Transduction, Alzheimer Disease, Cytokines, Inflammation, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Astrocytes become reactive in response to insults to the central nervous system by adopting context-specific cellular signatures and outputs, but a systematic understanding of the underlying molecular mechanisms is lacking. In this study, we developed CRISPR interference screening in human induced pluripotent stem cell-derived astrocytes coupled to single-cell transcriptomics to systematically interrogate cytokine-induced inflammatory astrocyte reactivity. We found that autocrine-paracrine IL-6 and interferon signaling downstream of canonical NF-κB activation drove two distinct inflammatory reactive signatures, one promoted by STAT3 and the other inhibited by STAT3. These signatures overlapped with those observed in other experimental contexts, including mouse models, and their markers were upregulated in human brains in Alzheimer's disease and hypoxic-ischemic encephalopathy. Furthermore, we validated that markers of these signatures were regulated by STAT3 in vivo using a mouse model of neuroinflammation. These results and the platform that we established have the potential to guide the development of therapeutics to selectively modulate different aspects of inflammatory astrocyte reactivity.

Published
2022

8. The Potential Role of Cytotoxic Immune Effectors in Induction, Progression and Pathogenesis of Amyotrophic Lateral Sclerosis (ALS).

Author

Kaur, Kawaljit, Chen, Po-Chun, Ko, Meng-Wei, Mei, Ao, Chovatiya, Nishant, Huerta-Yepez, Sara, Ni, Weiming, Mackay, Sean, Zhou, Jing, Maharaj, Dipanarine, Malarkannan, Subramaniam, and Jewett, Anahid

Subjects
CD8+ T cells, IFN-γ, NAC, NK cells, amyotrophic lateral sclerosis (ALS), cytotoxicity, Humans, Amyotrophic Lateral Sclerosis, CD8-Positive T-Lymphocytes, Cytokines, Granzymes, Leukocytes, Mononuclear, T-Lymphocytes, Cytotoxic
Abstract

Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neuron system. The causes of ALS are heterogeneous, and are only partially understood. We studied different aspects of immune pathogenesis in ALS and found several basic mechanisms which are potentially involved in the disease. Our findings demonstrated that ALS patients peripheral blood contains higher proportions of NK and B cells in comparison to healthy individuals. Significantly increased IFN-γ secretion by anti-CD3/28 mAbs-treated peripheral blood mononuclear cells (PBMCs) were observed in ALS patients, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism for ALS progression. In addition, elevated granzyme B and perforin secretion at a single cell level, and increased cytotoxicity and secretion of IFN-γ by patients NK cells under specific treatment conditions were also observed. Increased IFN-γ secretion by ALS patients CD8+ T cells in the absence of IFN-γ receptor expression, and increased CD8+ T cell effector/memory phenotype as well as increased granzyme B at the single cell level points to the CD8+ T cells as potential cells in targeting motor neurons. Along with the hyper-responsiveness of cytotoxic immune cells, significantly higher levels of inflammatory cytokines including IFN-γ was observed in peripheral blood-derived serum of ALS patients. Supernatants obtained from ALS patients CD8+ T cells induced augmented cell death and differentiation of the epithelial cells. Weekly N-acetyl cysteine (NAC) infusion in patients decreased the levels of many inflammatory cytokines in peripheral blood of ALS patient except IFN-γ, TNF-α, IL-17a and GMCSF which remained elevated. Findings of this study indicated that CD8+ T cells and NK cells are likely culprits in targeting motor neurons and therefore, strategies should be designed to decrease their function, and eliminate the aggressive nature of these cells. Analysis of genetic mutations in ALS patient in comparison to identical twin revealed a number of differences and similarities which may be important in the pathogenesis of the disease.

Published
2022

9. Systemic considerations for the surgical treatment of spinal metastatic disease: a scoping literature review.

Author

MacLean, Mark A, Touchette, Charles J, Georgiopoulos, Miltiadis, Brunette-Clément, Tristan, Abduljabbar, Fahad H, Ames, Christopher P, Bettegowda, Chetan, Charest-Morin, Raphaele, Dea, Nicolas, Fehlings, Michael G, Gokaslan, Ziya L, Goodwin, C Rory, Laufer, Ilya, Netzer, Cordula, Rhines, Laurence D, Sahgal, Arjun, Shin, John H, Sciubba, Daniel M, Stephens, Byron F, Fourney, Daryl R, Weber, Michael H, and AO Spine Knowledge Forum Tumor

Subjects
AO Spine Knowledge Forum Tumor, Humans, Spinal Cord Neoplasms, Neoplasm Metastasis, Female, Male, Cardiovascular, Patient Safety, Clinical Research, 7.3 Management and decision making, Management of diseases and conditions, Good Health and Well Being, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Systemic assessment is a pillar in the neurological, oncological, mechanical, and systemic (NOMS) decision-making framework for the treatment of patients with spinal metastatic disease. Despite this importance, emerging evidence relating systemic considerations to clinical outcomes following surgery for spinal metastatic disease has not been comprehensively summarised. We aimed to conduct a scoping literature review of this broad topic. We searched MEDLINE, Embase, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, and CINAHL databases from Jan 1, 2000, to July 31, 2021. 61 articles were included, accounting for a total of 22 335 patients. Preoperative systemic variables negatively associated with postoperative clinical outcomes included demographics (eg, older age [>60 years], Black race, male sex, low or elevated body-mass index, and smoking status), medical comorbidities (eg, cardiac, pulmonary, hepatic, renal, endocrine, vascular, and rheumatological), biochemical abnormalities (eg, hypoalbuminaemia, atypical blood cell counts, and elevated C-reactive protein concentration), low muscle mass, generalised motor weakness (American Spinal Cord Injury Association Impairment Scale grade and Frankel grade) and poor ambulation, reduced performance status, and systemic disease burden. This is the first comprehensive scoping review to broadly summarise emerging evidence relevant to the systemic assessment component of the widely used NOMS framework for spinal metastatic disease decision making. Medical, surgical, and radiation oncologists can consider these findings when prognosticating spinal metastatic disease-related surgical outcomes on the basis of patients' systemic condition. These factors might inform a shared decision-making approach with patients and their families.

Published
2022

10. Divergent transcriptional regulation of astrocyte reactivity across disorders

Author

Burda, Joshua E, O’Shea, Timothy M, Ao, Yan, Suresh, Keshav B, Wang, Shinong, Bernstein, Alexander M, Chandra, Ashu, Deverasetty, Sandeep, Kawaguchi, Riki, Kim, Jae H, McCallum, Sarah, Rogers, Alexandra, Wahane, Shalaka, and Sofroniew, Michael V

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Neurosciences, Brain Disorders, Human Genome, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, Animals, Astrocytes, Central Nervous System Diseases, Chromatin, Gene Expression Regulation, High-Throughput Nucleotide Sequencing, Humans, Mice, Sequence Analysis, RNA, Transcription Factors, Transcription, Genetic, General Science & Technology
Abstract

Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder1-4. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions.

Published
2022

11. Pooled testing efficiency increases with test frequency

Author

Augenblick, Ned, Kolstad, Jonathan, Obermeyer, Ziad, and Wang, Ao

Subjects
Infection, COVID-19, COVID-19 Testing, Cost-Benefit Analysis, Humans, Mass Screening, Population Surveillance, Prevalence, SARS-CoV-2, Uncertainty, pooled testing, surveillance testing
Abstract

Pooled testing increases efficiency by grouping individual samples and testing the combined sample, such that many individuals can be cleared with one negative test. This short paper demonstrates that pooled testing is particularly advantageous in the setting of pandemics, given repeated testing, rapid spread, and uncertain risk. Repeated testing mechanically lowers the infection probability at the time of the next test by removing positives from the population. This effect alone means that increasing frequency by x times only increases expected tests by around [Formula: see text] However, this calculation omits a further benefit of frequent testing: Removing infections from the population lowers intragroup transmission, which lowers infection probability and generates further efficiency. For this reason, increasing testing frequency can paradoxically reduce total testing cost. Our calculations are based on the assumption that infection rates are known, but predicting these rates is challenging in a fast-moving pandemic. However, given that frequent testing naturally suppresses the mean and variance of infection rates, we show that our results are very robust to uncertainty and misprediction. Finally, we note that efficiency further increases given natural sampling pools (e.g., workplaces, classrooms) that induce correlated risk via local transmission. We conclude that frequent pooled testing using natural groupings is a cost-effective way to provide consistent testing of a population to suppress infection risk in a pandemic.

Published
2022

12. Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin

Author

Kim, Hyosung, Leng, Kun, Park, Jinhee, Sorets, Alexander G, Kim, Suil, Shostak, Alena, Embalabala, Rebecca J, Mlouk, Kate, Katdare, Ketaki A, Rose, Indigo VL, Sturgeon, Sarah M, Neal, Emma H, Ao, Yan, Wang, Shinong, Sofroniew, Michael V, Brunger, Jonathan M, McMahon, Douglas G, Schrag, Matthew S, Kampmann, Martin, and Lippmann, Ethan S

Subjects
Stem Cell Research, Stem Cell Research - Nonembryonic - Human, Neurosciences, Brain Disorders, Stem Cell Research - Induced Pluripotent Stem Cell, 1.1 Normal biological development and functioning, Underpinning research, Humans, Animals, Mice, Blood-Brain Barrier, Astrocytes, alpha 1-Antichymotrypsin, Cells, Cultured, Induced Pluripotent Stem Cells, Inflammation, Tumor Necrosis Factor-alpha, STAT3 Transcription Factor
Abstract

Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function. Pathological transformation of astrocytes to reactive states can be protective or harmful to BBB function. Here, using a human induced pluripotent stem cell (iPSC)-derived BBB co-culture model, we show that tumor necrosis factor (TNF) transitions astrocytes to an inflammatory reactive state that causes BBB dysfunction through activation of STAT3 and increased expression of SERPINA3, which encodes alpha 1-antichymotrypsin (α1ACT). To contextualize these findings, we correlated astrocytic STAT3 activation to vascular inflammation in postmortem human tissue. Further, in murine brain organotypic cultures, astrocyte-specific silencing of Serpina3n reduced vascular inflammation after TNF challenge. Last, treatment with recombinant Serpina3n in both ex vivo explant cultures and in vivo was sufficient to induce BBB dysfunction-related molecular changes. Overall, our results define the TNF-STAT3-α1ACT signaling axis as a driver of an inflammatory reactive astrocyte signature that contributes to BBB dysfunction.

Published
2022

13. Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4.

Author

Toupin, Nicholas, Steinke, Sean, Nadella, Sandeep, Li, Ao, Rohrabaugh, Thomas, Samuels, Eric, Turro, Claudia, Sevrioukova, Irina, and Kodanko, Jeremy

Subjects
Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cell Survival, Coordination Complexes, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Drug Screening Assays, Antitumor, Humans, Models, Molecular, Molecular Structure, Photosensitizing Agents, Ruthenium
Abstract

We report the synthesis and photochemical and biological characterization of the first selective and potent metal-based inhibitors of cytochrome P450 3A4 (CYP3A4), the major human drug metabolizing enzyme. Five Ru(II)-based derivatives were prepared from two analogs of the CYP3A4 inhibitor ritonavir, 4 and 6: [Ru(tpy)(L)(6)]Cl2 (tpy = 2,2:6,2″-terpyridine) with L = 6,6-dimethyl-2,2-bipyridine (Me2bpy; 8), dimethylbenzo[i]dipyrido[3,2-a:2,3-c]phenazine (Me2dppn; 10) and 3,6-dimethyl-10,15-diphenylbenzo[i]dipyrido[3,2-a:2,3-c]phenazine (Me2Ph2dppn; 11), [Ru(tpy)(Me2bpy)(4)]Cl2 (7) and [Ru(tpy)(Me2dppn)(4)]Cl2 (9). Photochemical release of 4 or 6 from 7-11 was demonstrated, and the spectrophotometric evaluation of 7 showed that it behaves similarly to free 4 (type II heme ligation) after irradiation with visible light but not in the dark. Unexpectedly, the intact Ru(II) complexes 7 and 8 were found to inhibit CYP3A4 potently and specifically through direct binding to the active site without heme ligation. Caged inhibitors 9-11 showed dual action properties by combining photoactivated dissociation of 4 or 6 with efficient 1O2 production. In prostate adenocarcinoma DU-145 cells, compound 9 had the best synergistic effect with vinblastine, the anticancer drug primarily metabolized by CYP3A4 in vivo. Thus, our study establishes a new paradigm in CYP inhibition using metalated complexes and suggests possible utilization of photoactive CYP3A4 inhibitory compounds in clinical applications, such as enhancement of therapeutic efficacy of anticancer drugs.

Published
2021

14. Foreign body responses in mouse central nervous system mimic natural wound responses and alter biomaterial functions.

Author

OʼShea, Timothy M, Wollenberg, Alexander L, Kim, Jae H, Ao, Yan, Deming, Timothy J, and Sofroniew, Michael V

Subjects
Central Nervous System, Brain, Animals, Mice, Inbred C57BL, Mice, Transgenic, Humans, Foreign-Body Reaction, Biocompatible Materials, Hydrogels, Biomimetics, Female, Male, Mice, Inbred C57BL, Transgenic
Abstract

Biomaterials hold promise for therapeutic applications in the central nervous system (CNS). Little is known about molecular factors that determine CNS foreign body responses (FBRs) in vivo, or about how such responses influence biomaterial function. Here, we probed these factors in mice using a platform of injectable hydrogels readily modified to present interfaces with different physiochemical properties to host cells. We found that biomaterial FBRs mimic specialized multicellular CNS wound responses not present in peripheral tissues, which serve to isolate damaged neural tissue and restore barrier functions. We show that the nature and intensity of CNS FBRs are determined by definable properties that significantly influence hydrogel functions, including resorption and molecular delivery when injected into healthy brain or stroke injuries. Cationic interfaces elicit stromal cell infiltration, peripherally derived inflammation, neural damage and amyloid production. Nonionic and anionic formulations show minimal levels of these responses, which contributes to superior bioactive molecular delivery. Our results identify specific molecular mechanisms that drive FBRs in the CNS and have important implications for developing effective biomaterials for CNS applications.

Published
2020

15. GRK5 Controls SAP97-Dependent Cardiotoxic β1 Adrenergic Receptor-CaMKII Signaling in Heart Failure

Author

Xu, Bing, Li, Minghui, Wang, Ying, Zhao, Meimi, Morotti, Stefano, Shi, Qian, Wang, Qingtong, Barbagallo, Federica, Teoh, Jian-Peng, Reddy, Gopireddy R, Bayne, Elizabeth F, Liu, Yongming, Shen, Ao, Puglisi, Jose L, Ge, Ying, Li, Ji, Grandi, Eleonora, Nieves-Cintron, Madeline, and Xiang, Yang K

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Cardiovascular, Heart Disease, Aetiology, 2.1 Biological and endogenous factors, Animals, Apoptosis, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cells, Cultured, Cyclic AMP-Dependent Protein Kinases, Discs Large Homolog 1 Protein, Disease Models, Animal, Excitation Contraction Coupling, G-Protein-Coupled Receptor Kinase 5, Guanine Nucleotide Exchange Factors, Heart Failure, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Myocardial Contraction, Myocytes, Cardiac, Receptors, Adrenergic, beta-1, beta-Arrestin 1, calmodulin, heart failure, myocyte, cardiac, myocardium, signaling pathways, myocyte, cardiac, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

RationaleCardiotoxic β1 adrenergic receptor (β1AR)-CaMKII (calmodulin-dependent kinase II) signaling is a major and critical feature associated with development of heart failure. SAP97 (synapse-associated protein 97) is a multifunctional scaffold protein that binds directly to the C-terminus of β1AR and organizes a receptor signalosome.ObjectiveWe aim to elucidate the dynamics of β1AR-SAP97 signalosome and its potential role in chronic cardiotoxic β1AR-CaMKII signaling that contributes to development of heart failure.Methods and resultsThe integrity of cardiac β1AR-SAP97 complex was examined in heart failure. Cardiac-specific deletion of SAP97 was developed to examine β1AR signaling in aging mice, after chronic adrenergic stimulation, and in pressure overload hypertrophic heart failure. We show that the β1AR-SAP97 signaling complex is reduced in heart failure. Cardiac-specific deletion of SAP97 yields an aging-dependent cardiomyopathy and exacerbates cardiac dysfunction induced by chronic adrenergic stimulation and pressure overload, which are associated with elevated CaMKII activity. Loss of SAP97 promotes PKA (protein kinase A)-dependent association of β1AR with arrestin2 and CaMKII and turns on an Epac (exchange protein directly activated by cAMP)-dependent activation of CaMKII, which drives detrimental functional and structural remodeling in myocardium. Moreover, we have identified that GRK5 (G-protein receptor kinase-5) is necessary to promote agonist-induced dissociation of SAP97 from β1AR. Cardiac deletion of GRK5 prevents adrenergic-induced dissociation of β1AR-SAP97 complex and increases in CaMKII activity in hearts.ConclusionsThese data reveal a critical role of SAP97 in maintaining the integrity of cardiac β1AR signaling and a detrimental cardiac GRK5-CaMKII axis that can be potentially targeted in heart failure therapy. Graphical Abstract: A graphical abstract is available for this article.

Published
2020

16. TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

Author

Zhao, Limin, Ke, Hao, Xu, Haibo, Wang, Guo-Dong, Zhang, Honglei, Zou, Li, Xiang, Shu, Li, Mengyuan, Peng, Li, Zhou, Mingfang, Li, Lingling, Ao, Lei, Yang, Qin, Shen, Che-Kun James, Yi, Ping, Wang, Lu, and Jiao, Baowei

Subjects
Genetics, Nutrition, Clinical Research, 1.1 Normal biological development and functioning, Underpinning research, Animals, Breast, Butyrophilins, DNA-Binding Proteins, Epithelial Cells, Female, Gene Expression Regulation, Humans, Lactation, Lactation Disorders, Lipid Droplets, Lipids, Mammary Glands, Animal, Mice, Mice, Knockout, Milk, RNA, Messenger, Transcriptome, Xanthine Dehydrogenase
Abstract

Milk lipid secretion is a critical process for the delivery of nutrition and energy from parent to offspring. However, the underlying molecular mechanism is less clear. Here we report that TDP-43, a RNA-binding protein, underwent positive selection in the mammalian lineage. Furthermore, TDP-43 gene (Tardbp) loss induces accumulation of large lipid droplets and severe lipid secretion deficiency in mammary epithelial cells to outside alveolar lumens, eventually resulting in lactation failure and pup starvation within three weeks postpartum. In human milk samples from lactating women, the expression levels of TDP-43 is positively correlated with higher milk output. Mechanistically, TDP-43 exerts post-transcriptional regulation of Btn1a1 and Xdh mRNA stability, which are required for the secretion of lipid droplets from epithelial cells to the lumen. Taken together, our results highlights the critical role of TDP-43 in milk lipid secretion, providing a potential strategy for the screening and intervention of clinical lactation insufficiency.

Published
2020

17. Convergence of human and Old World monkey gut microbiomes demonstrates the importance of human ecology over phylogeny

Author

Amato, Katherine R, Mallott, Elizabeth K, McDonald, Daniel, Dominy, Nathaniel J, Goldberg, Tony, Lambert, Joanna E, Swedell, Larissa, Metcalf, Jessica L, Gomez, Andres, Britton, Gillian AO, Stumpf, Rebecca M, Leigh, Steven R, and Knight, Rob

Subjects
Climate Change Impacts and Adaptation, Biological Sciences, Microbiology, Environmental Sciences, History, Heritage and Archaeology, Human Society, Archaeology, Anthropology, Genetics, Nutrition, Human Genome, Clinical Research, Animals, Cercopithecidae, Diet, Ecosystem, Gastrointestinal Microbiome, Hominidae, Humans, Phylogeny, RNA, Ribosomal, 16S, Human gut microbiome, Primate gut microbiome, Cercopithecine, Human evolution, Information and Computing Sciences, Bioinformatics
Abstract

BackgroundComparative data from non-human primates provide insight into the processes that shaped the evolution of the human gut microbiome and highlight microbiome traits that differentiate humans from other primates. Here, in an effort to improve our understanding of the human microbiome, we compare gut microbiome composition and functional potential in 14 populations of humans from ten nations and 18 species of wild, non-human primates.ResultsContrary to expectations from host phylogenetics, we find that human gut microbiome composition and functional potential are more similar to those of cercopithecines, a subfamily of Old World monkey, particularly baboons, than to those of African apes. Additionally, our data reveal more inter-individual variation in gut microbiome functional potential within the human species than across other primate species, suggesting that the human gut microbiome may exhibit more plasticity in response to environmental variation compared to that of other primates.ConclusionsGiven similarities of ancestral human habitats and dietary strategies to those of baboons, these findings suggest that convergent ecologies shaped the gut microbiomes of both humans and cercopithecines, perhaps through environmental exposure to microbes, diet, and/or associated physiological adaptations. Increased inter-individual variation in the human microbiome may be associated with human dietary diversity or the ability of humans to inhabit novel environments. Overall, these findings show that diet, ecology, and physiological adaptations are more important than host-microbe co-diversification in shaping the human microbiome, providing a key foundation for comparative analyses of the role of the microbiome in human biology and health.

Published
2019

18. Incorporating selected non-communicable diseases into facility-based surveillance systems from a resource-limited setting in Africa

Author

Mocumbi, AO, Langa, DC, Chicumbe, S, Schumacher, AE, and Al-Delaimy, WK

Subjects
Health Services and Systems, Health Sciences, Brain Disorders, Prevention, Clinical Research, Health Services, Cardiovascular, Metabolic and endocrine, Respiratory, Good Health and Well Being, Adolescent, Adult, Aged, Child, Child, Preschool, Female, Health Resources, Hospitals, Urban, Humans, Infant, Infant, Newborn, Male, Middle Aged, Mozambique, Noncommunicable Diseases, Population Surveillance, Prospective Studies, Referral and Consultation, Young Adult, Non-communicable diseases, Health information system, Disease surveillance, Public Health and Health Services, Public Health, Epidemiology, Health services and systems, Public health
Abstract

BackgroundAs Mozambique faces a double burden of diseases, with a rise of Non Communicable Diseases (NCD) superimposed to uncontrolled communicable diseases (CD), routine disease surveillance system does not include NCD. The objectives of our study were to i) upgrade of the current surveillance system by adapting the data collection tools to NCD; ii) describe the occurrence and profile of selected NCD using these data collection tools.MethodsWorkshops were implemented in a first referral urban hospital of Mozambique to train clinical staff, administrative workers and nurses on NCD surveillance, as well as select conditions to be prioritized. Based on the WHO Global Action Plan and Brazaville Declaration for NCD prevention and control, we selected arterial hypertension, diabetes, stroke, chronic respiratory diseases, mental illness and cancers. Data collection tools used for CD were changed to include age, gender, outcome and visit type. Between February/2014 and January/2015 we collected data at an urban hospital in Mozambique's capital.ResultsOver 12 months 92,018 new patients were assisted in this hospital. Data was missing or diagnosis was unreadable in 2637 (2.9%) thus only 89,381 were used for analysis; of these 6423 (median age 27 years; 58.4% female) had at least one selected NCD as their primary diagnosis: arterial hypertension (2397;37.31%), mental illness (1497;23.30%), asthma (1495;23.28%), diabetes (628;9.78%), stroke (299;4.66%), chronic obstructive pulmonary disease 61 (0.95%) and cancers 46 (0.72%). Emergency transfers were needed for 76 patients (1.2%), mainly due to hypertensive emergencies (31; 40.8%) and stroke (18;23.7%). Twenty-four patients died at entry points (0.3%); 10 of them had hypertensive emergencies.ConclusionChanges in existing surveillance tools for communicable diseases provided important data on the burden and outcomes of the selected NCD helping to identify priority areas for training and health care improvement. This information can be used to design the local NCD clinics and to strengthen the health information system in resource-limited settings in a progressive and sustainable way.

Published
2019

19. β-blockers augment L-type Ca2+ channel activity by targeting spatially restricted β2AR signaling in neurons.

Author

Shen, Ao, Chen, Dana, Kaur, Manpreet, Bartels, Peter, Xu, Bing, Shi, Qian, Martinez, Joseph M, Man, Kwun-Nok Mimi, Nieves-Cintron, Madeline, Hell, Johannes W, Navedo, Manuel F, Yu, Xi-Yong, and Xiang, Yang K

Subjects
Neurons, Animals, Mice, Knockout, Humans, Mice, Rats, Alprenolol, Cyclic AMP-Dependent Protein Kinases, Calcium Channels, L-Type, Receptors, Adrenergic, beta-2, Cyclic AMP, Adrenergic beta-Antagonists, Signal Transduction, HEK293 Cells, Carvedilol, cell biology, hippocampus, ion channel, mouse, rat, signaling transduction, Knockout, Calcium Channels, L-Type, Receptors, Adrenergic, beta-2, Biochemistry and Cell Biology
Abstract

G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in mammalian cells. Here, we report neuronal excitability of β-blockers carvedilol and alprenolol at clinically relevant nanomolar concentrations. Carvedilol and alprenolol activate β2AR, which promote G protein signaling and cAMP/PKA activities without action of G protein receptor kinases (GRKs). The cAMP/PKA activities are restricted within the immediate vicinity of activated β2AR, leading to selectively enhance PKA-dependent phosphorylation and stimulation of endogenous L-type calcium channel (LTCC) but not AMPA receptor in rat hippocampal neurons. Moreover, we have engineered a mutant β2AR that lacks the catecholamine binding pocket. This mutant is preferentially activated by carvedilol but not the orthosteric agonist isoproterenol. Carvedilol activates the mutant β2AR in mouse hippocampal neurons augmenting LTCC activity through cAMP/PKA signaling. Together, our study identifies a mechanism by which β-blocker-dependent activation of GPCRs promotes spatially restricted cAMP/PKA signaling to selectively target membrane downstream effectors such as LTCC in neurons.

Published
2019

20. Outcomes of Multimodality In situ Recanalization in Hybrid Operating Room (MIRHOR) for symptomatic chronic internal carotid artery occlusions

Author

Jiang, Wei-jian, Liu, Ao-Fei, Yu, Wengui, Qiu, Han-Cheng, Zhang, Yi-Qun, Liu, Fang, Li, Chen, Wang, Rong, Zhao, Yuan-Li, Lv, Jin, Li, Tian-Xiao, Liu, Ce, Zhou, Ji, and Zhao, Ji-Zong

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Patient Safety, Neurosciences, Stroke, Aged, Carotid Artery Diseases, Carotid Artery, Internal, Cohort Studies, Combined Modality Therapy, Endarterectomy, Carotid, Female, Humans, Male, Middle Aged, Operating Rooms, Treatment Outcome, angioplasty, atherosclerosis, cervical, intervention, technique, Clinical sciences
Abstract

BackgroundAn in situ recanalization procedure of endovascular therapy (ET) or carotid endarterectomy (CEA) has been attempted in patients with symptomatic chronic internal carotid artery occlusions (ICAOs), though the recanalization rates of both are low.ObjectiveTo investigate the outcomes of Multimodality In situ Recanalization for ICAOs in a Hybrid Operating Room (MIRHOR) at the same session.MethodsSymptomatic chronic ICAOs were classified into type A or B (short occlusion with or without a tapered residual root [TRR]), and C or D (long occlusion with or without TRR), and managed in a hybrid operating room with ET, CEA, or both, as needed. Primary efficacy outcome was technical success of recanalization with Thrombolysis in Myocardial Infarction 3. Secondary efficacy outcome was any stroke or death within 30 days (primary safety outcome) plus an ipsilateral ischemic stroke after 30 days.ResultsTechnical success was finally achieved in 35 (83.3%) of 42 consecutively enrolled patients with ICAO, which was significantly higher than 35.7% (15/42, p

Published
2019

21. Substrate Elasticity Governs Differentiation of Renal Tubule Cells in Prolonged Culture

Author

Love, Harold D, Ao, Mingfang, Jorgensen, Seiver, Swearingen, Lindsey, Ferrell, Nicholas, Evans, Rachel, Gewin, Leslie, Harris, Raymond C, Zent, Roy, Roy, Shuvo, and Fissell, William H

Subjects
Engineering, Biomedical Engineering, Regenerative Medicine, Kidney Disease, Bioengineering, 1.1 Normal biological development and functioning, 5.2 Cellular and gene therapies, Renal and urogenital, Animals, Aquaporins, Cell Differentiation, Cell Proliferation, Cell Shape, Cells, Cultured, Elasticity, Humans, Hydrogels, Kidney Tubules, Mice, Receptors, Transforming Growth Factor beta, Signal Transduction, Sodium-Hydrogen Exchanger 3, Transforming Growth Factor beta, renal tubule cell, matrix elasticity, NHE3, Biochemistry and Cell Biology, Materials Engineering, Biomedical engineering
Abstract

Impact statementSuccessful clinical tissue engineering requires functional fidelity of the cultured cell to its in vivo counterpart, but this has been elusive in renal tissue engineering. Typically, renal proximal tubule cells in culture have a flattened morphology and do not express key transporters essential to their function. In this article, we show for the first time that in vitro substrate mechanical properties dictate differentiation of cultured renal proximal tubule cells. Remarkably, this effect was only discernable after 4 weeks in culture, longer than usually reported for this cell type. These results demonstrate a new tunable parameter to optimize cell differentiation in renal tissue engineering.

Published
2019

22. ATP-Independent Bioluminescent Reporter Variants To Improve in Vivo Imaging

Author

Yeh, Hsien-Wei, Xiong, Ying, Wu, Tianchen, Chen, Minghai, Ji, Ao, Li, Xinyu, and Ai, Hui-wang

Subjects
Cancer, Adenosine Triphosphate, Animals, Directed Molecular Evolution, Genes, Reporter, Heterografts, Humans, Luminescence, Mice, Chemical Sciences, Biological Sciences, Organic Chemistry
Abstract

Coelenterazine (CTZ)-utilizing marine luciferases and their derivatives have attracted significant attention because of their ATP-independency, fast enzymatic turnover, and high bioluminescence brightness. However, marine luciferases typically emit blue photons and their substrates, including CTZ and the recently developed diphenylterazine (DTZ), have poor water solubility, hindering their in vivo applications. Herein, we report a family of pyridyl CTZ and DTZ analogs that exhibit spectrally shifted emission and improved water solubility. Through directed evolution, we engineered a LumiLuc luciferase with broad substrate specificity. In the presence of corresponding pyridyl substrates (i.e., pyCTZ, 6pyDTZ, or 8pyDTZ), LumiLuc generates highly bright blue, teal, or yellow bioluminescence. We compared our LumiLuc-8pyDTZ pair with several benchmark reporters in a tumor xenograft mouse model. Our new pair, which does not need organic cosolvents for in vivo administration, surpasses other reporters by detecting early tumors. We further fused LumiLuc to a red fluorescent protein, resulting in a LumiScarlet reporter with further red-shifted emission and enhanced tissue penetration. LumiScarlet-8pyDTZ was comparable to Akaluc-AkaLumine, the brightest ATP-dependent luciferase-luciferin pair, for detecting cells in deep tissues of mice. In summary, we have engineered a new family of ATP-independent bioluminescent reporters, which will have broad applications because of their ATP-independency, excellent biocompatibility, and superior in vivo sensitivity.

Published
2019

23. Cost minimization analysis of line probe assay for detection of multidrug-resistant tuberculosis in Arkhangelsk region of Russian Federation

Author

Bogdanova, EN, Mariandyshev, AO, Balantcev, GA, Eliseev, PI, Nikishova, EI, Gaida, AI, Enarson, D, Detjen, A, Dacombe, R, Phillips, PPJ, Squire, SB, and Gospodarevskaya, E

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Rare Diseases, Cost Effectiveness Research, Emerging Infectious Diseases, Antimicrobial Resistance, Clinical Research, Tuberculosis, Infection, Good Health and Well Being, Adult, Algorithms, Bacteriological Techniques, Costs and Cost Analysis, Female, Health Care Costs, Health Expenditures, Humans, Male, Middle Aged, Reagent Kits, Diagnostic, Russia, Surveys and Questionnaires, Tuberculosis, Multidrug-Resistant, General Science & Technology
Abstract

BACKGROUND:The development of new diagnostic tools allows for faster detection of both tuberculosis (TB) and multidrug-resistant (MDR) TB and should lead to reduced transmission by earlier initiation of anti TB therapy. The research conducted in the Arkhangelsk region of the Russian Federation in 2012-14 included economic evaluation of Line Probe Assay (LPA) implementation in MDR-TB diagnostics compared to existing culture-based diagnostics of Löwenstein Jensen (LJ) and BacTAlert. Clinical superiority of LPA was demonstrated and results were reported elsewhere. STUDY AIM:The PROVE-IT Russia study aimed to report the outcomes of the cost minimization analysis. METHODS:Costs of LPA-based diagnostic algorithm (smear positive (SSm+) and for smear negative (SSm-) culture confirmed TB patients by Bactec MGIT or LJ were compared with conventional culture-based algorithm (LJ-for SSm- and SSm+ patients and BacTAlert-for SSm+ patients). Cost minimization analysis was conducted from the healthcare system, patient and societal perspectives and included the direct and indirect costs to the healthcare system (microscopy and drug susceptibility test (DST), hospitalization, medications obtained from electronic medical records) and non-hospital direct costs (patient's travel cost, additional expenses associated with hospitalization, supplementary medicine and food) collected at the baseline and two subsequent interviews using the WHO-approved questionnaire. RESULTS:Over the period of treatment the LPA-based diagnostic corresponded to lesser direct and indirect costs comparing to the alternative algorithms. For SSm+ LPA-based diagnostics resulted in the costs 4.5 times less (808.21 US$) than LJ (3593.81 US$) and 2.5 times less than BacTAlert liquid culture (2009.61 US$). For SSm- LPA in combination with Bactec MGIT (1480.75 US$) vs LJ (1785.83 US$) showed the highest cost minimization compared to LJ (2566.09 US$). One-way sensitivity analyses of the key parameters and threshold analyses were conducted and demonstrated that the results were robust to variations in the cost of hospitalization, medications and length of stay. CONCLUSION:From the perspective of Russian Federation healthcare system, TB diagnostic algorithms incorporating LPA method proved to be both more clinically effective and less expensive due to reduction in the number of hospital days to the correct MDR-TB diagnosis and treatment initiation. LPA diagnostics comparing conventional culture diagnostic algorithm MDR-TB was a cost minimizing strategy for both patients and healthcare system.

Published
2019

24. The THO Complex Coordinates Transcripts for Synapse Development and Dopamine Neuron Survival

Author

Maeder, Celine I, Kim, Jae-Ick, Liang, Xing, Kaganovsky, Konstantin, Shen, Ao, Li, Qin, Li, Zhaoyu, Wang, Sui, Xu, XZ Shawn, Li, Jin Billy, Xiang, Yang Kevin, Ding, Jun B, and Shen, Kang

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Genetics, Biological Sciences, Neurodegenerative, Neurosciences, Brain Disorders, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, Neurological, Active Transport, Cell Nucleus, Amyotrophic Lateral Sclerosis, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Calcium Signaling, Cell Nucleus, Cyclic AMP Response Element-Binding Protein, Dopaminergic Neurons, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutagenesis, Mutation, Missense, Nuclear Proteins, Protein Subunits, Synapses, CREB, THO complex, coordinated genetic program, dopamine neurons, neurodegeneration, nuclear export, presynapse assembly, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Synaptic vesicle and active zone proteins are required for synaptogenesis. The molecular mechanisms for coordinated synthesis of these proteins are not understood. Using forward genetic screens, we identified the conserved THO nuclear export complex (THOC) as an important regulator of presynapse development in C. elegans dopaminergic neurons. In THOC mutants, synaptic messenger RNAs are retained in the nucleus, resulting in dramatic decrease of synaptic protein expression, near complete loss of synapses, and compromised dopamine function. CRE binding protein (CREB) interacts with THOC to mark synaptic transcripts for efficient nuclear export. Deletion of Thoc5, a THOC subunit, in mouse dopaminergic neurons causes severe defects in synapse maintenance and subsequent neuronal death in the substantia nigra compacta. These cellular defects lead to abrogated dopamine release, ataxia, and animal death. Together, our results argue that nuclear export mechanisms can select specific mRNAs and be a rate-limiting step for neuronal differentiation and survival.

Published
2018

25. Genomic and epidemiological monitoring of yellow fever virus transmission potential

Author

Faria, NR, Kraemer, MUG, Hill, SC, Goes de Jesus, J, Aguiar, RS, Iani, FCM, Xavier, J, Quick, J, du Plessis, L, Dellicour, S, Thézé, J, Carvalho, RDO, Baele, G, Wu, C-H, Silveira, PP, Arruda, MB, Pereira, MA, Pereira, GC, Lourenço, J, Obolski, U, Abade, L, Vasylyeva, TI, Giovanetti, M, Yi, D, Weiss, DJ, Wint, GRW, Shearer, FM, Funk, S, Nikolay, B, Fonseca, V, Adelino, TER, Oliveira, MAA, Silva, MVF, Sacchetto, L, Figueiredo, PO, Rezende, IM, Mello, EM, Said, RFC, Santos, DA, Ferraz, ML, Brito, MG, Santana, LF, Menezes, MT, Brindeiro, RM, Tanuri, A, Dos Santos, FCP, Cunha, MS, Nogueira, JS, Rocco, IM, da Costa, AC, Komninakis, SCV, Azevedo, V, Chieppe, AO, Araujo, ESM, Mendonça, MCL, Dos Santos, CC, Dos Santos, CD, Mares-Guia, AM, Nogueira, RMR, Sequeira, PC, Abreu, RG, Garcia, MHO, Abreu, AL, Okumoto, O, Kroon, EG, de Albuquerque, CFC, Lewandowski, K, Pullan, ST, Carroll, M, de Oliveira, T, Sabino, EC, Souza, RP, Suchard, MA, Lemey, P, Trindade, GS, Drumond, BP, Filippis, AMB, Loman, NJ, Cauchemez, S, Alcantara, LCJ, and Pybus, OG

Subjects
Prevention, Genetics, Emerging Infectious Diseases, Rare Diseases, Infectious Diseases, Vaccine Related, Biodefense, Aetiology, 2.2 Factors relating to the physical environment, Infection, Aedes, Age Factors, Animals, Brazil, Disease Outbreaks, Epidemiological Monitoring, Evolution, Molecular, Genomics, Humans, Phylogeny, Polymerase Chain Reaction, Risk, Sex Factors, Spatio-Temporal Analysis, Yellow Fever, Yellow fever virus, General Science & Technology
Abstract

The yellow fever virus (YFV) epidemic in Brazil is the largest in decades. The recent discovery of YFV in Brazilian Aedes species mosquitos highlights a need to monitor the risk of reestablishment of urban YFV transmission in the Americas. We use a suite of epidemiological, spatial, and genomic approaches to characterize YFV transmission. We show that the age and sex distribution of human cases is characteristic of sylvatic transmission. Analysis of YFV cases combined with genomes generated locally reveals an early phase of sylvatic YFV transmission and spatial expansion toward previously YFV-free areas, followed by a rise in viral spillover to humans in late 2016. Our results establish a framework for monitoring YFV transmission in real time that will contribute to a global strategy to eliminate future YFV epidemics.

Published
2018

26. Frequency of Chronic Joint Pain Following Chikungunya Virus Infection

Author

Chang, Aileen Y, Encinales, Liliana, Porras, Alexandra, Pacheco, Nelly, Reid, St Patrick, Martins, Karen AO, Pacheco, Shamila, Bravo, Eyda, Navarno, Marianda, Rico Mendoza, Alejandro, Amdur, Richard, Kamalapathy, Priyanka, Firestein, Gary S, Bethony, Jeffrey M, and Simon, Gary L

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Rare Diseases, Pain Research, Prevention, Chronic Pain, Arthritis, Clinical Research, Musculoskeletal, Infection, Good Health and Well Being, Adult, Arthralgia, Arthritis, Infectious, Chikungunya Fever, Chikungunya virus, Colombia, Cross-Sectional Studies, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prospective Studies, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveTo estimate the frequency of chronic joint pain after infection with chikungunya virus in a Latin American cohort.MethodsA cross-sectional follow-up of a prospective cohort of 500 patients from the Atlántico Department, Colombia who were clinically diagnosed as having chikungunya virus during the 2014-2015 epidemic was conducted. Baseline symptoms and follow-up symptoms at 20 months were evaluated in serologically confirmed cases.ResultsAmong the 500 patients enrolled, 485 had serologically confirmed chikungunya virus and reported joint pain status. Patients were predominantly adults (mean ± SD age 49 ± 16 years) and female, had an education level of high school or less, and were of Mestizo ethnicity. The most commonly affected joints were the small joints, including the wrists, ankles, and fingers. The initial virus symptoms lasted a median of 4 days (interquartile range [IQR] 3-8 days). Sixteen percent of the participants reported missing school or work (median 4 days [IQR 2-7 days]). After 20 months, one-fourth of the participants had persistent joint pain. A multivariable analysis indicated that significant predictors of persistent joint pain included college graduate status, initial symptoms of headache or knee pain, missed work, normal activities affected, ≥4 days of initial symptoms, and ≥4 weeks of initial joint pain.ConclusionThis is the first report to describe the frequency of chikungunya virus-related arthritis in the Americas after a 20-month follow-up. The high frequency of chronic disease highlights the need for the development of prevention and treatment methods.

Published
2018

27. Chikungunya Arthritis Mechanisms in the Americas

Author

Chang, Aileen Y, Martins, Karen AO, Encinales, Liliana, Reid, St Patrick, Acuña, Marlon, Encinales, Carlos, Matranga, Christian B, Pacheco, Nelly, Cure, Carlos, Shukla, Bhavarth, Ruiz Arteta, Teofilo, Amdur, Richard, Cazares, Lisa H, Gregory, Melissa, Ward, Michael D, Porras, Alexandra, Rico Mendoza, Alejandro, Dong, Lian, Kenny, Tara, Brueggemann, Ernie, Downey, Lydia G, Kamalapathy, Priyanka, Lichtenberger, Paola, Falls, Orlando, Simon, Gary L, Bethony, Jeffrey M, and Firestein, Gary S

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Arthritis, Vector-Borne Diseases, Rare Diseases, Infectious Diseases, Emerging Infectious Diseases, Genetics, 2.1 Biological and endogenous factors, Aetiology, Infection, Inflammatory and immune system, Good Health and Well Being, Arthritis, Infectious, Chikungunya Fever, Chikungunya virus, Cross-Sectional Studies, Female, Humans, Male, Synovial Fluid, Time Factors, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveTo determine if chikungunya virus persists in synovial fluid after infection, potentially acting as a causative mechanism of persistent arthritis.MethodsWe conducted a cross-sectional study of 38 Colombian participants with clinical chikungunya virus infection during the 2014-2015 epidemic who reported chronic arthritis and 10 location-matched controls without chikungunya virus or arthritis. Prior chikungunya virus infection status was serologically confirmed, and the presence of synovial fluid chikungunya virus, viral RNA, and viral proteins was determined by viral culture, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and mass spectrometry, respectively. Biomarkers were assessed by multiplex analysis.ResultsPatients with serologically confirmed chikungunya arthritis (33 of 38 [87%]) were predominantly female (82%) and African Colombian (55%) or white Colombian (33%), with moderate disease activity (mean ± SD Disease Activity Score in 28 joints 4.52 ± 0.77) a median of 22 months after infection (interquartile range 21-23 months). Initial symptoms of chikungunya virus infection included joint pain (97%), swelling (97%), stiffness (91%), and fever (91%). The most commonly affected joints were the knees (87%), elbows (76%), wrists (75%), ankles (56%), fingers (56%), and toes (56%). Synovial fluid samples from all patients with chikungunya arthritis were negative for chikungunya virus on qRT-PCR, showed no viral proteins on mass spectrometry, and cultures were negative. Case and control plasma cytokine and chemokine concentrations did not differ significantly.ConclusionThis is one of the largest observational studies involving analysis of the synovial fluid of chikungunya arthritis patients. Synovial fluid analysis revealed no detectable chikungunya virus. This finding suggests that chikungunya virus may cause arthritis through induction of potential host autoimmunity, suggesting a role for immunomodulating agents in the treatment of chikungunya arthritis, or that low-level viral persistence exists in synovial tissue only and is undetectable in synovial fluid.

Published
2018

28. Lower Extremity Motor Function Following Complex Adult Spinal Deformity Surgery: Two-Year Follow-up in the Scoli-RISK-1 Prospective, Multicenter, International Study.

Author

Lenke, Lawrence G, Shaffrey, Christopher I, Carreon, Leah Y, Cheung, Kenneth MC, Dahl, Benny T, Fehlings, Michael G, Ames, Christopher P, Boachie-Adjei, Oheneba, Dekutoski, Mark B, Kebaish, Khaled M, Lewis, Stephen J, Matsuyama, Yukihiro, Mehdian, Hossein, Pellisé, Ferran, Qiu, Yong, Schwab, Frank J, and AO Spine International and SRS Scoli-RISK-1 Study Group

Subjects
AO Spine International and SRS Scoli-RISK-1 Study Group, Lower Extremity, Humans, Spinal Curvatures, Osteotomy, Prospective Studies, Middle Aged, Female, Biomedical Engineering, Clinical Sciences, Orthopedics
Abstract

BACKGROUND:The reported neurologic complication rate following surgery for complex adult spinal deformity (ASD) is variable due to several factors. Most series have been retrospective with heterogeneous patient populations and use of nonuniform neurologic assessments. The aim of this study was to prospectively document lower extremity motor function by means of the American Spinal Injury Association (ASIA) lower extremity motor score (LEMS) before and through 2 years after surgical correction of complex ASD. METHODS:The Scoli-RISK-1 study enrolled 272 patients with ASD, from 15 centers, who had undergone primary or revision surgery for a major Cobb angle of ≥80°, corrective osteotomy for congenital spinal deformity or as a revision procedure for any type of deformity, and/or a complex 3-column osteotomy. RESULTS:One of 272 patients lacked preoperative data and was excluded from the analysis, and 62 (22.9%) of the remaining 271 patients, who were included, lacked a 2-year postoperative assessment. Patients with no preoperative motor impairment (normal LEMS group; n = 203) had a small but significant decline from the mean preoperative LEMS value (50) to that at 2 years postoperatively (49.66 [95% confidence interval = 49.46 to 49.85]; p = 0.002). Patients who did have a motor deficit preoperatively (n = 68; mean LEMS, 43.79) had significant LEMS improvement at 6 months (47.21, p < 0.001) and 2 years (46.12, p = 0.003) postoperatively. The overall percentage of patients (in both groups combined) who had a postoperative LEMS decline, compared with the preoperative value, was 23.0% at discharge, 17.1% at 6 weeks, 9.9% at 6 months, and 10.0% at 2 years. CONCLUSIONS:The percentage of patients who had a LEMS decline (compared with the preoperative score) after undergoing complex spinal reconstructive surgery for ASD was 23.0% at discharge, which improved to 10.0% at 2 years postoperatively. These rates are higher than previously reported, which we concluded was due to the prospective, strict nature of the LEMS testing of patients with these challenging deformities. LEVEL OF EVIDENCE:Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Published
2018

29. Functionally distinct and selectively phosphorylated GPCR subpopulations co-exist in a single cell.

Author

Shen, Ao, Nieves-Cintron, Madeline, Deng, Yawen, Shi, Qian, Chowdhury, Dhrubajyoti, Qi, Jinyi, Hell, Johannes W, Navedo, Manuel F, and Xiang, Yang K

Subjects
Hippocampus, Neurons, Animals, Humans, Mice, Cyclic AMP-Dependent Protein Kinases, Calcium Channels, L-Type, Receptors, Adrenergic, beta-2, Phosphorylation, G-Protein-Coupled Receptor Kinases, HEK293 Cells, Single-Cell Analysis, Single Molecule Imaging, Calcium Channels, L-Type, Receptors, Adrenergic, beta-2
Abstract

G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in a broad range of physiological responses and disease states. Activated GPCRs can undergo agonist-induced phosphorylation by G protein receptor kinases (GRKs) and second messenger-dependent protein kinases such as protein kinase A (PKA). Here, we characterize spatially segregated subpopulations of β2-adrenergic receptor (β2AR) undergoing selective phosphorylation by GRKs or PKA in a single cell. GRKs primarily label monomeric β2ARs that undergo endocytosis, whereas PKA modifies dimeric β2ARs that remain at the cell surface. In hippocampal neurons, PKA-phosphorylated β2ARs are enriched in dendrites, whereas GRK-phosphorylated β2ARs accumulate in soma, being excluded from dendrites in a neuron maturation-dependent manner. Moreover, we show that PKA-phosphorylated β2ARs are necessary to augment the activity of L-type calcium channel. Collectively, these findings provide evidence that functionally distinct subpopulations of this prototypical GPCR exist in a single cell.

Published
2018

30. Nanodelivery of a functional membrane receptor to manipulate cellular phenotype.

Author

Patriarchi, Tommaso, Shen, Ao, He, Wei, Baikoghli, Mo, Cheng, R Holland, Xiang, Yang K, Coleman, Matthew A, and Tian, Lin

Subjects
Cell Membrane, Humans, Receptors, Adrenergic, beta-2, Receptors, Cytoplasmic and Nuclear, DNA, RNA, Wound Healing, Phenotype, Nanomedicine, Nanoparticles, Synthetic Biology, Receptors, Adrenergic, beta-2, Cytoplasmic and Nuclear
Abstract

Modification of membrane receptor makeup is one of the most efficient ways to control input-output signals but is usually achieved by expressing DNA or RNA-encoded proteins or by using other genome-editing methods, which can be technically challenging and produce unwanted side effects. Here we develop and validate a nanodelivery approach to transfer in vitro synthesized, functional membrane receptors into the plasma membrane of living cells. Using β2-adrenergic receptor (β2AR), a prototypical G-protein coupled receptor, as an example, we demonstrated efficient incorporation of a full-length β2AR into a variety of mammalian cells, which imparts pharmacologic control over cellular signaling and affects cellular phenotype in an ex-vivo wound-healing model. Our approach for nanodelivery of functional membrane receptors expands the current toolkit for DNA and RNA-free manipulation of cellular function. We expect this approach to be readily applicable to the synthesis and nanodelivery of other types of GPCRs and membrane receptors, opening new doors for therapeutic development at the intersection between synthetic biology and nanomedicine.

Published
2018

31. Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

Author

Walton, E, Hibar, DP, van Erp, TGM, Potkin, SG, Roiz-Santiañez, R, Crespo-Facorro, B, Suarez-Pinilla, P, van Haren, NEM, de Zwarte, SMC, Kahn, RS, Cahn, W, Doan, NT, Jørgensen, KN, Gurholt, TP, Agartz, I, Andreassen, OA, Westlye, LT, Melle, I, Berg, AO, Morch-Johnsen, L, Færden, A, Flyckt, L, Fatouros-Bergman, H, Karolinska Schizophrenia Project Consortium (KaSP), Jönsson, EG, Hashimoto, R, Yamamori, H, Fukunaga, M, Jahanshad, N, De Rossi, P, Piras, F, Banaj, N, Spalletta, G, Gur, RE, Gur, RC, Wolf, DH, Satterthwaite, TD, Beard, LM, Sommer, IE, Koops, S, Gruber, O, Richter, A, Krämer, B, Kelly, S, Donohoe, G, McDonald, C, Cannon, DM, Corvin, A, Gill, M, Di Giorgio, A, Bertolino, A, Lawrie, S, Nickson, T, Whalley, HC, Neilson, E, Calhoun, VD, Thompson, PM, Turner, JA, and Ehrlich, S

Subjects
Karolinska Schizophrenia Project Consortium, Prefrontal Cortex, Humans, Magnetic Resonance Imaging, Linear Models, Schizophrenia, Psychiatric Status Rating Scales, Schizophrenic Psychology, Internationality, Image Processing, Computer-Assisted, Adult, Female, Male, Functional Laterality, Cortical thickness, ENIGMA, FreeSurfer, MRI, PANSS, SANS, medial orbitofrontal cortex, negative symptoms, schizophrenia, Image Processing, Computer-Assisted, Psychiatry, Psychology, Public Health and Health Services, Neurosciences
Abstract

BackgroundOur understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.MethodsThis study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).ResultsMeta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (β std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.ConclusionsUsing an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Published
2018

32. Red-shifted luciferase-luciferin pairs for enhanced bioluminescence imaging.

Author

Yeh, Hsien-Wei, Karmach, Omran, Ji, Ao, Carter, David, Martins-Green, Manuela M, and Ai, Hui-Wang

Subjects
Animals, Mice, Inbred BALB C, Humans, Mice, Firefly Luciferin, Luciferases, Luminescent Measurements, Staining and Labeling, Cell Survival, HEK293 Cells, Biomedical Imaging, Generic health relevance, Biological Sciences, Technology, Medical and Health Sciences, Developmental Biology
Abstract

Red-shifted bioluminescence reporters are desirable for biological imaging. We describe the development of red-shifted luciferins based on synthetic coelenterazine analogs and corresponding mutants of NanoLuc that enable bright bioluminescence. One pair in particular showed superior in vitro and in vivo sensitivity over commonly used bioluminescence reporters. We adapted this pair to develop a bioluminescence resonance-energy-based Antares reporter called Antares2, which offers improved signal from deep tissues.

Published
2017

33. A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter.

Author

Wu, Jun, Ao, Ming-Tao, Shao, Rui, Wang, Hui-Ru, Yu, Diao, Fang, Mei-Juan, Gao, Xiang, Wu, Zhen, Zhou, Qiang, and Xue, Yu-Hua

Subjects
Chalcones, Cyclin-Dependent Kinase 9, Gene Expression Regulation, Viral, Genes, Reporter, HIV Infections, HIV-1, Humans, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Virus Activation, Virus Latency, tat Gene Products, Human Immunodeficiency Virus
Abstract

The principal barrier to the eradication of HIV/AIDS is the existence of latent viral reservoirs. One strategy to overcome this barrier is to use latency-reversing agents (LRAs) to reactivate the latent proviruses, which can then be eliminated by effective anti-retroviral therapy. Although a number of LRAs have been found to reactivate latent HIV, they have not been used clinically due to high toxicity and poor efficacy. In this study, we report the identification of a chalcone analogue called Amt-87 that can significantly reactivate the transcription of latent HIV provirses and act synergistically with known LRAs such as prostratin and JQ1 to reverse latency. Amt-87 works by activating the human transcriptional elongation factor P-TEFb, a CDK9-cyclin T1 heterodimer that is part of the super elongation complex (SEC) used by the viral encoded Tat protein to activate HIV transcription. Amt-87 does so by promoting the phosphorylation of CDK9 at the T-loop, liberating P-TEFb from the inactive 7SK snRNP, and inducing the formation of the Tat-SEC complex at the viral promoter. Together, our data reveal chalcones as a promising category of compounds that should be further explored to identify effective LRAs for targeted reversal of HIV latency.

Published
2017

34. Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium

Author

Walton, E, Hibar, DP, Erp, TGM, Potkin, SG, Roiz‐Santiañez, R, Crespo‐Facorro, B, Suarez‐Pinilla, P, Van Haren, NEM, Zwarte, SMC, Kahn, RS, Cahn, W, Doan, NT, Jørgensen, KN, Gurholt, TP, Agartz, I, Andreassen, OA, Westlye, LT, Melle, I, Berg, AO, Mørch‐Johnsen, L, Færden, A, Flyckt, L, Fatouros‐Bergman, H, Consortium, Karolinska Schizophrenia Project, Jönsson, EG, Hashimoto, R, Yamamori, H, Fukunaga, M, Preda, A, De Rossi, P, Piras, F, Banaj, N, Ciullo, V, Spalletta, G, Gur, RE, Gur, RC, Wolf, DH, Satterthwaite, TD, Beard, LM, Sommer, IE, Koops, S, Gruber, O, Richter, A, Krämer, B, Kelly, S, Donohoe, G, McDonald, C, Cannon, DM, Corvin, A, Gill, M, Di Giorgio, A, Bertolino, A, Lawrie, S, Nickson, T, Whalley, HC, Neilson, E, Calhoun, VD, Thompson, PM, Turner, JA, and Ehrlich, S

Subjects
Schizophrenia, Mental Health, Brain Disorders, Mental health, Good Health and Well Being, Adult, Brain Mapping, Female, Humans, Magnetic Resonance Imaging, Male, Prospective Studies, Psychiatric Status Rating Scales, Schizophrenic Psychology, Temporal Lobe, schizophrenia, positive symptoms, superior temporal gyrus, cortical thickness, ENIGMA, FreeSurfer, MRI, scale for the assessment of positive symptoms, positive and negative syndrome scale, Karolinska Schizophrenia Project Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveBased on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia.MethodThis prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness.ResultsPositive symptom severity was negatively related to STG thickness in both hemispheres (left: βstd = -0.052; P = 0.021; right: βstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness.ConclusionOur findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

Published
2017

35. Effects of hospital facilities on patient outcomes after cancer surgery

Author

Knight, Sr, Chu, K, Lapitan, Mc, Dare, Aj, Pius, R, Shaw, Ca, Drake, Tm, Norman, L, Ademuyiwa, Ao, Adisa, Ao, Aguilera, Ml, Al-Saqqa, Sw, Al-Slaibi, I, Bhangu, A, Biccard, Bm, Brocklehurst, P, Costas-Chavarri, A, Elhadi, M, Fairfield, Cj, Fitzgerald, Je, Ghosh, D, Glasbey, J, Henegouwen, Miv, Ingabire, Jca, Kingham, Tp, Lawani, I, Lieske, B, Lilford, R, Martin, J, Mclean, Ka, Moore, R, Morton, D, Nepogodiev, D, Ntirenganya, F, Pata, F, Pinkney, T, Stephen, R Knight, Catherine, A Shaw, Riinu, Pius, Thomas, M Drake, Lisa, Norman, Adesoji, O Ademuyiwa, Adewale, O Adisa, Maria Lorena Aguilera, Sara, W Al-Saqqa, Ibrahim, Al-Slaibi, Aneel, Bhangu, Bruce, M Biccard, Peter, Brocklehurst, Ainhoa, Costas-Chavarri, Kathryn, Chu, Anna, Dare, Muhammed, Elhadi, Cameron, J Fairfield, J Edward Fitzgerald, Dhruv, Ghosh, James, Glasbey, Mark, I van Berge Henegouwen, C Allen Ingabire, J, T Peter Kingham, Marie Carmela Lapitan, Ismaïl, Lawani, Bettina, Lieske, Richard, Lilford, Janet, Martin, Kenneth, A McLean, Rachel, Moore, Dion, Morton, Dmitri, Nepogodiev, Faustin, Ntirenganya, Francesco, Pata, Thomas, Pinkney, Ahmad Uzair Qureshi, Antonio Ramos-De la Medina, Aya, Riad, Hosni Khairy Salem, Joana, Simões, Richard, Spence, Neil, Smart, Stephen, Tabiri, Hannah, Thomas, Thomas, G Weiser, Malcolm, West, John, Whitaker, Ewen, M Harrison, Arben, Gjata, Maria Marta Modolo, Sebastian, King, Erick, Chan, Sayeda Nazmun Nahar, Ade, Waterman, Dominique, Vervoort, Alemayehu Ginbo Bedada, Bernardo De Azevedo, Ana Gabriela Figueiredo, Manol, Sokolov, Venerand, Barendegere, Gerald, Ekwen, Arnav, Agarwal, Qinyang, Liu, Juan Camilo Correa, Kalisya Luc Malemo, Jacques, Bake, Jakov, Mihanovic, Kamila, Kunčarová, Julius, Orhalmi, Hosni, Salem, Jyri, Teras, Aristotelis, Kechagias, Alexis, P Arnaud, Judith, Lindert, Vasileios, Kalles, Maria-Lorena, Aguilera-Arevalo, Gustavo, Recinos, Zsolt, Baranyai, Basant, Kumar, Harish Neelamraju Lakshmi, Sanoop Koshy Zachariah, Philip, Alexander, Sunil Kumar Venkatappa, Pramesh, C, Radhian, Amandito, Christina, Fleming, Luca, Ansaloni, Gianluca, Pellino, Ahmed, M Altibi, Ibrahim, Nour, Intisar, Hamdun, Ali, M Ghellai, Donatas, Venskutonis, Tomas, Poskus, Justas, Zilinskas, Precious, Malemia, Yong Yong Tew, Elaine, Borg, Sarah, Ellul, Fatima Zahraa Wafqui, David, W Borowski, Anne Sophie van Dalen, Cameron, Wells, Harissou, Adamou, Adesoji, Ademuyiwa, Adewale, Adisa, Kjetil, Søreide, Sara Al Saqqa, Osaid, Alser, Haya, Tahboub, Helmut Alfredo Segovia Lohse, Sebastian Shu Yip, Piotr, Major, António Sampaio Soares, Matei Razvan Bratu, Andrey, Litvin, Armen, Vardanyan, Ahmad, Gudal, Naif, Albati, Jovan, Juloski, Miran, Rems, Sarah, Rayne, Stephanie Van Straten, Yoshan, Moodley, Irene Ortega Vázquez, Jaime, Ruiz-Tovar, Kithsiri Janakantha Senanayake, Sujeewa Priyantha Bandara Thalgaspitiya, Omer Abdelbagi Omer, Anmar, Homeida, Yucel, Cengiz, Daniel, Clerc, Muhammad, Alshaar, Hanen, Bouaziz, Yuksel, Altinel, Matthew, Doe, Maryna, Freigofer, Ella, Teasdale, Rakan, Kabariti, Joshua Michael Clements, Stephen Richard Knight, Ahsan, Ashfaq, Ijeoma, Azodo, Gabriela, Wagner, Ivan, Trostchansky, Mayaba, Maimbo, David, Linyama, Helidon, Nina, Amanda, Zeko, Claudio Gabriel Fermani, Santiago, Villalobos, Federico, Carballo, Pablo, Farina, Sebastian, Guckenheimer, Marilla, Dickfos, Ankit, Ajmera, Chester, Chong, Ralph, Gourlay, Sikandar, Hussaini, Yi Jia Lee, Adeeb, Majid, Peter, Martin, Rebecca, Miles, Owen James Morris, Jamie, Phua, William, Ridley, Tarunpreet, Saluja, Ryan Renxin Tan, Jen, Teh, Anna, Wells, Bharti, Arora, Qaasim, Dollie, Debbie, Ho, Yanru, Ma, Omattage Mahasha Perera, Anthony, Truong, Amanda Caroline Dawson, Bryan, Lim, Upuli, Pahalawatta, Jacqueline, Phan, Xiao-Ming Sarah Woon-Shoo-Tong, Andrea, Yeoh, Lillian, Charman, Andrew, Drane, Sharon, Laura, Charmaine Chu Wen Lo, Amy, Mozes, Rita, Poon, Hao Han Tan, Ellen, Wall, Prakshi, Chopra, Jasmine De Giovanni, Bal, Dhital, Brian, Draganic, Alexander, Duller, Jonathan, Gani, Yao Kuan Goh, Jun Young Jeong, Brendan, Mcmanus, Prakash, Nagappan, Peter, Pockney, Anya, Rugendyke, Mahsa, Sarrami, Stephen, Smith, Vanessa, Wills, Hsu Ven Wong, Geoffrey, Ye, Geoffrey, Zhang, Ethan, Brooker, Daniel, Feng, Bonnie, Lau, Carlin, Ngai, Sarah, Birks, David, Gyorki, Jaime Otero de Pablos, Ali, Abbosh, Chris, Gillespie, Ahmed, Mahmoud, Bianca, Kwan, Joshua, Lawson, Andrea, Warwick, Janne, Bingham, Andrew, J Cockbain, Nagendra Naidu Dudi-Venkata, Jordan, Ellaby-Hall, Ben, Finlay, Emily, Humphries, Jade, Pisaniello, Monique, Pisaniello, Salma, Salih, Tarik, Sammour, Haidar Hadri Abd Wahab, April De Silva, Nicola, Hayward, Kartik, Iyer, Guy, Maddern, Gian Andrea Prevost, Naga, Annapureddy, Krishna Pranathi Settipalli, Jeremy, Yeo, Lucy, Hempenstall, Lily, Pham, Shaun, Purcell, Cherry, Talavera, Ashish, I Vaska, Gurpreet, Chaggar, Phillip, Chrapko, Annelise, Cocco, Sarah Michelle Crystal Jade Coulter-Nile, Grahame, Ctercteko, James, French, Houchen, Gong, Martijn, Gosselink, Thuvarahan, Jegathees, Ivan, Jin, Michelle, Kalachov, Kathryn, Kiefhaber, Katherine, Lee, Jason, Luong, Steven, Phan, Henry, Pleass, Kelly, Veale, Zhi, Zeng, Angela, Au, Ashe, Debiasio, Idy, Deng, Jananee, Myooran, Amrita, Nair, Peter, Stewart, Anton, Stift, Lukas Walter Unger, Kerstin, Wimmer, Nabila, Ahmed, Syed, Hasan, Saber, Rahman, Margaret, O'Shea, Greg, Padmore, Adrian, Peters, Pietro, Perduca, Guenda, Pulcina, Nicolas, Tinton, Frederic, Buxant, Elsa, Dabin, Giulia, Garofalo, Francis, Dossou, Freddy Houehanou Rodrigue Gnangnon, Yacoubou Imorou Souaibou, Pako, Motlaleselelo, Omphile, Tlhomelang, Igor Lima Buarque, Gustavo Mendonça Ataíde Gomes, Aldo Vieira Barros, Ilia, Batashki, Nikolai, Damianov, Vladislav, Stoyanov, Dragomir, Dardanov, Svilen, Maslyankov, Plamen, Petkov, George, Todorov, Evgeni, Zhivkov, Aygulya, Akisheva, Miguel Angel Castilla Moreno, Geno, Genov, Ivelina, Ilieva, Tsvetomir, Ivanov, Martin, Karamanliev, Azhar, Khan, Emil, Mitkov, Tsanko, Yotsov, Boyko, Atanasov, Nikolay, Belev, Mihail, Slavchev, Carlos, Nsengiyumva, Elgan, Jones, Simon, Stock, Steve, Kyota, James, Brown, Tresor Mabanza, K, Lemery Nigo Samuel, Chidi, Otuneme, Ngwang, Prosper, Franklin, Umenze, Marylise, Boutros, Natasha, Caminsky, Sinziana, Dumitra, Richard, Garfinkle, Dominique, Morency, Ebram, Salama, Alexander, Banks, Lorenzo, Ferri, Haitian, He, Amit, Katz, Alexander Sender Liberman, Sarkis, Meterissian, Allison, Pang, Elena, Parvez, Usmaan, Hameed, Fahima, Osman, Sangita, Sequeira, Natalie, Coburn, Alisha, Jaffer, Paul, Karanicolas, Matthew, Mosseler, Reilly, Musselman, Xinyuan, Liu, Ching Wan Yip, Juan Sebastian Garces-Otero, Carolina, Guzman, Sebastian, Sierra, Andres Uribe Valencia, Paulo Andrés Cabrera Rivera, Saul, Camelo, Andrea, Gonzalez, Alejandro, González-Orozco, Manuel Santiago Mosquera Paz, Carlos J- Perez Rivera, Felipe, Gonzalez, Andres, Isaza-Restrepo, Laura, Nino-Torres, Natalia Arias Madrid, Maria Clara Mendoza Arango, Justin, Tsandiraki, Damir, Jemendžić, Branislav, Kocman, Oliver, Šuman, Renata, Canic, Darko, Jurišić, Ivana, Karakas, Ana Krizanovic Rupcic, Vlatka, Pitlovic, Josip, Samardžić, Mario, Kopljar, Ivan, Bacic, Edgar, Domini, Robert, Karlo, Danijela, Miljanić, Andrea, Simic, Mariam, Ahmed, Majdi Al Nassrallah, Rabiya, Altaf, Talal, Amjad, Ruba, Eltoum, Heba, Haidar, Alhassan, Hassan, Omar, Khalil, Marwan, Qasem, Rommel, Ramesh, Gautham, Sajith, Maham, Wisal, Jan, Žatecký, Michele, Bujda, Katerina, Jirankova, Ales, Paclik, Aya, Abdallah, Mariam Abdulgawad Almogy, Esraa Ayman El-Sawy, Ahmed Moustafa ElFayoumy, Nourhan, Elghareeb, Nourhan Ahmed Esmat, Ahmed, Fadel, Abdullah, Habater, Heba, Hamdy, Amr, Hefni, Marwa, Kamal, Norhan Mohamed Abobakr, Ahmed, Sayed, Nancy, Shaker, Ehab, Taha, Hoda, Tharwat, Omar, Zakaria, Ibrahem, Abdelmotaleb, Ali, Al-Dhufri, Hamza, S Al-Himyari, Enas El Sheikh, Asmaa, Eldmaty, Aya, Elkhalawy, Ahmed, M Elkhashen, Kithara, Magdy, Safa, Mostafa, Habib Doutoum Sadia, Mohamed Mahmoud Saleh, Dina, Samir, Mohamed Yahia Mohamed Ali, Mahmoud, A Nassar, Samar, Abdelhady, Aly, Abdelrazek, Israa, Abdelsalam, Aya, El-Sawy, Eman, Essam, Mohamed, Gadelkarim, Khaled, Ghaly, Mohamed, Hassabalnaby, Rana, Masarani, Nourhan Mohamed Shaaban, Ahmed, Sabry, Menatalla, Salem, Nourhan Akram Soliman, Diaaaldin, Zahran, Moustafa Ramadan Abou El Soud, Esraa Tarek Badr, Hala, Borham, Nehal, Elmeslemany, Mohammad, Elsayed, Fawzia, Elsherif, Sara, Eslam, Gehad, Gaber, Sondos, Ibrahim, Yara, Kamh, Abdelrahman, Mahmoud, Shimaa Gamal Mohamed, Eman, Morshedy, Cinderella, Omar, Fatima Salem Soliman, Shaza, Abdelkawy, Naglaa, Abdelmohsen, Mahmoud, Abdelshakour, Ahmed, Dahy, Norhan, Gamal, Mohammed, Gamal, Ahmad, Hasan, Helal, Hetta, Nehad, Mousa, Mohamed, Omar, Somia, Rabie, Mahmoud, Saad, Bakeer, Saleh, Marwa Sayed Mohamed, Muhammad, Shawqi, Heba Abdelhady Mousa, Mostafa, Alnoury, Mohamed, Elbealawy, Ahmed, Elshafey, Muhammad Essam Ibrahim El Desouki Muhammad Ahmed, Mennatullah, Ghonaim, Fawzy, Hgag, Mohamed, Ibrahim, Mahmoud, Morsy, Mohamed Reda Loaloa, Ahmed, Refaat, Hadeer, Samir, Fatma, Shahien, Mohamed, Sobhy, Fathy, Sroor, Esraa, Abdellatif, Marina, Adel, Amr Abdelghani Afifi, Eman, Afifi, Marco, Antaky, Amr, Dawoud, Naira El Zoghby, Amira, El-Remaily, Ali Abdelazez Elzanfaly, Ahmed, Gadallah, Fatma Alzahraa Gamal, Omar, Hashem, Shrouk Medhat Youssef, Aliaa Muhammad Attyah, Malak, Munir, Omar, Shazly, Esraa, Taha, Karim, Wilson, Sawsan, Adel, Asmaa, Ali, Esraa, Eid, Esraa, Elhelow, Marwa, Elmahdy, Bassant, Elshatby, Amany Hossam El-Din Zakaria, Ahmad, Hossny, Eman, Ibrahim, Ahmed, M Yonis, Maram, Metwalli, Basant, Yousry, Esraa, Zid, Mina, A Yacoub, Ahmed, Abdelhakim, Nervana, Abouelsoad, Mo'Min, Alkhatib, Ahmed, Ashraf, Alaa, Ashraf, Yasmin, Elazab, Mahmoud, Elfanty, Osama, Elkabir, Mai, Elsayed, Ahmed, Elshimy, Hager, Elsobky, John, Eskander, Ahmed, Gad, Ward, Hamsho, Noura Khaled Abdelwahed, Menna, Magdy, Dalia, Moharam, Abeer, Osama, Shereen, Ramadan, Radwa, Roum, Taqwa, Sayed, Tarneem, Shehada, Ahmed Mohy Zidan, Khalid, Abbas, Amr, Ali, Mohamed, Attia, Mohamed, Balata, Ayman El Nakeeb, Mohamed Ibrahim Elsayed Elewaily, Ahmed, Elfallal, Hossam, Elfeki, Ahmed, Elkhadragy, Sameh, Emile, Helmy, Ezzat, Hasnaa, Hosni, Islam, Mansour, Waleed, Omar, Gehad, Othman, Kareem, Sadek, Mostafa, Shalaby, Noura, Shehab-Eldeen, Rawda Anas Khalifa, Helmy, Badr, Mostafa, Eldeep, Ahmed, Eldeep, Amany Eldoseuky Mohammed, Salwa, Khallaf, Eman Magdy Hegazy, Rokia, Mahmoud, Pola, Mikhail, Mahmoud, Morsi, Sara, Mowafy, Dina, Raafat, Amina, Safy, Marwa, Sera, Ahmed Shible Sera, Mostafa Salim Mohamed AbdAllah, Muhammad, Abdelkader, Abdulrahman Osama Abdou, Ahmedgaber, Ahmed, Shireen, Gaafar, Fatma Ibrahim Negm, Mina, Lapic, Ahmed, Maher, Hagar, Mahmoud, Ahmed, Mostafa, Mohamed, Samir, Fatma, Samy, Nourhan, Semeda, Hind, I Shalaby, Alaa, El-Taweel, Ahmed Galal Elnagar, Ahmed Gamal Hemidan, Mohamed, Hussein, Ahmed, A Kandil, Moawad, Mf, Ayat Allah Nasser Hamamah, Mostafa, Soliman, Mohamed, Abdelkhalek, Noura Abdelmaksoud Tawakel, Ahmed Mohamed Abdelwahed, Alrawy, Abdou, Khalid, Atallah, Mohammed Yasser Elsherbeny, Eman, Emara, Mohamed, Hamdy, Omar, Hamdy, Amira, Haron, Salma, Ismail, Islam Hany Metwally, Nihal Mohamed Hamed Elgaml, Ahmed, Nassar, Basel, Refky, Mirna, Sadek, Mahmoud, Saleh, Asmaa, Yunes, Mai, Zakaria, Mohammed, Zuhdy, Notila, Fayed, Mohammed Mustafa Hassan Mohammed, Sander, Kütner, Priit, Melnik, Indrek, Seire, Toomas, Ümarik, Eppu, Ainoa, Verner, Eerola, Hanna, Koppatz, Laura, Koskenvuo, Ville, Sallinen, Sini, Takala, Jevgeni, Katunin, Arto, Turunen, Niki, Christou, Muriel, Mathonnet, Vincent, Lavoue, Krystel Nyangoh Timoh, Lucie, Soulabaille, Romain, Lesourd, Aude, Merdrignac, Laurent, Sulpice, Benoît, André, Elodie, Chantalat, Charlotte, Vaysse, Bertrand, Dousset, Sebastien, Gaujoux, Gregory, Martin, Octavian, Clonda, Domantas, Juodis, Klaus, Kienle, Andras, Mravik, Samuel, Palmer, Gabor, Szabadhegyi, Anita Eseenam Agbeko, Solomon, Gyabaah, Frank Enoch Gyamfi, Nuhu, Naabo, Atta Owusu Senior, Joseph, Yorke, Frank, Owusu, Francis, Abantanga, Theophilus Teddy Kojo Anyomih, Abdul-Jalilu Mohammed Muntaka, Emmanuel Owusu Abem, Mohammed, Sheriff, Paul, M Wondoh, Dimitrios, Balalis, Dimitrios, Korkolis, Georgios, Gkiokas, Eirini, Pantiora, Theodosios, Theodosopoulos, Argyrios, Ioannidis, Konstantinos, Konstantinidis, Sofia, Konstantinidou, Nikolaos, Machairas, Anna, Paspala, Anastasia, Prodromidou, Christos, Chouliaras, Konstantinos, Papadopoulos, Ioannis, Baloyiannis, Ioannis, Mamaloudis, George, Tzovaras, Ioanna, Akrida, Maria-Ioanna, Argentou, Stylianos, Germanos, Evangelos, Iliopoulos, Ioannis, Maroulis, George, Skroubis, George, Theofanis, Christos, Chatzakis, Orestis, Ioannidis, Lydia, Loutzidou, Panagiotis, Karathanasis, Nikolaos, Michalopoulos, Charalampos, Theodoropoulos, Dimitrios, Theodorou, Tania, Triantafyllou, Zoe, Garoufalia, Natasha, Hasemaki, Michalis, Kontos, Gregory, Kouraklis, Stylianos, Kykalos, Theodore, Liakakos, Eustratia, Mpaili, Alexandros, Papalampros, Dimitrios, Schizas, Athanasios, Syllaios, Ekaterini Christina Tampaki, Antonios, Tsimpoukelis, Maria Ioanna Antonopoulou, Eirini, Deskou, Dimitrios, K Manatakis, Dimitrios, Papageorgiou, Menelaos, Zoulamoglou, Christos, Anthoulakis, Michalis, Margaritis, Nikolaos, Nikoloudis, Veronica, Campo, André, Ceballos, Mario-Andrés, Flores, Waleska, Giron, Donghyun, Ko, Gabriel, Martinez, Verónica Rivera Lara, Nataly, Rueda, Andres, Sanchez, Jorge Carlos Guillermo Tejeda Garrido, Alvaro Eduardo Alvarez Rivera, Elvis Benjamin Bamaca Ixcajoc, Lilian Elizabeth Barreda Zelaya, Patricia, Chacòn-Herrera, Ligia Margarita Corea Ruiz, Guillermo, Echeverria-Davila, Mario, Garcia, Danilo, García, Edgar Fernando Gutiérrez Mayen, Noriega, José, Nery, Mazariegos, Diego, Méndez, Michael Paniagua Espinoza, David, Bardos, Marton, Benke, Kristof, Illes, Balint András Kokas, Réka, Szabó, Akhila, Appukuttan, Anjitha, Asok, D K, Vijaykumar, Kapil, 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Jabaiti, Jamal, Melhem, Yasmeen, Z Qwaider, Mohammad Hasan Salameh, Ahmad, Suleihat, Haya, H Suradi, Mohammad, Alammarin, Almoutuz, Aljaafreh, Mohammad Bani Hani, Zeina Bani Hani, Farah Bani Hani, Toqa, Fahmawee, Shadi, Hamouri, Cyrine, Katanani, Ra'Fat, Tawalbeh, Tamara, Tawalbeh, Hassan, Zawahrah, Mohamad, K Abou Chaar, Lana, Abusalem, Mahmoud, Al-Masri, Hani, Al-Najjar, Lutfi, Barghuthi, Zahra, Ahmed, Adnan, Maulana, Omar, Ngotho, Charbel, Kamau, Aruyaru Stanley Mwenda, Fridah, Bosire, Elizabeth, Mwachiro, Robert, Parker, Ian, Simel, Kimutai, Sylvester, Abdulmunem Ahmed Mustafa Althini, Sofian, Elbarouni, Aya Elseed Elbeshina, Ahmed, Gwea, Ans, Malek, Wedad Albashir Masoud Farag, Abdulwahab, Abdalei, Abu Baker Abdel Malik, Areej, Abo-Khammash, Ma'Aly, Abuhlaiga, Nour, Adnan, Marwa, Albaggar, Asma, Alfitory, Asma, Aljanfi, Fakhruddin, Almuzghi, Zohoor, Altumei, Fatima, Alzabti, Hana, Ashoushan, Mohamed, Assalhi, Joma, Azzubia, Sondos, Bnhameida, Malik, Delhen, Houssein, Elshafei, 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Eray, Eray, Kurnaz, Saygin, Altiner, Mustafa Deniz Tepe, Can, Şahin, Evrim, Savli, Aryon, Innocent, Lilian, Babirye, Andrii, Diachenko, Vladislav, Hordoskiy, Heather, Curry, Charlene Yat Che Chau, Harry, Robertson, Arin, Mahmoud, Hannah, Lennon, Lynette, Loi, Emily, Kirkham, Cameron, Mccann, Daniel, Watts, Binay, Gurung, Michael, Wilson, Thomas, Tribedi, Eleonora, Garofalo, Baryab, Zahra, Scott, Macdonald, Ian, Daniels, Nathan, Ng, Shivun, Khosla, James, Olivier, Sum Yu Pansy Yue, Gayathri, Suresh, Jack, Wellington, Emmanuel, Lorejo, Mafdi, Mossaad, Madison, Crutcher, Marjan, Alimi, Ioana, Baiu, Hossam, Abdou, Alison, Conway, Connor, Peck, Mauro Andres Perdomo Perez, Stanley, Zulu, Mildred, Nakazwe, Sule, Burger, Justine, Davies, Rachel, Donaldson, Chikwendu, Ede, O James Garden, Chiapo, Lesetedi, Charles, Mabedi, Laura, Magill, Felix Makinde Alakaloko, Alex, Makupe, Mark, Monahan, Soloman, Mulira, Elmi, Muller, Jospeh, Musowoyo, Jean Léon Olory-Togbe, Tracey, Roberts, Martin, Smith, Viki, Tayler, John, Windsor, Raul, Yepez, Sudha, Sundar, Emmy, Runigamugabo, Azmina, Verjee, José, Chen, Leonid, Daya, Nouhaila El Aroussi, Valeria, Farina, Tchianze Gnintedeme Olivier, Mauricio Gonzales Nacarino, Aamr, Hammani, Sarah, Honjo, Rebecca, Jacobs, Hitomi, Kimura, Mugisha, Nkoronko, Jasson Javier Oscullo Yepez, Wei Pin Hung, Ankit, Raj, Alina Romani Pozo, Muna, Rommaneh, Samuel Chimbioputo Sassamela Fabiano, Camila Milagros Shiroma Gago, Abhishekh, Srinivas, Chia-Yen, Sung, Aswan, Tai, Yener Cristyell Valle Aranda, Sara, Venturini, Jean Wilguens Lartigue, Abhinav, Tiwari, Andreas, Karwath, Dawson, Brett E., Chetan, Khatri, Daoud, Chaudhry, Elizabeth, Li, Ella, J Marson, Taylor, Elliott H., Georgios, Gkoutos, Harvinder, Mann, Trout, Isobel M., James, C Glasbey, Keatley, James M., Mclean, Kenneth A., Kwabena, Siaw-Acheampong, Laura, Bravo, Leah, Argus, Luke, Slater, Maria, Picciochi, Mary, Venn, Omar, M Omar, Gujjuri, Rohan R., Kamarajah, Sivesh K., Victor Roth Cardoso, 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Albashir Masoud Farag, Abdulwahab Abdalei, Abu Baker Abdel Malik, Areej Abo-Khammash, Ma'aly Abuhlaiga, Nour Adnan, Marwa Albaggar, Asma Alfitory, Asma Aljanfi, Fakhruddin Almuzghi, Zohoor Altumei, Fatima Alzabti, Hana Ashoushan, Mohamed Assalhi, Joma Azzubia, Sondos Bnhameida, Malik Delhen, Houssein Elshafei, Hana Elteir, Fatima Esbaga, Abdel Aziz Gobbi, Fatma Hamouda, Hamdan Hilan, Rania Ismail, Fieruz Jebran, Muataz Kasbour, Galia Maderi, Saja Mohammad, Burooj Mohammed, Habib Murtadi, Hamassat Mustafa, Mohamed Rajab, Sarah Trenba, Mariam Wafaa, Eman Al Sagheir, Alabas Almigheerbi, Ahmed Alzahaf, Sumayyah Ghayth Bahroun, Najah Ben Dallah, Mahmoud Elshaibani, Haitem Eswaye, Maha Karar, Samah Omar, Eman Younes, Maha Younes, Dafer Zreeg, Saleh Abujamra, Firas Ashour, Mala Elgammudi, Wesal Omar F Aljadidi, Enas Saddouh, Randa Sharif, Aya Alabuzidi, AbdulMawlay Alwerfally, Sarra Aribi, Fatma Bibas, Taha Elfaituri, Yasmine Elhajjaji, Ala Khaled, Wegdan Khalil, Tesneem Layas, Enas Soula, Ahmed Tarek, Muad Fathi Khalleefah Abu Hallalah, Saleh Abujamra, Hazem Abdelkarem Ahmed, Tagwa Alsharef, Abdulsalam Ali Ben Saoud, Tasnim El Gharmoul, Ahmed Elhadi, Safa Elrais, Abdulhalim Shebani, Heba Zarti, Asaid Zeiton, Marijus Ambrazevicius, Nerijus Kaselis, Migle Stakyte, Oleg Aliosin, Agne Cizauskaite, Sarunas Dailidenas, Vitalijus Eismontas, Migle Kybransiene, Vitalija Nutautiene, Narimantas Samalavicius, Dainius Simcikas, Algirdas Slepavicius, Albinas Tamosiunas, Nerijus Ubartas, Paulius Zeromskas, Saulius Bradulskis, Edvinas Dainius, Juozas Juočas, Egle Kubiliute, Juozas Kutkevičius, Aurimas Opolskis, Audrius Parseliunas, Andrejus Subocius, Donatas Venskutonis, Egle Virbickaite, Diana Zuikyte, Algirdas Bogusevicius, Kristina Buzaite, Daiva Čepuliené, Ieva Cesleviciene, Vaidotas Cesna, Jolanta Gribauskaite, Povilas Ignatavicius, Mantas Jokubauskas, Monika Liugailaitè, Ernest Margelis, Ruta Mazelyte, Lina Pankratjevaitè, Matas Pažusis, Agne Rackeviciute, Justina Saladyte, Monika Škimelytè, Vygintas Šlenfuktas, Monika Sudeikyte, Algimantas Tamelis, Tomas Vanagas, Žygimantas Žumbakys, Aivaras Atkociunas, Audrius Dulskas, Justas Kuliavas, Justas Birutis, Sigitas Paškevičius, Mindaugas Šatkauskas, Donatas Danys, Matas Jakubauskas, Lina Jakubauskiene, Marius Kryzauskas, Vytautas Lipnickas, Gabija Makūnaitè, Fanjandrainy Rasoaherinomenjanahary, Herizo Rasolofonarivo, Luc Hervé Samison, Bitiel Banda, Precious Malemia, Vanessa Msosa, Ahmad Imran Ahmad Izzuddin, Andre Das, Ying Yee Gan, Tan Shong Sheng, Jia Yng Siaw, Mohd Fadliyazid Ab Rahim, Dyg Zahratul Hamrak Abang Jamari, Nurfariza Che Husin, Muhd Yusairi Kamarulzaman, Yi Ping Lim, Nil Amri Mohamed Kamil, Mohd Razeen Mohd Hassan, Saidah Mohd Sahid, Johari Mustafa, Elaine Hui Been Ng, Wan Khamizar Wan Khazim, Ng Chang Ern, P G Lingeshan, Syariz Ezuan Sulaiman, Sue Ean Ang, Muhammad Navid Bin Mohamad Sithik, Yih Jeng Cheong, Mahadevan Deva Tata, Law Jia Xian, Aravinthan Kadravello, I-Ern Koh, Li-Yen Ng, Yuki Julius Ng We Yong, Kandasami Palayan, Chi Xuan Sam, Phuah Siow Jin, Jeremy Tan Ern Hwei, Yita Tang, Alvin Zubin Ter, Michael Pak-Kai Wong, Andee Dzulkarnaen Zakaria, Zaidi Zakaria, Fitjerald Henry, Thyivya Kalaiselvan, Muhammad Fairuz Shah Abd Karim, Mohamed Rezal Abdul Aziz, Nora Abdul Aziz, Tak Loon Khong, Peng Choong Lau, Hiong Chin Lim, April Camilla Roslani, Jonathan Chen Ken Seak, Sui-Weng Wong, Lai Fen Wong, Leow Yeen Chin, Mercy Chinemerem Anyanwu, Elaine Borg, Zachary Busuttil, Thomas Calleja, Kurt Lee Chircop, Ruth Cutajar, Andrew Michael Dimech, Sarah Ellul, Joseph Galea, Kiara Gascon Perai, Ruth Gatt, Lisa Kelman, Elizabeth Micallef, Favour Nwolu, Kim Sammut, Joanna Thompson, Sean Warwicker, Matthew Zammit, Fernando Cordera, Efraín Cruz González, Jorge Sánchez-García, Francisco José Barbosa Camacho, Francisco Javier Barrera López, Carlos Jose Zuloaga Fernandez Del Valle, Eric Acosta, Iván Romarico González Espinoza, Perla Moreno, Ana Olivia Cortes-Flores, Clotilde Fuentes Orozco, Alejandro Gonzalez Ojeda, Samantha Corro Díaz González, Laura Martinez, Antonio Ramos-De la Medina, Bonifacio Mosqueda Amador, Armando Novoa, Dennet Arturo Olazo Espejo, Alejandro Jimenez, Federico Lopez Rosales, Elva Gabriela Vanoye, Luis Alberto Garcia Gonzalez, Roberto Carlos Miranda-Ackerman, Manuel Solano-Genesta, Alethia Alvarez-Cano, Hector Hugo Romero-Garza, Heriberto Medina-Franco, Lorelí Mejía-Fernández, Noel Salgado-Nesme, Omar Vergara-Fernandez, Guadalupe Montserrat Gutiérrez-Mota, Francisco Xavier Hernandez Vera, Anabella Llantada Lopez, Gilberto Morgan Villela, Felipe de Jesus Ramirez Padilla, Walezka Tapia Marin, Mónica Martínez Maldonado, Ramses Sánchez Suárez, José Manuel Troche, Chaymae Benyaiche, Oumaima Outani, Souadka Amine, Amine Benkabbou, Anass Mohammed Majbar, Raouf Mohsine, Ali Rafik, Thida Oung, Moe Moe Tin, David W Borowski, Philipp Plarre, David W Borowski, Philipp Plarre, Anna Alberga, Nina Sluiter, Jurriaan Tuynman, Robin Blok, Didem Cömert, Roel Hompes, Marianne Kalff, Merel Elisabeth Stellingwerf, Pieter Tanis, Mark van Berge Henegouwen, Elise Maria van Praag, Daan Wisselink, Michael Gerhards, Josephine Lopes Cardozo, Emma Westerduin, Joske de Jonge, Aaw van Geloven, Kaz van Schilt, Frank den Boer, Simone Stoots, Stijn Vlek, Jamie Adams, Ibrahim S Al-Busaidi, Gabrielle Budd, Seung Il Choi, Michael Jen Jie Chu, Anurag Ganugapati, Lucy McKinstry, Rebecca Pascoe, Simon Richards, Kenrick Rosser, Annie Stevenson, Rebecca White, Shebani Farik, Jin Kwun, Ahmed Murad, Sarah Cowan, Timothy Hall, Michael Hayton, Laminou Malam Sani, Souleymane Oumarou Garba, Harissou Adamou, Ibrahim Amadou Magagi, Oumarou Habou, Halima Aliyu, Muhammad Daniyan, Tunde T Sholadoye, Lawal Abdullahi, Lofty-John Anyanwu, Aminu Mohammad Mohammad, Abubakar Bala Muhammad, Abdurrahman Abba Sheshe, Ibrahim Suleiman, Alaba Adesina, Ajibola Awolowo, Clement Onuoha, Omotayo Salami, Ogechukwu Taiwo, Agboola Taiwo, Stephen Kache, Jerry Godfrey Makama, Danjuma Sale, Olajide Abiola, Akinlabi Ajao, Anthony Ajiboye, Amarachukwu Etonyeaku, Julius Olaogun, Ademola Adebanjo, Opeoluwa Adesanya, Michael Olatunji Afolayan, Olanrewaju Balogun, Ayomide Makanjuola, Samuel Nwokocha, Rufus Wale Ojewola, Thomas Olagboyega Olajide, Adewale Aderounmu, Abdul-Rashid Adesunkanmi, Adewale Adisa, Augustine Agbakwuru, Adeleke Akeem Aderogba, Olusegun Isaac Alatise, Olukayode Arowolo, Oladejo Lawal, Tajudeen Mohammed, Chinedu Ndegbu, Olalekan Olasehinde, Funmilola Wuraola, Akinbolaji Akinkuolie, Amarachukwu Etonyeaku, Arinzechukwu Mosanya, Omobolaji Ayandipo, Peter Elemile, Taiwo Akeem Lawal, Samuel Ali Sani, Stephen Garba, Rebecca Hauwa Sani, Samson Olori, Henry Onyebuashi, Ifeanyi Umoke, Adedire Adenuga, Ademola Adeyeye, Olufemi Habeeb, Bashir Lawal, Abdulrasheed Nasir, Eirik Kjus Aahlin, Didrik Kjønås, Elisabeth Myrseth, Jibran Abbasy, Abdul Alvi, Omair Saleem, Asma Afzal, Anam Nazir, Muhammad Farooq, Ayesha Liaqat, Syed Asghar Naqi, Ali Raza, Muzna Sarfraz, Muhammad Sarwar, Muntaha Banglani, Ambreen Munir, Rahmat Sehrish, Bushra Ayub, Raza Sayyed, Amna Altaf, Saima Ayub, Ahmad Uzair Qureshi, Komal Saeed, Bilal Syed, Sana Amir Akbar, Abdul Wahid Anwer, Ruqayya Naheed Khan, Amina Iqbal Khan, Shahid Khattak, Sameen Mohtasham, Muhammad Asad Parvaiz, Aamir Ali Syed, Abdul Basit Ansari, Noman Shahzad, Tanwir Khaliq, Isbah Rashid, Shahzad Hussain Waqar, Hasan Abu Al-Saleem, Amjad Abu Alqumboz, Mohammad Alqadi, Adham Amro, Rawan Assa, Eman Awesat, Rawan Ayyad, Mohammed Hammad, Ayat Haymony, Bassel Hijazi, Bara Hmeidat, Rowaa Lahaseh, Aseel Qawasmi, Alaa Rajabi, Mohammed Shehada, Sundus Shkokani, Yasmine Yaghi, Nadine Yaghi, Mohammad AlZohour, Mohammad Farid, Yousef Mahmoud Habes, Wesam Juba, Yanal Nubani, Abdelrahman Rabee, Mohammad Sa'deh, Saeed Abed, Iyad Al Basos, Mohammad Alswerki, Dina Ashour, Israa Awad, Samar Diab, Alaa El Jamassi, Sahar El-Kahlout, Somaya Elhout, Ahmed N K Hajjaj, Doaa Hasanain, Baraa Nabil Hajjaj, Mohammed Obaid, Eman Saikaly, Ahmed Salhi, Hiba Al-Tammam, Murad Almasri, Muath Baniowda, Doha Beshtawi, Ali Horoub, Rami Misk, Bayan Mohammad, Rami Qasrawi, Tasnim Sholi, Samar Abu-Nimeh, Abrar Abu-Srour, Sadi A Abukhalaf, Samer Adawi, Barah Alsalameh, Kholoud Ayesh, Muawiyah Elqadi, Ahmad Hammouri, Fatima Karim Mustafa, Natalie Marzouqa, Shatha Melhem, Dima Miqdad, Balqees Mohamad, Mhammed Rawhi, Ayman B Abu Ahammala, Ahmed Abu Ataya, Israa Abu Jayyab, Samar Al-Shwaikh, Othman Alagha, Mohammed Alasttal, Haneen Awadallah, Mahmood Elblbessy, Jehad Fares, Akram Jarbou, Ibtisam Mahfouz, Moath A Albahnasawi, Asmaa' Abo Mahadi, Hasan Abuelhatal, Ayham Abuelqomboz, Abdelrahman Almoqayyad, Abdallah Alwali, Reem Balaawi, Mahmoud Hamouda, Mohammed Humeid, Abdullah Jedyan, Tasneem Mahmoud Abu Hamam, Ghadeer Matar, Ali Salem, Tahani Samra, Nureddin Shaheen, Karam Shihada, Ayoob A Nemer, Mahmoud Abu Al Amrain, Abdulwhhab Abu Alamrain, Najlaa Abu Jamie, Mohammed R Abu-Rous, Nada Alfarra, Mohammed AlTaweel, Noor Alwhaidi, Ramadan Hamed, Bader Saqqa, Ahmad Shaheen, Dana Aljaber, Loay Aljaberi, Malak Alwaheidi, Assef Jawaada, Hani Khaldi, Rami Qahoush, Jalil Qari, Rana Saadeh, Ahlam Salim, Aseel Yacoub, Abbas Abbas, Rana Abu Shua'ib, Baraa Abu Zainah, Mahmoud AbuSirrees, Basheer Babaa, Ola Barhoush, Asef Belal Qadomi, Laith Daraghmeh, Reema Haji, Alaa Khatatbeh, Lana Khatib, Salsabeel Qarariah, Yara Quzmar, Khalil Safadi, Roqaya Salameh, Mohammad Hassan, Shifaa Herzallah, Loai Massad, Ahmed Nazzal, Ranin Nazzal, Dennis Escobar, Gustavo Miguel Machain V, Agustin Rodriguez Gonzalez, Jorge Emerson Chachaima Mar, Nathaly Olga Chinchihualpa Paredes, Vicente Cuba, Walter Lopez, Maria Milagros Niquen Jimenez, Nestor Alberto Sanchez Bartra, Olenka Sapallanay Ojeda, Diego Sequeiros, Andrea Toscano Pacheco, María Vergara, Sol Abarca, Rodrigo Alcorta, Giuliano Borda-Luque, Ivan Edward Eusebio Zegarra, Claudia Luján López, Mirella Marrufo, Cinthya Mogrovejo, Andrea Nomura, Yamile Rodríguez Angeles, Maitza Rosario Vidal Meza, Gabriela Zavala, José Neiser Castillo Arrascue, Jomara Caroline Hidrogo Cabrera, José Julio Mariano Larrea Vera, Miguel Osorio, Edgar Alcides Ylatoma Díaz, Mark Anthony Fontanilla, Joseph Roy Fuentes, Anna Leah Salazar, Genieve Dominguez, Marc Paul Lopez, Shiela Macalindong, Mark Augustine Onglao, Arjel Ramirez, Marie Dione Sacdalan, Mayou Martin Tampo, Gemma Leonora Uy, Jeremiah Mangahas, Kenneth Yabut, Joannes Paul Cañete, Bernalynn Eris Cansana, Ernes John Castro, Maria Kaiserin Lipana, Manuel Francisco Roxas, Vlu Jean Zara, Maciej Chroł, Paula Franczak, Michał Orłowski, Piotr Budzyński, Andrzej Budzyński, Pawel Bury, Agata Czerwińska, Jadwiga Dworak, Jacek Dziedzic, Michał Kisielewski, Jan Kulawik, Anna Lasek, Piotr Major, Piotr Małczak, Marcin Migaczewski, Michał Pędziwiatr, Magdalena Pisarska, Dorota Radkowiak, Mateusz Rubinkiewicz, Anna Rzepa, Tomasz Skoczylas, Maciej Stanek, Katarzyna Truszkiewicz, Mateusz Wierdak, Marek Winiarski, Piotr Zarzycki, Anna Zub-Pokrowiecka, Piotr Kowalewski, Rafał Roszkowski, Maciej Walędziak, Miguel Tomé, Sara Patrocinio, Ines Guerreiro, Filipe Almeida, Xavier de Sousa, Nuno Monteiro, Maria Teresa Costa Santos, Daniela de Oliveira, Marta Lopes Serra, Daniela Morgado, Christian Neves, Ana Carolina Oliveira, Alice Pimentel, Sofia Silva, Márcia Carvalho, Lúcia Carvalho, Joana Magalhães, Leonor Matos, Tânia Monteiro, Carlota Ramos, Vanessa Santos, José Barbosa, Jose Costa-Maia, Vítor Devezas, Ana Fareleira, Cristina Fernandes, Diana Gonçalves, Henrique Mora, Marina Morais, Fabiana Silva de Sousa, Sara Catarino Santos, Ana Logrado, André Tojal, Edgar Amorim, Miguel F Cunha, Ana Fazenda, João Pedro Melo Neves, Inês Isabel Sampaio da Nóvoa Gomes Miguel, Diogo Veiga, José Azevedo, Hugo Cardoso Louro, Mariana Leite, José Azevedo, Maria Bairos Menezes, Bárbara Gama, Diana Brito, Marta Cristina Cruz Martins, André Graça E Magalhães, Ana Catarina Longras, Rita Lourenço, Diana Matos, Luis Castro, Filipa Policarpo, Joana Romano, Mariana Leite, Cristina Monteiro, Diogo Pinto, Marina Duarte, Sónia Fortuna Martins, Mariline Oliveira, Diogo Galvão, Lisandra Martins, Anaisa Silva, Viorel Taranu, Bárbara Vieira, Jessica Neves, Simone Oliveira, Hugo Ribeiro, Margarida Cinza, Rosa Felix, Arnaldo Machado, Joana Oliveira, Joana Patrício, Rita Pedroso de Lima, Mário Pereira, Miguel Rocha Melo, Cristina Velez, Alberto Abreu da Silva, Mariana Claro, Daniel Costa Santos, Andreia Ferreira, Hugo Capote, Daniela Rosado, Filipa Taré, Oriana Nogueira, Miguel Ângelo, José Miguel Baiao, Andreia Guimarães, João Marques, Miguel Nico Albano, Marta Silva, Ana Valente da Costa, Teresa Vieira Caroço, Sara Almeida Braga, Ines Capunge, Marta Fragoso, João Guimarães, Bruno Pinto, João Ribeiro, Miguel Angel, Guilherme Fialho, Monica Guerrero, Filipa Campos Costa, Diogo Cardoso, Vasco Cardoso, Magda Alves, Inês Estalagem, Tiago Louro, Cláudia Marques, Rita Martelo, Miguel Morgado, Rita Canotilho, Ana Margarida Correia, Pedro 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Noor, Reantha Pillay, Leandi Steynfaardt, Lucía González González, José Miguel Marín Santos, Paula Martín-Borregón, Javier Martínez Caballero, Cristina Nevado García, Pastora Rodriguez Fraga, Gonzalo De Castro Parga, Maria Pilar Fernández Veiga, Lucía Garrido López, Hugo Infante Pino, Irene Lages Cal, Marta López Otero, Manuel Nogueira Sixto, Marta Paniagua García Señorans, Laura Rodríguez Fernández, Alejandro Ruano Poblador, Erika Rufo Crespo, Raquel Sanchez-Santos, Vincenzo Vigorita, Ester Alonso Batanero, Dorisme Asnel, Isabel Cifrian Canales, Elisa Contreras Saiz, Irene De Santiago Alvarez, Tamara Díaz Vico, Sebastian Fernandez Arias, Daniel Fernández Martínez, Carmen García Bernardo, Luis Joaquín García Flórez, Carmen Garcia Gutierrez, Manuel García Munar, Carlos Alberto Márquez Zorrilla Molina, Marta Merayo, José Luis Michi Campos, Maria Moreno Gijon, Jorge L Otero-Diez, Jose Luis Rodicio Miravalles, Lorena Solar-Garcia, Aida Suárez Sánchez, Nuria Truan, Cristina Alejandre 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M., Srinivas, A., Sung, C. -Y., Tai, A., Valle Aranda, Y. C., Venturini, S., Wilguens Lartigue, J., Public and occupational health, AMS - Sports, APH - Health Behaviors & Chronic Diseases, CCA - Cancer Treatment and quality of life, Amsterdam Gastroenterology Endocrinology Metabolism, Cancer Center Amsterdam, and Albarella, Sara

Subjects
global surgery, hospitals, humans, income, neoplasms, postoperative period, poverty, prospective studies, no keywords listed, General Medicine, Prospective Studie, Hospital, Settore MED/18 - Chirurgia Generale, outcome, Hospitals, Humans, Income, Neoplasms, surgery, Postoperative Period, Poverty, Prospective Studies, cancer surgery, Human, hospital facilities
Abstract

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p

Published
2022

36. A membrane-activatable near-infrared fluorescent probe with ultra-photostability for mitochondrial membrane potentials

Author

Ren, Wei, Ji, Ao, Karmach, Omran, Carter, David G, Martins-Green, Manuela M, and Ai, Hui-wang

Subjects
Bioengineering, Animals, Fluorescence, Fluorescent Dyes, HEK293 Cells, HeLa Cells, Humans, Membrane Potential, Mitochondrial, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Structure, Spectroscopy, Near-Infrared, Hela Cells, Analytical Chemistry, Other Chemical Sciences
Abstract

Mitochondrial membrane potential (MMP) is a frequently used indicator for mitochondrial function. Herein, we report a photostable near-infrared (NIR) fluorescent dye for monitoring MMP. This new probe, named NIMAP, is non-fluorescent in aqueous solution and can be activated by cell membranes, providing high fluorescence contrast and low background fluorescence. NIMAP has been validated for monitoring MMP in living mammalian cells and in mice. Due to the large fluorescence response, low fluorescence background, high photostability, and excellent tissue penetration resulting from red-shifted excitation and emission in the "optical window" above 600 nm, broad applications of this new probe are expected.

Published
2016

37. Symptomatic BK Virus Infection Is Associated With Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients

Author

Abudayyeh, A, Hamdi, A, Lin, H, Abdelrahim, M, Rondon, G, Andersson, BS, Afrough, A, Martinez, CS, Tarrand, JJ, Kontoyiannis, DP, Marin, D, Gaber, AO, Salahudeen, A, Oran, B, Chemaly, RF, Olson, A, Jones, R, Popat, U, Champlin, RE, Shpall, EJ, Winkelmayer, WC, and Rezvani, K

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Kidney Disease, Infectious Diseases, Stem Cell Research, Transplantation, Aging, Prevention, Regenerative Medicine, Stem Cell Research - Nonembryonic - Human, Patient Safety, Renal and urogenital, Adolescent, Adult, Aged, BK Virus, Child, Child, Preschool, Female, Follow-Up Studies, Glomerular Filtration Rate, Graft vs Host Disease, Hematologic Diseases, Hematopoietic Stem Cell Transplantation, Humans, Infant, Infant, Newborn, Kidney Diseases, Kidney Function Tests, Male, Middle Aged, Polyomavirus Infections, Prognosis, Retrospective Studies, Risk Factors, Survival Rate, Transplantation, Homologous, Tumor Virus Infections, Young Adult, Medical and Health Sciences, Surgery, Clinical sciences, Immunology
Abstract

Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.

Published
2016

38. Oxidative stress, anti-oxidants and the cross-sectional and longitudinal association with depressive symptoms: results from the CARDIA study.

Author

Black, CN, Penninx, BWJH, Bot, M, Odegaard, AO, Gross, MD, Matthews, KA, and Jacobs, DR

Subjects
Humans, Antioxidants, Risk, Longitudinal Studies, Cross-Sectional Studies, Depressive Disorder, Oxidative Stress, Socioeconomic Factors, Adult, Female, Male, Coronary Artery Disease, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Depression may be accompanied by increased oxidative stress and decreased circulating anti-oxidants. This study examines the association between depressive symptoms, F2-isoprostanes and carotenoids in a US community sample. The study includes 3009 participants (mean age 40.3, 54.2% female) from CARDIA (Coronary Artery Risk Development in Young Adults). Cross-sectional analyses were performed on data from the year 15 examination (2000-2001) including subjects whose depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) and had measurements of plasma F2-isoprostanes (gas chromatography/mass spectrometry) or serum carotenoids (high-performance liquid chromatography). Carotenoids zeaxanthin/lutein, β-cryptoxanthin, lycopene, α-carotene, β-carotene were standardized and summed. Longitudinal analyses were conducted using the data from other examinations at 5-year intervals. Cross-lagged analyses investigated whether CES-D predicted F2-isoprostanes or carotenoids at the following exam, and vice versa. Regression analyses were controlled for sociodemographics, health and lifestyle factors. F2-isoprostanes were higher in subjects with depressive symptoms (CES-D ⩾ 16) after adjustment for sociodemographics (55.7 vs 52.0 pg ml(-1); Cohen's d = 0.14, P < 0.001). There was no difference in F2-isoprostanes after further adjustment for health and lifestyle factors. Carotenoids were lower in those with CES-D scores ⩾ 16, even after adjustment for health and lifestyle factors (standardized sum 238.7 vs 244.0, Cohen's d = -0.16, P < 0.001). Longitudinal analyses confirmed that depression predicts subsequent F2-isoprostane and carotenoid levels. Neither F2-isoprostanes nor carotenoids predicted subsequent depression. In conclusion, depressive symptoms were cross-sectionally and longitudinally associated with increased F2-isoprostanes and decreased carotenoids. The association with F2-isoprostanes can largely be explained by lifestyle factors, but lower carotenoids were independently associated with depressive symptoms.

Published
2016

39. Three Recombinant Engineered Antibodies against Recombinant Tags with High Affinity and Specificity.

Author

Zhao, Hongyu, Shen, Ao, Xiang, Yang K, and Corey, David P

Subjects
Animals, Humans, Mice, Peptides, Green Fluorescent Proteins, Recombinant Proteins, Recombinant Fusion Proteins, Antibodies, Bispecific, Epitopes, Protein Engineering, Antibody Specificity, Protein Binding, Protein Multimerization, HEK293 Cells, Antibodies, Bispecific, General Science & Technology
Abstract

We describe three recombinant engineered antibodies against three recombinant epitope tags, constructed with divalent binding arms to recognize divalent epitopes and so achieve high affinity and specificity. In two versions, an epitope is inserted in tandem into a protein of interest, and a homodimeric antibody is constructed by fusing a high-affinity epitope-binding domain to a human or mouse Fc domain. In a third, a heterodimeric antibody is constructed by fusing two different epitope-binding domains which target two different binding sites in GFP, to polarized Fc fragments. These antibody/epitope pairs have affinities in the low picomolar range and are useful tools for many antibody-based applications.

Published
2016

40. Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice.

Author

Stobdan, Tsering, Zhou, Dan, Ao-Ieong, Eilleen, Ortiz, Daniel, Ronen, Roy, Hartley, Iain, Gan, Zhuohui, McCulloch, Andrew D, Bafna, Vineet, Cabrales, Pedro, and Haddad, Gabriel G

Subjects
Heart, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Oxygen, Lactic Acid, Atrial Natriuretic Factor, Proteolipids, Myosin Light Chains, Muscle Proteins, Receptor, Endothelin B, Cardiac Output, Sequence Analysis, DNA, Altitude, Acclimatization, Tissue Distribution, Myocardial Contraction, Heterozygote, Quantitative Trait Loci, Ethiopia, Female, Male, Hypoxia, Endothelin receptor type B, cardiac output, high altitude, hypoxia, lactate, Genetics, Heart Disease, Cardiovascular, Clinical Research, Aetiology, Underpinning research, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning
Abstract

To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature's experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB (-/+) heterozygote mice are treated with lower levels of oxygen (O2), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O2) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB (-/+) compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB (-/+) mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB (-/+) and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.

Published
2015

41. Neurorestoratologic Strategies and Mechanisms in the Nervous System

Author

Chen, Lin, Ao, Qiang, Sharma, Hari Shanker, Wang, Aijun, and Feng, Shiqing

Subjects
Alzheimer Disease, Animals, Brain, Brain Ischemia, Humans, Rats, Regenerative Medicine, Stroke, Biological Sciences, Information and Computing Sciences, Technology
Published
2015

42. 30-Year Trends in Stroke Rates and Outcome in Auckland, New Zealand (1981-2012): A Multi-Ethnic Population-Based Series of Studies.

Author

Feigin, Valery L, Krishnamurthi, Rita V, Barker-Collo, Suzanne, McPherson, Kathryn M, Barber, P Alan, Parag, Varsha, Arroll, Bruce, Bennett, Derrick A, Tobias, Martin, Jones, Amy, Witt, Emma, Brown, Paul, Abbott, Max, Bhattacharjee, Rohit, Rush, Elaine, Suh, Flora Minsun, Theadom, Alice, Rathnasabapathy, Yogini, Te Ao, Braden, Parmar, Priya G, Anderson, Craig, Bonita, Ruth, and ARCOS IV Group

Subjects
ARCOS IV Group, Humans, Myocardial Infarction, Hypertension, Diabetes Mellitus, Hospitalization, Registries, Morbidity, Incidence, Risk Factors, Smoking, Age Distribution, Aged, Middle Aged, New Zealand, Female, Male, Stroke, Ethnicity, Clinical Research, Prevention, Neurosciences, Brain Disorders, Aging, Good Health and Well Being, General Science & Technology
Abstract

BackgroundInsufficient data exist on population-based trends in morbidity and mortality to determine the success of prevention strategies and improvements in health care delivery in stroke. The aim of this study was to determine trends in incidence and outcome (1-year mortality, 28-day case-fatality) in relation to management and risk factors for stroke in the multi-ethnic population of Auckland, New Zealand (NZ) over 30-years.MethodsFour stroke incidence population-based register studies were undertaken in adult residents (aged ≥15 years) of Auckland NZ in 1981-1982, 1991-1992, 2002-2003 and 2011-2012. All used standard World Health Organization (WHO) diagnostic criteria and multiple overlapping sources of case-ascertainment for hospitalised and non-hospitalised, fatal and non-fatal, new stroke events. Ethnicity was consistently self-identified into four major groups. Crude and age-adjusted (WHO world population standard) annual incidence and mortality with corresponding 95% confidence intervals (CI) were calculated per 100,000 people, assuming a Poisson distribution.Results5400 new stroke patients were registered in four 12 month recruitment phases over the 30-year study period; 79% were NZ/European, 6% Māori, 8% Pacific people, and 7% were of Asian or other origin. Overall stroke incidence and 1-year mortality decreased by 23% (95% CI 5%-31%) and 62% (95% CI 36%-86%), respectively, from 1981 to 2012. Whilst stroke incidence and mortality declined across all groups in NZ from 1991, Māori and Pacific groups had the slowest rate of decline and continue to experience stroke at a significantly younger age (mean ages 60 and 62 years, respectively) compared with NZ/Europeans (mean age 75 years). There was also a decline in 28-day stroke case fatality (overall by 14%, 95% CI 11%-17%) across all ethnic groups from 1981 to 2012. However, there were significant increases in the frequencies of pre-morbid hypertension, myocardial infarction, and diabetes mellitus, but a reduction in frequency of current smoking among stroke patients.ConclusionsIn this unique temporal series of studies spanning 30 years, stroke incidence, early case-fatality and 1-year mortality have declined, but ethnic disparities in risk and outcome for stroke persisted suggesting that primary stroke prevention remains crucial to reducing the burden of this disease.

Published
2015

43. Diet quality and markers of endothelial function: The CARDIA study

Author

Sijtsma, FPC, Meyer, KA, Steffen, LM, Van Horn, L, Shikany, JM, Odegaard, AO, Gross, MD, Kromhout, D, and Jacobs, DR

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Nutrition, Prevention, Cardiovascular, Adolescent, Adult, Biomarkers, Cohort Studies, Coronary Artery Disease, Cross-Sectional Studies, Diet, E-Selectin, Endothelium, Vascular, Female, Humans, Intercellular Adhesion Molecule-1, Longitudinal Studies, Male, Meat, P-Selectin, Principal Component Analysis, Risk, United States, Up-Regulation, Vascular Cell Adhesion Molecule-1, Young Adult, Cellular adhesion molecules, Cohort, Endothelial function, Epidemiology, Medical and Health Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Medical biochemistry and metabolomics, Nutrition and dietetics
Abstract

Background and aimDietary patterns are associated cross-sectionally with cellular adhesion molecules (CAMs). We studied prospective associations of three dietary patterns with CAMs.Methods and resultsIn the Coronary Artery Risk Development in Young Adults (CARDIA) study, diet was assessed at years 0 (1985-86) and 7 (1992-93) examinations. Four circulating CAMs (E-selectin, P-selectin, soluble intercellular adhesion molecule 1 (sICAM-1), and vascular cellular adhesion molecule (VCAM)) were assayed at years 7 and 15 (2000-01). We created one index score "A Priori Diet Quality Score" and derived dietary patterns using principal components analysis (PCA). Multivariable linear regression models predicted year 15 CAMs from averaged (year 0/7) dietary patterns. The A Priori Diet Quality Score rated 46 food groups beneficial, neutral or adverse based on hypothesized health effects. We derived two PCA dietary patterns: "fruit and vegetables (FV)" (high intakes of fruit, vegetables, and whole grains) and "meat" (high intakes of red meat, refined grain, and butter). All dietary patterns were related to E-selectin and sICAM-1. P-selectin was not related to the FV dietary pattern. VCAM was only related to the A Priori Diet Quality Score. Strongest associations were for the meat dietary pattern with E-selectin (effect size 28% of an SD (+3.9/13.7 ng/mL)) and P-selectin (effect size 37% of an SD (+4.1/11.2 ng/mL)) and the A Priori Diet Quality Score with sICAM-1 (effect size 34% of an SD (-15.1/44.7 ng/mL)) and VCAM (effect size of 26% of an SD (-45.1/170.3 ng/mL)).ConclusionThis prospective analysis suggests that dietary patterns are associated with CAMs.

Published
2014

44. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice

Author

Tong, Xiaoping, Ao, Yan, Faas, Guido C, Nwaobi, Sinifunanya E, Xu, Ji, Haustein, Martin D, Anderson, Mark A, Mody, Istvan, Olsen, Michelle L, Sofroniew, Michael V, and Khakh, Baljit S

Subjects
Biomedical and Clinical Sciences, Neurosciences, Rare Diseases, Huntington's Disease, Neurodegenerative, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Age Factors, Animals, Astrocytes, Corpus Striatum, Disease Models, Animal, Green Fluorescent Proteins, HEK293 Cells, Hindlimb Suspension, Humans, Huntingtin Protein, Huntington Disease, In Vitro Techniques, Locomotion, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Potassium Channels, Inwardly Rectifying, Survival Analysis, Trinucleotide Repeats, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Huntington's disease (HD) is characterized by striatal medium spiny neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, in which mutant huntingtin is expressed in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models was not associated with classical astrogliosis, but was associated with decreased Kir4.1 K(+) channel functional expression, leading to elevated in vivo striatal extracellular K(+), which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K(+), ameliorated aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte-mediated K(+) homeostasis, revealing astrocytes and Kir4.1 channels as therapeutic targets.

Published
2014

45. Heterogeneity of reactive astrocytes

Author

Anderson, Mark A, Ao, Yan, and Sofroniew, Michael V

Subjects
Brain Disorders, Neurosciences, Animals, Astrocytes, Brain, Cell Proliferation, Cell Size, Cicatrix, Gene Expression, Gliosis, Humans, Signal Transduction, Spinal Cord, Terminology as Topic, Reactive astrogliosis, Glial scar, Trauma, Inflammation, Autoimmune disease, Heterogeneity, Psychology, Cognitive Sciences
Abstract

Astrocytes respond to injury and disease in the central nervous system (CNS) with a process referred to as reactive astrogliosis. Recent progress demonstrates that reactive astrogliosis is not a simple all-or-none phenomenon, but is a finely gradated continuum of changes that range from reversible alterations in gene expression and cell hypertrophy, to scar formation with permanent tissue rearrangement. There is now compelling evidence that reactive astrocytes exhibit a substantial potential for heterogeneity at multiple levels, including gene expression, cell morphology, topography (distance from lesions), CNS regions, local (among neighboring cells), cell signaling and cell function. Structural and functional changes are regulated in reactive astrocytes by many different potential signaling events that occur in a context dependent manner. It is noteworthy that different stimuli of astrocyte reactivity can lead to similar degrees of GFAP upregulation while causing substantially different changes in transcriptome profiles and cell function. Thus, it is not possible to equate simple and uniform measures such as cell hypertrophy and upregulation of GFAP expression with a single, uniform concept of astrocyte reactivity. Instead, it is necessary to recognize the considerable potential for heterogeneity and determine the functional implications of astrocyte reactivity in a context specific manner as regulated by specific signaling events.

Published
2014

46. Targeted ablation of nesprin 1 and nesprin 2 from murine myocardium results in cardiomyopathy, altered nuclear morphology and inhibition of the biomechanical gene response.

Author

Banerjee, Indroneal, Zhang, Jianlin, Moore-Morris, Thomas, Pfeiffer, Emily, Buchholz, Kyle S, Liu, Ao, Ouyang, Kunfu, Stroud, Matthew J, Gerace, Larry, Evans, Sylvia M, McCulloch, Andrew, and Chen, Ju

Subjects
Myocardium, Nuclear Envelope, Cell Nucleus, Nuclear Matrix, Myocytes, Cardiac, Animals, Humans, Mice, Cardiomyopathies, Cytoskeletal Proteins, Nerve Tissue Proteins, Nuclear Proteins, Gene Expression Regulation, Mutation, Biomechanical Phenomena, Developmental Biology, Genetics
Abstract

Recent interest has focused on the importance of the nucleus and associated nucleoskeleton in regulating changes in cardiac gene expression in response to biomechanical load. Mutations in genes encoding proteins of the inner nuclear membrane and nucleoskeleton, which cause cardiomyopathy, also disrupt expression of a biomechanically responsive gene program. Furthermore, mutations in the outer nuclear membrane protein Nesprin 1 and 2 have been implicated in cardiomyopathy. Here, we identify for the first time a role for the outer nuclear membrane proteins, Nesprin 1 and Nesprin 2, in regulating gene expression in response to biomechanical load. Ablation of both Nesprin 1 and 2 in cardiomyocytes, but neither alone, resulted in early onset cardiomyopathy. Mutant cardiomyocytes exhibited altered nuclear positioning, shape, and chromatin positioning. Loss of Nesprin 1 or 2, or both, led to impairment of gene expression changes in response to biomechanical stimuli. These data suggest a model whereby biomechanical signals are communicated from proteins of the outer nuclear membrane, to the inner nuclear membrane and nucleoskeleton, to result in changes in gene expression required for adaptation of the cardiomyocyte to changes in biomechanical load, and give insights into etiologies underlying cardiomyopathy consequent to mutations in Nesprin 1 and 2.

Published
2014

47. Chieh Mei Ching Yi: A randomized controlled trial of a culturally tailored HIV prevention intervention for Chinese massage parlor women in Los Angeles.

Author

Takahashi, Lois M, Tobin, Karin E, To, Stacy, Ou, Samuel, Ma, Chui Hing Helen, Ao, Fiona Ka Wa, and Candelario, Jury

Subjects
Public Health, Health Sciences, Clinical Trials and Supportive Activities, Pediatric, Pediatric AIDS, Complementary and Integrative Health, Infectious Diseases, Clinical Research, Prevention, HIV/AIDS, Prevention of disease and conditions, and promotion of well-being, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, Infection, Good Health and Well Being, Adult, Aged, Asians, China, Condoms, Counseling, Culture, Female, Follow-Up Studies, HIV Infections, Health Knowledge, Attitudes, Practice, Health Promotion, Humans, Los Angeles, Massage, Middle Aged, Outcome Assessment, Health Care, Risk Reduction Behavior, Safe Sex, Socioeconomic Factors, Surveys and Questionnaires, Young Adult, Asian People, Public Health and Health Services, Social Work, Public health
Abstract

Asian heterosexual women in the U.S. have experienced relative rising HIV case rates, but there remain few studies and no evidence-based interventions that focus on this population. This study was a randomized controlled trial of a gender and ethnically tailored HIV prevention intervention for monolingual Chinese-speaking women who work as masseuses in Los Angeles. The intervention was two group-based sessions focused on HIV risk and prevention knowledge and condom skills. The control condition was a single-session HIV review. Participants were recruited using newspaper advertisements and referrals from agencies and massage schools. Two hundred women were randomly assigned to one of each condition. Retention in both conditions exceeded 90% at 3-month follow-up. Participants in both conditions demonstrated increases in knowledge on how to use male and female condoms. These effects were sustained at 3-month follow-up. The results highlight the possible efficacy of a one-workshop intervention in increasing HIV knowledge, but that more intensive participant interaction may be needed for improved condom use knowledge.

Published
2013

48. Health care utilization and outcomes in older adults after Traumatic Brain Injury: A CENTER-TBI study

Author

van der Vlegel, Marjolein, Mikolić, Ana, Wilson, Lindsay, Gomez, Pedro A., Lagares, Alfonso, Chevallard, Giorgio, Chieregato, Arturo, Citerio, Giuseppe, Vargiolu, Alessia, Ceyisakar, Iris, Gravesteijn, Benjamin, Haagsma, Juanita A., Huijben, Jilske, Maas, Andrew I. R., Lingsma, Hester, Nieboer, Daan, Mikolic, Ana, Polinder, Suzanne, Sewalt, Charlie, Steyerberg, Ewout W., Velt, Kimberley, Voormolen, Daphne, Wiegers, Eveline, Peul, Wilco, van Dijck, Jeroen T. J. M., van Essen, Thomas A., van Wijk, Roel P. J., Clusmann, Hans, Coburn, Mark, Kowark, Ana, Rossaint, Rolf, Coles, Jonathan, Cooper, Jamie D., Correia, Marta, Čovid, Amra, von Steinbüchel, Nicole, Curry, Nicola, Stanworth, Simon, Dahyot-Fizelier, Claire, Dark, Paul, Johnson, Faye, Dawes, Helen, Esser, Patrick, van Heugten, Caroline, CENTER-TBI Participants and Investigators, De Keyser, Véronique, Menovsky, Tomas, Van der Steen, Gregory, Della Corte, Francesco, Grossi, Francesca, Depreitere, Bart, Đilvesi, Đula, Golubovic, Jagoš, Karan, Mladen, Åkerlund, Cecilia, Vulekovic, Petar, Dreier, Jens, Vajkoczy, Peter, Wolf, Stefan, Dulière, Guy-Loup, Maréchal, Hugues, Fabricius, Martin, Kondziella, Daniel, Feigin, Valery L., Jones, Kelly, George, Pradeep, Ao, Braden Te, Theadom, Alice, Foks, Kelly, Haitsma, Iain, Volovici, Victor, Furmanov, Alex, Rosenthal, Guy, Gagliardo, Pablo, Gao, Guoyi, Jiang, Ji-yao, Lanyon, Linda, Ghuysen, Alexandre, Giga, Lelde, Valeinis, Egils, Ziverte, Agate, Glocker, Ben, Rueckert, Daniel, Gratz, Johannes, Gruen, Russell L., Gupta, Deepak, Roe, Cecilie, Muraleedharan, Visakh, Helseth, Eirik, Roise, Olav, Horton, Lindsay, Hutchinson, Peter J., Kolias, Angelos G., Jacobs, Bram, van der Naalt, Joukje, Jankowski, Stefan, Kompanje, Erwin, Nelson, David, Timmers, Marjolein, Laureys, Steven, Ledoux, Didier, Misset, Benoit, Lecky, Fiona, Olubukola, Otesile, Lefering, Rolf, Schäfer, Nadine, Legrand, Valerie, Lejeune, Aurelie, Lee Hee, Quentin, Amrein, Krisztina, Vega, Emmanuel, Mattern, Julia, Levi, Leon, Lightfoot, Roger, Maegele, Marc, Manara, Alex, Thomas, Matt, Manley, Geoffrey, Martino, Costanza, Sakowitz, Oliver, Ezer, Erzsébet, Sanchez-Porras, Renan, Younsi, Alexander, McMahon, Catherine, Negru, Ancuta, Oresic, Matej, Palotie, Aarno, Parizel, Paul M., Payen, Jean-François, Persona, Paolo, Piippo-Karjalainen, Anna, Kovács, Noémi, Pirinen, Matti, Ples, Horia, Posti, Jussi P., Puybasset, Louis, Radoi, Andreea, Ragauskas, Arminas, Raj, Rahul, Rambadagalla, Malinka, Rhodes, Jonathan, Richardson, Sylvia, Melegh, Béla, Ripatti, Samuli, Rocka, Saulius, Rosand, Jonathan, Rosenfeld, Jeffrey V., Rossi, Sandra, Rusnák, Martin, Sahuquillo, Juan, Sandor, Janos, Schmidt, Silke, Schoechl, Herbert, Nyirádi, József, Schoonman, Guus, Skandsen, Toril, Stevens, Robert, Stewart, William, Takala, Riikka, Tamosuitis, Tomas, Tenovuo, Olli, Tibboel, Dick, Tolias, Christos, Tudora, Cristina Maria, Tamás, Viktória, van der Jagt, Mathieu, Van Hecke, Wim, Van Praag, Dominique, Vyvere, Thijs Vande, Verheyden, Jan, Vespa, Paul M., Vik, Anne, Vilcinis, Rimantas, Wang, Kevin K. W., Yang, Zhihui, Vámos, Zoltán, Ylén, Peter, Sorinola, Abayomi, Andelic, Nada, Andreassen, Lasse, Kaplan, Z. L. Rana, Anke, Audny, Frisvold, Shirin, Antoni, Anna, Schwendenwein, Elisabeth, Audibert, Gérard, Azouvi, Philippe, Azzolini, Maria Luisa, Beretta, Luigi, Calvi, Maria Rosa, Bartels, Ronald, Retel Helmrich, Isabel R. A., Boogert, Hugo den, Barzó, Pál, Beauvais, Romuald, Perera, Natascha, Beer, Ronny, Helbok, Raimund, Bellander, Bo-Michael, Belli, Antonio, Benali, Habib, Degos, Vincent, van Veen, Ernest, Galanaud, Damien, Perlbarg, Vincent, Berardino, Maurizio, Cavallo, Simona, Blaabjerg, Morten, Rosenlund, Christina, Schou, Rico Frederik, Bragge, Peter, Brazinova, Alexandra, Majdan, Marek, Taylor, Mark Steven, Zelinkova, Veronika, Brinck, Vibeke, Jarrett, Mike, Brooker, Joanne, Donoghue, Emma, Synnot, Anneliese, Brorsson, Camilla, Koskinen, Lars-Owe, Sundström, Nina, Steinbuechel, Nicole V., Buki, Andras, Czeiter, Endre, Bullinger, Monika, Cabeleira, Manuel, Czosnyka, Marek, Dixit, Abhishek, Ercole, Ari, Koraropoulos, Evgenios, Menon, David, Newcombe, Virginia, Plass, Anne Marie, Richter, Sophie, Smielewski, Peter, Stamatakis, Emmanuel, Williams, Guy, Winzeck, Stefan, Zeiler, Frederick A., Caccioppola, Alessio, Calappi, Emiliana, Carbonara, Marco, Ortolano, Fabrizio, Zeldovich, Marina, Zoerle, Tommaso, Stocchetti, Nino, Cameron, Peter, Gantner, Dashiell, Murray, Lynnette, Trapani, Tony, Vallance, Shirley, Lozano, Guillermo Carbayo, Pomposo, Inigo, Castaño-León, Ana M., Molecular Neuroscience and Ageing Research (MOLAR), CENTER-TBI Participants and Investigators, van der Vlegel, M, Mikolić, A, Hee, Q, Kaplan, Z, Helmrich, I, van Veen, E, Andelic, N, Steinbuechel, N, Plass, A, Zeldovich, M, Wilson, L, Maas, A, Haagsma, J, Polinder, S, Åkerlund, C, George, P, Lanyon, L, Muraleedharan, V, Nelson, D, Amrein, K, Ezer, E, Kovács, N, Melegh, B, Nyirádi, J, Tamás, V, Vámos, Z, Sorinola, A, Andreassen, L, Anke, A, Frisvold, S, Antoni, A, Schwendenwein, E, Audibert, G, Azouvi, P, Azzolini, M, Beretta, L, Calvi, M, Bartels, R, Boogert, H, Barzó, P, Beauvais, R, Perera, N, Beer, R, Helbok, R, Bellander, B, Belli, A, Benali, H, Degos, V, Galanaud, D, Perlbarg, V, Berardino, M, Cavallo, S, Blaabjerg, M, Rosenlund, C, Schou, R, Bragge, P, Brazinova, A, Majdan, M, Taylor, M, Zelinkova, V, Brinck, V, Jarrett, M, Brooker, J, Donoghue, E, Synnot, A, Brorsson, C, Koskinen, L, Sundström, N, Buki, A, Czeiter, E, Bullinger, M, Cabeleira, M, Czosnyka, M, Dixit, A, Ercole, A, Koraropoulos, E, Menon, D, Newcombe, V, Richter, S, Smielewski, P, Stamatakis, E, Williams, G, Winzeck, S, Zeiler, F, Caccioppola, A, Calappi, E, Carbonara, M, Ortolano, F, Zoerle, T, Stocchetti, N, Cameron, P, Gantner, D, Murray, L, Trapani, T, Vallance, S, Lozano, G, Pomposo, I, Castaño-León, A, Gomez, P, Lagares, A, Chevallard, G, Chieregato, A, Citerio, G, Vargiolu, A, Ceyisakar, I, Gravesteijn, B, Huijben, J, Lingsma, H, Nieboer, D, Mikolic, A, Sewalt, C, Steyerberg, E, Velt, K, Voormolen, D, Wiegers, E, Peul, W, van Dijck, J, van Essen, T, van Wijk, R, Clusmann, H, Coburn, M, Kowark, A, Rossaint, R, Coles, J, Cooper, J, Correia, M, Čovid, A, von Steinbüchel, N, Curry, N, Stanworth, S, Dahyot-Fizelier, C, Dark, P, Johnson, F, Dawes, H, Esser, P, van Heugten, C, De Keyser, V, Menovsky, T, Van der Steen, G, Corte, F, Grossi, F, Depreitere, B, Đilvesi, Đ, Golubovic, J, Karan, M, Vulekovic, P, Dreier, J, Vajkoczy, P, Wolf, S, Dulière, G, Maréchal, H, Fabricius, M, Kondziella, D, Feigin, V, Jones, K, Ao, B, Theadom, A, Foks, K, Haitsma, I, Volovici, V, Furmanov, A, Rosenthal, G, Gagliardo, P, Gao, G, Jiang, J, Ghuysen, A, Giga, L, Valeinis, E, Ziverte, A, Glocker, B, Rueckert, D, Gratz, J, Gruen, R, Gupta, D, Roe, C, Helseth, E, Roise, O, Horton, L, Hutchinson, P, Kolias, A, Jacobs, B, van der Naalt, J, Jankowski, S, Kompanje, E, Timmers, M, Laureys, S, Ledoux, D, Misset, B, Lecky, F, Olubukola, O, Lefering, R, Schäfer, N, Legrand, V, Lejeune, A, Vega, E, Mattern, J, Levi, L, Lightfoot, R, Maegele, M, Manara, A, Thomas, M, Manley, G, Martino, C, Sakowitz, O, Sanchez-Porras, R, Younsi, A, Mcmahon, C, Negru, A, Oresic, M, Palotie, A, Parizel, P, Payen, J, Persona, P, Piippo-Karjalainen, A, Pirinen, M, Ples, H, Posti, J, Puybasset, L, Radoi, A, Ragauskas, A, Raj, R, Rambadagalla, M, Rhodes, J, Richardson, S, Ripatti, S, Rocka, S, Rosand, J, Rosenfeld, J, Rossi, S, Rusnák, M, Sahuquillo, J, Sandor, J, Schmidt, S, Schoechl, H, Schoonman, G, Skandsen, T, Stevens, R, Stewart, W, Takala, R, Tamosuitis, T, Tenovuo, O, Tibboel, D, Tolias, C, Tudora, C, van der Jagt, M, Van Hecke, W, Van Praag, D, Vyvere, T, Verheyden, J, Vespa, P, Vik, A, Vilcinis, R, Wang, K, Yang, Z, Ylén, P, Public Health, Otorhinolaryngology and Head and Neck Surgery, Intensive Care, Neurology, Neurosurgery, Pediatric Surgery, University of Helsinki, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Neurocenter, Department of Mathematics and Statistics, Helsinki Institute for Information Technology, Statistical and population genetics, Clinicum, Helsinki University Hospital Area, Neurokirurgian yksikkö, Faculty Common Matters (Faculty of Social Sciences), Department of Public Health, Samuli Olli Ripatti / Principal Investigator, and Complex Disease Genetics

Subjects
Traumatic, Quality of Life/psychology, Traumatic Brain Injury, Health-related quality of life, Health care utilization, 3112 Neurosciences, Glasgow Outcome Scale, Outcomes, Patient Acceptance of Health Care, SDG 3 - Good Health and Well-being, Older adults, Brain Injuries, Brain Injuries, Traumatic, Quality of Life, Humans, General Earth and Planetary Sciences, Mental health, 3111 Biomedicine, Prospective Studies, Human medicine, Older adult, Aged, Outcome, General Environmental Science
Abstract

Injury : international journal of the care of the injured 53(8), 2774-2782 (2022). doi:10.1016/j.injury.2022.05.009, Published by Elsevier Science, Amsterdam [u.a.]

Published
2022

49. A Single Nucleotide Polymorphism in

Author

Matthew R, Alexander, Samuel, Hank, Bethany L, Dale, Lauren, Himmel, Xue, Zhong, Charles D, Smart, Daniel J, Fehrenbach, Yuhan, Chen, Nitin, Prabakaran, Brian, Tirado, Megan, Centrella, Mingfang, Ao, Liping, Du, Yu, Shyr, Daniel, Levy, and Meena S, Madhur

Subjects
Mice, Knockout, Hypertension, Renal, Angiotensin II, Tryptophan, CD8-Positive T-Lymphocytes, Arginine, Kidney, Fibrosis, Interleukin-12, Polymorphism, Single Nucleotide, Mice, Inbred C57BL, Interferon-gamma, Mice, Hypertension, Animals, Humans, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
Abstract

SH2B3 (SH2B adaptor protein 3) is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. A common missense single nucleotide polymorphism inWe used CRISPR-Cas9 technology to create mice homozygous for the major (Arg/Arg) and minor (Trp/Trp) alleles of thisTrp/Trp mice exhibit 10 mmHg higher systolic BP during chronic Ang II infusion compared to Arg/Arg controls. Renal injury and perivascular fibrosis are exacerbated in Trp/Trp mice compared to Arg/Arg controls following Ang II infusion. Renal and ex vivo stimulated splenic CD8Taken together, these results suggest that the Trp encoding allele of rs3184504 is causal for BP elevation and renal dysfunction, in part through loss of SH2B3-mediated repression of T cell IL-12 signaling leading to enhanced IFNg production.

Published
2023

50. Staphylococcal virulence factor HlgB targets the endoplasmic-reticulum-resident E3 ubiquitin ligase AMFR to promote pneumonia

Author

Lei Sun, Haibo Zhang, Huihui Zhang, Xinyi Lou, Zhiming Wang, Yaxian Wu, Xinyi Yang, Daijie Chen, Beining Guo, Ao Zhang, and Feng Qian

Subjects
Inflammation, Microbiology (medical), Staphylococcus aureus, Ubiquitin-Protein Ligases, Immunology, Pneumonia, Cell Biology, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Applied Microbiology and Biotechnology, Microbiology, Receptors, Autocrine Motility Factor, Genetics, Humans
Abstract

Staphylococcus aureus invades cells and persists intracellularly, causing persistent inflammation that is notoriously difficult to treat. Here we investigated host-pathogen interactions underlying intracellular S. aureus infection in macrophages and discovered that the endoplasmic reticulum (ER) is an important cellular compartment for intracellular S. aureus infection. Using CRISPR-Cas9 guide RNA library screening, we determined that the autocrine motility factor receptor (AMFR), an ER-resident E3 ubiquitin ligase, played an essential role in mediating intracellular S. aureus-induced inflammation. AMFR directly interacted with TAK1-binding protein 3 (TAB3) in the ER, inducing K27-linked polyubiquitination of TAB3 on lysine 649 and promoting TAK1 activation. Moreover, the virulence factor γ-haemolysin B (HIgB) of S. aureus bound to the AMFR and regulated TAB3. Our findings highlight an unknown role of AMFR in intracellular S. aureus infection-induced pneumonia and suggest that pharmacological interruption of AMFR-mediated TAB3 signalling cascades and HIgB targeting may prevent invasive staphylococci-mediated pneumonia.

Published
2023

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