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Sociodemographic, Clinical Characteristics, And Outcomes Of Influenza Pneumonia Patients Admitted In A Tertiary Care Hospital In Karachi, Pakistan: Findings From A Cross-Sectional Study, Fazal Ur Rehman, Muhammad Arslan Ahmed, Kashif Aziz, Mahmooda Jabeen Ashraf, Tazein Amber, Sumera Aziz Ali 2021 Aga Khan University

Sociodemographic, Clinical Characteristics, And Outcomes Of Influenza Pneumonia Patients Admitted In A Tertiary Care Hospital In Karachi, Pakistan: Findings From A Cross-Sectional Study, Fazal Ur Rehman, Muhammad Arslan Ahmed, Kashif Aziz, Mahmooda Jabeen Ashraf, Tazein Amber, Sumera Aziz Ali

Section of Internal Medicine

Objective: To determine the sociodemographic, clinical characteristics, and outcomes of influenza pneumonia patients in tertiary care hospital, Karachi Pakistan.
Study design: A cross-sectional study.
Place and duration of study: The Aga Khan University Hospital Karachi Pakistan from January 2013 to December 2018. Methodology: All adult patients who were older than 18 years and suspected to have viral pneumonia were included in the study. Data were abstracted on 105 patients and were entered on preformed proforma after reviewing the files of patients.
Results: Ninety-four (89.5%) patients were influenza positive and 15.2% (n=16) had been vaccinated. Around 92.4 ...


Single-Cell Rna-Seq Reveals Transcriptomic Heterogeneity Mediated By Host-Pathogen Dynamics In Lymphoblastoid Cell Lines, Elliott D. SoRelle, Joanne Dai, Emmanuela N. Bonglack, Emma M. Heckenberg, Jeffrey Y. Zhou, Stephanie N. Giamberardino, Jeffrey A. Bailey, Simon G. Gregory, Cliburn Chan, Micah A. Luftig 2021 Duke University

Single-Cell Rna-Seq Reveals Transcriptomic Heterogeneity Mediated By Host-Pathogen Dynamics In Lymphoblastoid Cell Lines, Elliott D. Sorelle, Joanne Dai, Emmanuela N. Bonglack, Emma M. Heckenberg, Jeffrey Y. Zhou, Stephanie N. Giamberardino, Jeffrey A. Bailey, Simon G. Gregory, Cliburn Chan, Micah A. Luftig

Open Access Publications by UMMS Authors

Lymphoblastoid cell lines (LCLs) are generated by transforming primary B cells with Epstein-Barr virus (EBV) and are used extensively as model systems in viral oncology, immunology, and human genetics research. In this study, we characterized single-cell transcriptomic profiles of five LCLs and present a simple discrete-time simulation to explore the influence of stochasticity on LCL clonal evolution. Single-cell RNA sequencing (scRNA-seq) revealed substantial phenotypic heterogeneity within and across LCLs with respect to immunoglobulin isotype; virus-modulated host pathways involved in survival, activation, and differentiation; viral replication state; and oxidative stress. This heterogeneity is likely attributable to intrinsic variance in primary B ...


Unique Structural Solution From A Vh3-30 Antibody Targeting The Hemagglutinin Stem Of Influenza A Viruses, Wayne D. Harshbarger, Derrick Deming, Gordon J. Lockbaum, Nattapol Attatippaholkun, Maliwan Kamkaew, Shurong Hou, Mohan Somasundaran, Jennifer P. Wang, Robert W. Finberg, Quan Karen Zhu, Celia A. Schiffer, Wayne A Marasco 2021 Dana-Farber Cancer Institute

Unique Structural Solution From A Vh3-30 Antibody Targeting The Hemagglutinin Stem Of Influenza A Viruses, Wayne D. Harshbarger, Derrick Deming, Gordon J. Lockbaum, Nattapol Attatippaholkun, Maliwan Kamkaew, Shurong Hou, Mohan Somasundaran, Jennifer P. Wang, Robert W. Finberg, Quan Karen Zhu, Celia A. Schiffer, Wayne A Marasco

Schiffer Lab Publications

Broadly neutralizing antibodies (bnAbs) targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs. Here, we report structural details for heterosubtypic recognition of HA from circulating and emerging IAVs by the human antibody 3I14. Somatic hypermutations play a critical role in shaping the HCDR3, which alone and uniquely among VH3-30 derived antibodies, forms contacts with five sub-pockets within the HA-stem hydrophobic groove. 3I14 light-chain interactions are also key for binding HA and contribute a large buried surface area spanning two HA protomers. Comparison of 3I14 to bnAbs from several defined ...


Pulmonary Restriction Predicts Long-Term Pulmonary Impairment In People With Hiv And Tuberculosis, Sara C. Auld, Hardy Kornfeld, Pholo Maenetje, Mandla Mlotshwa, William Chase, Mboyo di-Tamba Vangu, Drew A. Torigian, Robert S. Wallis, Gavin Churchyard, Gregory P. Bisson 2021 Emory University

Pulmonary Restriction Predicts Long-Term Pulmonary Impairment In People With Hiv And Tuberculosis, Sara C. Auld, Hardy Kornfeld, Pholo Maenetje, Mandla Mlotshwa, William Chase, Mboyo Di-Tamba Vangu, Drew A. Torigian, Robert S. Wallis, Gavin Churchyard, Gregory P. Bisson

Open Access Publications by UMMS Authors

BACKGROUND: While tuberculosis is considered a risk factor for chronic obstructive pulmonary disease, a restrictive pattern of pulmonary impairment may actually be more common among tuberculosis survivors. We aimed to determine the nature of pulmonary impairment before and after treatment among people with HIV and tuberculosis and identify risk factors for long-term impairment.

METHODS: In this prospective cohort study conducted in South Africa, we enrolled adults newly diagnosed with HIV and tuberculosis who were initiating antiretroviral therapy and tuberculosis treatment. We measured lung function and symptoms at baseline, 6, and 12 months. We compared participants with and without pulmonary impairment ...


Covid-19 Presenting With Spontaneous Pneumothorax, Intisar Ahmed, Hunaina Shahab, Muhammad Arslan Ahmed, Muhammad Sohaib 2021 Aga Khan University

Covid-19 Presenting With Spontaneous Pneumothorax, Intisar Ahmed, Hunaina Shahab, Muhammad Arslan Ahmed, Muhammad Sohaib

Section of Cardiology

The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease mainly affects respiratory system. Its common clinical findings include fever, cough and shortness of breath. Characteristic radiological features of the disease include peripherally distributed, bilateral ground-glass opacities, predominantly involving the lower lung zones. In this report, we present a case of COVID-19 disease presenting with spontaneous pneumothorax. A 26-year male patient was admitted to the Emergency Department with fever, dry cough, shortness of breath and right-sided chest pain. Radiographic imaging of the patient revealed pneumothorax on the right and peripherally distributed non-homogenous opacification ...


Covid-19: Race For Vaccine, L. Hayley Burgess, Jason J. Braithwaite, Emily Singleton, Aaron M. Young, Mandelin K. Cooper 2020 HCA Healthcare

Covid-19: Race For Vaccine, L. Hayley Burgess, Jason J. Braithwaite, Emily Singleton, Aaron M. Young, Mandelin K. Cooper

HCA Healthcare Journal of Medicine

The world is in the midst of a pandemic from COVID-19, a disease caused by the virus SARS-CoV-2. Despite broad mitigation efforts, new cases continue with 74 million cases and 1.6 million deaths worldwide. Regardless of previous research efforts, there is no commercially available vaccine for any coronavirus. Novel vaccine development has historically taken at least 10 years from discovery to availability with only a 6% market entry probability.

With the global impact, there is an urgency to expedite a vaccine to protect the population. The U.S. government launched Operation Warp Speed with the goal to produce and ...


In Vitro And In Vivo Characterization Of A Recombinant Rhesus Cytomegalovirus Containing A Complete Genome, Husam Taher, Xiaofei E, Timothy F. Kowalik, Daniel Malouli 2020 Oregon Health and Science University

In Vitro And In Vivo Characterization Of A Recombinant Rhesus Cytomegalovirus Containing A Complete Genome, Husam Taher, Xiaofei E, Timothy F. Kowalik, Daniel Malouli

Open Access Publications by UMMS Authors

Cytomegaloviruses (CMVs) are highly adapted to their host species resulting in strict species specificity. Hence, in vivo examination of all aspects of CMV biology employs animal models using host-specific CMVs. Infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a representative model for infection of humans with HCMV due to the close evolutionary relationships of both host and virus. However, the only available RhCMV clone that permits genetic modifications is based on the 68-1 strain which has been passaged in fibroblasts for decades resulting in multiple genomic changes due to tissue culture adaptations. As a result ...


Cytomegalovirus-Specific T Cell Epitope Recognition In Congenital Cytomegalovirus Mother-Infant Pairs, Emma C. Materne, Daniele Lilleri, Francesca Garofoli, Giuseppina Lombardi, Milena Furione, Maurizio Zavattoni, Laura L. Gibson 2020 University of Massachusetts Medical School

Cytomegalovirus-Specific T Cell Epitope Recognition In Congenital Cytomegalovirus Mother-Infant Pairs, Emma C. Materne, Daniele Lilleri, Francesca Garofoli, Giuseppina Lombardi, Milena Furione, Maurizio Zavattoni, Laura L. Gibson

Open Access Publications by UMMS Authors

Background: Congenital cytomegalovirus (cCMV) infection is the most common infection acquired before birth and from which about 20% of infants develop permanent neurodevelopmental effects regardless of presence or absence of symptoms at birth. Viral escape from host immune control may be a mechanism of CMV transmission and infant disease severity. We sought to identify and compare CMV epitopes recognized by mother-infant pairs. We also hypothesized that if immune escape were occurring, then one pattern of longitudinal CD8 T cell responses restricted by shared HLA alleles would be maternal loss (by viral escape) and infant gain (by viral reversion to wildtype ...


Deep Gene Sequence Cluster Analyses Of Multi-Virus Infected Mucosal Tissue Reveal Enhanced Transmission Of Acute Hiv-1, Katja Klein, Nicholas J. Hathaway, Eric J. Arts 2020 University of Western Ontario

Deep Gene Sequence Cluster Analyses Of Multi-Virus Infected Mucosal Tissue Reveal Enhanced Transmission Of Acute Hiv-1, Katja Klein, Nicholas J. Hathaway, Eric J. Arts

Open Access Publications by UMMS Authors

Exposure of the genital mucosa to a genetically diverse viral swarm from the donor HIV-1 can result in breakthrough and systemic infection by a single transmitted/founder (TF) virus in the recipient. The highly diverse HIV-1 envelope (Env) in this inoculating viral swarm may have critical role in transmission and subsequent immune response. Thus, chronic (Envchronic) and acute (Envacute) Env chimeric HIV-1 were tested using multi-virus competition assays in human mucosal penile and cervical tissues. Viral competition analysis revealed that Envchronic viruses resided and replicated mainly in the tissue while Envacute viruses penetrated the human tissue and established infection of ...


Coxsackievirus B Type 4 Infection In Beta Cells Downregulates The Chaperone Prefoldin Uri To Induce A Mody4-Like Diabetes Via Pdx1 Silencing, Hugo Bernard, Ana Teijeiro, Almudena Chaves-Perez, Cristian Perna, Basanthi Satish, Anna Novials, Jennifer P. Wang, Nabil Djouder 2020 National Cancer Research Center

Coxsackievirus B Type 4 Infection In Beta Cells Downregulates The Chaperone Prefoldin Uri To Induce A Mody4-Like Diabetes Via Pdx1 Silencing, Hugo Bernard, Ana Teijeiro, Almudena Chaves-Perez, Cristian Perna, Basanthi Satish, Anna Novials, Jennifer P. Wang, Nabil Djouder

University of Massachusetts Medical School Faculty Publications

Enteroviruses are suspected to contribute to insulin-producing beta cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting beta cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in beta cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in beta cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces Pdx1 promoter ...


Two-Plasmid Packaging System For Recombinant Adeno-Associated Virus, Qiushi Tang, Allison M. Keeler, Songbo Zhang, Qin Su, Zhuoyao Lyu, Yangfan Cheng, Guangping Gao, Terence R. Flotte 2020 University of Massachusetts Medical School

Two-Plasmid Packaging System For Recombinant Adeno-Associated Virus, Qiushi Tang, Allison M. Keeler, Songbo Zhang, Qin Su, Zhuoyao Lyu, Yangfan Cheng, Guangping Gao, Terence R. Flotte

Open Access Publications by UMMS Authors

A number of packaging systems are available for production of recombinant adeno-associated virus vectors (rAAVs). Among these, the use of a two-plasmid cotransfection system, in which Rep and Cap genes and Ad helper genes are on the same plasmid, has not been frequently employed for good manufacturing practices (GMP) production, even though it presents some practical advantages over the common three-plasmid (triple) transfection method. To confirm and expand the utility of the two-plasmid system, we generated GMP-compatible versions of this system and used those package reporter genes in multiple capsid variants in direct comparison with triple transfection. Vector yields, purity ...


Precision Cas9 Genome Editing In Vivo With All-In-One, Self-Targeting Aav Vectors [Preprint], Raed Ibraheim, Phillip W. L. Tai, Aamir Mir, Nida Javeed, Jiaming Wang, Tomas Rodriguez, Samantha J. Nelson, Eraj Khokhar, Esther Mintzer, Stacy Maitland​, Yueying Cao, Guangping Gao, Erik J. Sontheimer 2020 University of Massachusetts Medical School

Precision Cas9 Genome Editing In Vivo With All-In-One, Self-Targeting Aav Vectors [Preprint], Raed Ibraheim, Phillip W. L. Tai, Aamir Mir, Nida Javeed, Jiaming Wang, Tomas Rodriguez, Samantha J. Nelson, Eraj Khokhar, Esther Mintzer, Stacy Maitland​, Yueying Cao, Guangping Gao, Erik J. Sontheimer

University of Massachusetts Medical School Faculty Publications

Adeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits, especially for large effectors like Cas9s. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. The use of compact effectors has enabled single-AAV delivery of Cas9s with 1-3 guides for edits that use end-joining repair pathways, but many precise edits that correct disease-causing mutations in vivo require homology-directed repair (HDR) templates. Here, we describe single-vector, ~4.8-kb AAV platforms that express Nme2Cas9 and either two sgRNAs to produce segmental deletions, or a single sgRNA with an ...


Vitamin D In Covid-19 Pneumonia: High Yield With Low Risk, Shahan Waheed, Emaduddin Siddiqui 2020 Aga Khan University

Vitamin D In Covid-19 Pneumonia: High Yield With Low Risk, Shahan Waheed, Emaduddin Siddiqui

Department of Emergency Medicine

No abstract provided.


Astrocyte- And Neuron-Derived Cxcl1 Drives Neutrophil Transmigration And Blood-Brain Barrier Permeability In Viral Encephalitis, Benedict D. Michael, Laura Bricio-Moreno, Elizabeth W. Sorensen, Yoshishige Miyabe, Jeffrey Lian, Tom Solomon, Evelyn A. Kurt-Jones, Andrew D. Luster 2020 Harvard Medical School

Astrocyte- And Neuron-Derived Cxcl1 Drives Neutrophil Transmigration And Blood-Brain Barrier Permeability In Viral Encephalitis, Benedict D. Michael, Laura Bricio-Moreno, Elizabeth W. Sorensen, Yoshishige Miyabe, Jeffrey Lian, Tom Solomon, Evelyn A. Kurt-Jones, Andrew D. Luster

Open Access Publications by UMMS Authors

Herpes simplex virus (HSV)-1 encephalitis has significant morbidity partly because of an over-exuberant immune response characterized by leukocyte infiltration into the brain and increased blood-brain barrier (BBB) permeability. Determining the role of specific leukocyte subsets and the factors that mediate their recruitment into the brain is critical to developing targeted immune therapies. In a murine model, we find that the chemokines CXCL1 and CCL2 are induced in the brain following HSV-1 infection. Ccr2 (CCL2 receptor)-deficient mice have reduced monocyte recruitment, uncontrolled viral replication, and increased morbidity. Contrastingly, Cxcr2 (CXCL1 receptor)-deficient mice exhibit markedly reduced neutrophil recruitment, BBB ...


Epstein-Barr Virus Genomes Reveal Population Structure And Type 1 Association With Endemic Burkitt Lymphoma, Yasin Kaymaz, Cliff I. Oduor, Ozkan Aydemir, Micah A. Luftig, Juliana A. Otieno, John Michael. Ong'echa, Jeffrey A. Bailey, Ann M. Moormann 2020 University of Massachusetts Medical School

Epstein-Barr Virus Genomes Reveal Population Structure And Type 1 Association With Endemic Burkitt Lymphoma, Yasin Kaymaz, Cliff I. Oduor, Ozkan Aydemir, Micah A. Luftig, Juliana A. Otieno, John Michael. Ong'echa, Jeffrey A. Bailey, Ann M. Moormann

UMass Center for Clinical and Translational Science Supported Publications

Endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in sub-Saharan Africa, is distinguished by its inclusion of Epstein-Barr virus (EBV). In order to better understand the impact of EBV variation in eBL tumorigenesis, we improved viral DNA enrichment methods and generated a total of 98 new EBV genomes from both eBL cases (n = 58) and healthy controls (n = 40) residing in the same geographic region in Kenya. Using our unbiased methods, we found that EBV type 1 was significantly more prevalent in eBL patients (74.5%) than in healthy children (47.5%) (odds ratio = 3.24, 95% confidence interval ...


Investigating Virological, Immunological, And Pathological Avenues To Identify Potential Targets For Developing Covid-19 Treatment And Prevention Strategies, Zafar Mahmood, Hani Alrefai Alrefai, Helal F. Hetta, Hidaya A. Kader 2020 United Arab Emirates University

Investigating Virological, Immunological, And Pathological Avenues To Identify Potential Targets For Developing Covid-19 Treatment And Prevention Strategies, Zafar Mahmood, Hani Alrefai Alrefai, Helal F. Hetta, Hidaya A. Kader

Books and Book Chapters

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging coronavirus causing respiratory disease commonly known as COVID-19. This novel coronavirus transmits from human to human and has caused profound morbidity and mortality worldwide leading to the ongoing pandemic. Moreover, disease severity differs considerably from individual to individual. Investigating the virology of COVID-19 and immunological pathways underlying its clinical manifestations will enable the identification and design of effective vaccines and potential therapies. In this review, we explore COVID-19 virology, the contribution of the immune system (innate and adaptive) during infection and control of the virus. Finally, we highlight vaccine development ...


Molecular Mechanisms Lead To Sex-Specific Covid-19 Prognosis And Targeted Therapies, Thushara Galbadage, Brent M. Peterson, Jeffrey S. Wang, Avishka Jayasekara, Danny A. Ramirez, Joseph Awada, John P. Walsh, Richard S. Gunasekera 2020 Biola University

Molecular Mechanisms Lead To Sex-Specific Covid-19 Prognosis And Targeted Therapies, Thushara Galbadage, Brent M. Peterson, Jeffrey S. Wang, Avishka Jayasekara, Danny A. Ramirez, Joseph Awada, John P. Walsh, Richard S. Gunasekera

Faculty Articles & Research

Clinical and epidemiological studies have identified male sex as an important risk factor for COVID-19 clinical outcomes and mortality. This raises the question as to how this risk factor can be addressed in the prognosis, clinical management, and the treatment of patients with Coronavirus disease 2019 (COVID-19). Currently, there are no guidelines or protocols to help alter the course of sex-specific COVID-19 prognosis, especially in severe disease presentations. This is partly due to the lack of research studies characterizing the differences in male vs. female host response to the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection and a lack of ...


Delayed Interventions, Low Compliance, And Health Disparities Amplified The Early Spread Of Covid-19, Aliea M. Jalali, Sumaia G. Khoury, JongWon See, Alexis M. Gulsvig, Brent M. Peterson, Richard S. Gunasekera, Gentian Buzi, Jason Wilson, Thushara Galbadage 2020 Biola University

Delayed Interventions, Low Compliance, And Health Disparities Amplified The Early Spread Of Covid-19, Aliea M. Jalali, Sumaia G. Khoury, Jongwon See, Alexis M. Gulsvig, Brent M. Peterson, Richard S. Gunasekera, Gentian Buzi, Jason Wilson, Thushara Galbadage

Faculty Articles & Research

The United States (US) public health interventions were rigorous and rapid, yet failed to arrest the spread of the Coronavirus Disease 2019 (COVID-19) pandemic as infections spread throughout the US. Many factors have contributed to the spread of COVID-19, and the success of public health interventions depends on the level of community adherence to preventative measures. Public health professionals must also understand regional demographic variation in health disparities and determinants to target interventions more effectively. In this study, a systematic evaluation of three significant interventions employed in the US, and their effectiveness in slowing the early spread of COVID-19 was ...


Structural Analysis Of Potent Hybrid Hiv-1 Protease Inhibitors Containing Bis-Tetrahydrofuran In A Pseudo-Symmetric Dipeptide Isostere, Linah Rusere, Gordon J. Lockbaum, Mina Henes, Sook-Kyung Lee, Ean Spielvogel, Desaboini Nageswara Rao, Klajdi Kosovrasti, Ellen A. Nalivaika, Ronald Swanstrom, Nese Kurt Yilmaz, Celia A. Schiffer, Akbar Ali 2020 University of Massachusetts Medical School

Structural Analysis Of Potent Hybrid Hiv-1 Protease Inhibitors Containing Bis-Tetrahydrofuran In A Pseudo-Symmetric Dipeptide Isostere, Linah Rusere, Gordon J. Lockbaum, Mina Henes, Sook-Kyung Lee, Ean Spielvogel, Desaboini Nageswara Rao, Klajdi Kosovrasti, Ellen A. Nalivaika, Ronald Swanstrom, Nese Kurt Yilmaz, Celia A. Schiffer, Akbar Ali

University of Massachusetts Medical School Faculty Publications

The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C2-symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2' position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2' position without significantly affecting potency. However, the group on the opposite P2/P2' position had a dramatic effect on potency depending on the size and shape of the ...


Acidic Ph Triggers Lipid Mixing Mediated By Lassa Virus Gp, Uriel Bulow, Ramesh Govindan, James B. Munro 2020 Tufts University

Acidic Ph Triggers Lipid Mixing Mediated By Lassa Virus Gp, Uriel Bulow, Ramesh Govindan, James B. Munro

Open Access Publications by UMMS Authors

Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever, a lethal disease endemic to Western Africa. LASV entry is mediated by the viral envelope glycoprotein (GP), a class I membrane fusogen and the sole viral surface antigen. Previous studies have identified components of the LASV entry pathway, including several cellular receptors and the requirement of endosomal acidification for infection. Here, we first demonstrate that incubation at a physiological temperature and pH consistent with the late endosome is sufficient to render pseudovirions, bearing LASV GP, non-infectious. Antibody binding indicates that this loss of infectivity is due to a conformational ...


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