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1.
Clin Infect Dis ; 2021 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-33822010

RESUMEN

BACKGROUND: Following the 2013-2016 West African Ebola outbreak, distinct, persistent health complaints were recognized in Ebola virus disease (EVD) survivors. Here we provide an in-depth characterization of post-Ebola syndrome over 2.5 years after resolution of disease. Additionally, we report sub-phenotypes of post-Ebola syndrome with overlapping symptom clusters in survivors from Eastern Sierra Leone. METHODS: Participants in Eastern Sierra Leone were identified by the Sierra Leone Association of Ebola survivors. Survivors and their contacts were administered a questionnaire assessing self-reported symptoms and a physical exam. Comparisons between survivors and contacts were conducted using conditional logistic regression. Symptom groupings were identified using hierarchical clustering approaches. Simplified Presentation of Incredibly Complex Evaluations (SPICE), correlation analysis, logistic regression and principal component analysis (PCA) were performed to explore the relationships between symptom clusters. RESULTS: 375 EVD survivors and 1040 contacts were enrolled into the study. At enrollment, EVD survivors reported significantly more symptoms than their contacts in all categories (p<.001). Symptom clusters representing distinct organ systems were identified. Correlation and logistic regression analysis identified relationships between symptom clusters, including stronger relationships between clusters including musculoskeletal symptoms (r=0.63, p<.001; and p<.001 for correlation and logistic regression, respectively). SPICE and PCA further highlighted sub-phenotypes with or without musculoskeletal symptoms. CONCLUSIONS: This study presents an in-depth characterization of post-Ebola syndrome in Sierra Leonean survivors over 2.5 years after disease. The interrelationship between symptom clusters indicates that post-Ebola syndrome is a heterogeneous disease. The distinct musculoskeletal and non-musculoskeletal phenotypes identified likely require targeted therapies to optimize long-term treatment for EVD survivors.

2.
Cell Host Microbe ; 29(4): 529-539.e3, 2021 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-33705729

RESUMEN

All current vaccines for COVID-19 utilize ancestral SARS-CoV-2 spike with the goal of generating protective neutralizing antibodies. The recent emergence and rapid spread of several SARS-CoV-2 variants carrying multiple spike mutations raise concerns about possible immune escape. One variant, first identified in the United Kingdom (B.1.1.7, also called 20I/501Y.V1), contains eight spike mutations with potential to impact antibody therapy, vaccine efficacy, and risk of reinfection. Here, we show that B.1.1.7 remains sensitive to neutralization, albeit at moderately reduced levels (∼sim;2-fold), by serum samples from convalescent individuals and recipients of an mRNA vaccine (mRNA-1273, Moderna) and a protein nanoparticle vaccine (NVX-CoV2373, Novavax). A subset of monoclonal antibodies to the receptor binding domain (RBD) of spike are less effective against the variant, while others are largely unaffected. These findings indicate that variant B.1.1.7 is unlikely to be a major concern for current vaccines or for an increased risk of reinfection.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , /inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pruebas de Neutralización , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto Joven
3.
Sci Rep ; 11(1): 4465, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33627703

RESUMEN

Respiratory viral (RV) infections represent a major threat for human health worldwide. Persons with HIV (PWH) have a compromised immune response and are thought to be at higher risk for severe RV disease. However, very little is known about the host immune response to RV infection in PWH. Here, we investigated gene expression changes in the peripheral blood of PWH co-infected with RV. Only very few differentially expressed genes could be detected between PWH with and without RV infection, suggesting that the immune response to RV in PWH is strongly dampened. Our data provides important insights into the host response to RV infections in HIV patients.

4.
Biomolecules ; 11(1)2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33477938

RESUMEN

Seasonal flu is an acute respiratory disease that exacts a massive toll on human populations, healthcare systems and economies. The disease is caused by an enveloped Influenza virus containing eight ribonucleoprotein (RNP) complexes. Each RNP incorporates multiple copies of nucleoprotein (NP), a fragment of the viral genome (vRNA), and a viral RNA-dependent RNA polymerase (POL), and is responsible for packaging the viral genome and performing critical functions including replication and transcription. A complete model of an Influenza RNP in atomic detail can elucidate the structural basis for viral genome functions, and identify potential targets for viral therapeutics. In this work we construct a model of a complete Influenza A RNP complex in atomic detail using multiple sources of structural and sequence information and a series of homology-modeling techniques, including a motif-matching fragment assembly method. Our final model provides a rationale for experimentally-observed changes to viral polymerase activity in numerous mutational assays. Further, our model reveals specific interactions between the three primary structural components of the RNP, including potential targets for blocking POL-binding to the NP-vRNA complex. The methods developed in this work open the possibility of elucidating other functionally-relevant atomic-scale interactions in additional RNP structures and other biomolecular complexes.

5.
PLoS Negl Trop Dis ; 14(9): e0008556, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32925964

RESUMEN

Sexual transmission of Ebola virus (EBOV) is well established and has been implicated in multiple resurgences during the West African Ebola epidemic. Given the persistence of viral RNA in semen, guidelines from the World Health Organization (WHO) recommend abstinence or condom use for at least 1 year or until two semen PCR tests are negative. To better understand the impact of semen testing on sexual behavior, male EVD survivors were surveyed regarding their sexual behavior before and after semen testing. Of the 171 men who enrolled, 148 reported being sexually active following discharge from an ETU with 59% reporting episodes of condomless sex. At least one semen sample for testing was provided by 149 men and 13 of these men had EBOV RNA detected in their semen. When comparing sexual behaviors before and after semen testing, a positive semen test result had limited impact on behavior. Of those with seminal EBOV RNA detected, 61% reported no change in behavior pre- and post-semen testing with 46% engaging in condomless sex before and after testing and only 1 adopted safer sex behaviors following receipt of a positive result. Similarly, among men with undetectable EBOV in their semen, 66% reported no change in sexual behaviors with semen testing, with 55% forgoing condoms during sex. In only 11% was a negative semen result followed by abandoning condoms. There were no known sexual transmission events of Ebola virus in this cohort despite viral presence in semen during periods of condomless sex. This highlights the need to better understand the infectious potential of viral RNA persistence and determine what constitutes effective counseling for survivors and their partners.


Asunto(s)
Consejo , ARN Viral/análisis , Semen/virología , Conducta Sexual/psicología , Adolescente , Adulto , Portador Sano , Niño , Condones/estadística & datos numéricos , Ebolavirus , Fiebre Hemorrágica Ebola/prevención & control , Fiebre Hemorrágica Ebola/transmisión , Humanos , Liberia/epidemiología , Masculino , Persona de Mediana Edad , Conducta Sexual/estadística & datos numéricos , Encuestas y Cuestionarios , Sobrevivientes
6.
Nat Commun ; 11(1): 1703, 2020 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-32245977

RESUMEN

Optogenetic therapies for vision restoration aim to confer intrinsic light sensitivity to retinal ganglion cells when photoreceptors have degenerated and light sensitivity has been irreversibly lost. We combine adaptive optics ophthalmoscopy with calcium imaging to optically record optogenetically restored retinal ganglion cell activity in the fovea of the living primate. Recording from the intact eye of a living animal, we compare the patterns of activity evoked by the optogenetic actuator ChrimsonR with natural photoreceptor mediated stimulation in the same retinal ganglion cells. Optogenetic responses are recorded more than one year following administration of the therapy and two weeks after acute loss of photoreceptor input in the living animal. This in vivo imaging approach could be paired with any therapy to minimize the number of primates required to evaluate restored activity on the retinal level, while maximizing translational benefit by using an appropriate pre-clinical model of the human visual system.


Asunto(s)
Ceguera/terapia , Optogenética/métodos , Células Fotorreceptoras de Vertebrados/patología , Degeneración Retiniana/terapia , Células Ganglionares de la Retina/fisiología , Animales , Ceguera/diagnóstico , Ceguera/etiología , Modelos Animales de Enfermedad , Femenino , Fóvea Central/citología , Fóvea Central/diagnóstico por imagen , Fóvea Central/patología , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Humanos , Macaca fascicularis , Masculino , Oftalmoscopía , Imagen Óptica , Parvovirinae/genética , Degeneración Retiniana/complicaciones , Degeneración Retiniana/diagnóstico por imagen , Degeneración Retiniana/patología
7.
Influenza Other Respir Viruses ; 14(4): 465-469, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32153113

RESUMEN

This study was conducted to determine the prevalence of respiratory viral infections (RVI) in persons living with HIV (PLH) admitted with a respiratory complaint using real-time reverse transcription polymerase chain reaction and primer-independent next-generation sequencing (NGS). Of 82 subjects, respiratory viruses were the most common pathogen identified in 27 (33%), followed by fungus and bacteria in 8 (10%) and 4 (5%) subjects, respectively. Among subjects with RVI, 11 (41%) required ICU admission and 16 (59%) required mechanical ventilation. The proportion of respiratory viruses identified, and the associated complicated hospital course highlights the significant role that RVIs play in the lung health of PLH.

8.
Nat Rev Dis Primers ; 6(1): 13, 2020 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-32080199

RESUMEN

Ebola virus disease (EVD) is a severe and frequently lethal disease caused by Ebola virus (EBOV). EVD outbreaks typically start from a single case of probable zoonotic transmission, followed by human-to-human transmission via direct contact or contact with infected bodily fluids or contaminated fomites. EVD has a high case-fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome. Diagnosis requires a combination of case definition and laboratory tests, typically real-time reverse transcription PCR to detect viral RNA or rapid diagnostic tests based on immunoassays to detect EBOV antigens. Recent advances in medical countermeasure research resulted in the recent approval of an EBOV-targeted vaccine by European and US regulatory agencies. The results of a randomized clinical trial of investigational therapeutics for EVD demonstrated survival benefits from two monoclonal antibody products targeting the EBOV membrane glycoprotein. New observations emerging from the unprecedented 2013-2016 Western African EVD outbreak (the largest in history) and the ongoing EVD outbreak in the Democratic Republic of the Congo have substantially improved the understanding of EVD and viral persistence in survivors of EVD, resulting in new strategies toward prevention of infection and optimization of clinical management, acute illness outcomes and attendance to the clinical care needs of patients.

9.
Br J Ophthalmol ; 104(10): 1430-1434, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31949093

RESUMEN

BACKGROUND/AIMS: Prior studies support an association between increased retinal venule diameter and elevated intracranial pressure (ICP). The purpose of this study was to test the hypothesis that retinal venule diameters decrease in association with long-term therapy for high ICP in subjects with idiopathic intracranial hypertension (IIH). METHODS: This is a retrospective analysis of multicentre randomised controlled trial data. Standardised procedures were used to measure area of optic nerve head elevation (ONHA) and diameters of 4 arterioles and 4 venules 2.7 mm from the optic disc centre on fundus photos collected at baseline and after 6 months of randomised treatment with placebo+diet or acetazolamide+diet in subjects participating in the IIH Treatment Trial (IIHTT) (n=115). Change in arteriole (Da) and venule (Dv) diameters from baseline to 6 months was studied as a function of IIH, haemodynamic and demographic variables. RESULTS: Dv decreased following 6 months of therapy (8.1 µm, 5.9%, p<0.0005) but Da did not change. Dv change was associated with ONHA change (p<0.0005, r=0.47) and this association persisted in multiple variable models. CONCLUSIONS: Retinal venule diameter decreased, and arteriole diameter did not change in association with treatment for elevated ICP with a weight loss intervention and placebo or acetazolamide in IIHTT participants. Further study is needed to determine how retinal vessel measurements can be combined with other clinical observations to inform disease management.

10.
Virology ; 539: 18-25, 2020 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-31629226

RESUMEN

KSHV-associated inflammatory cytokine syndrome (KICS) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). KICS is associated with high-level, systemic replication of KSHV. This study characterized the clinical and virologic features of a KICS patient over time. Additionally, it compared the cytokine profiles of the KICS case to Kaposi's sarcoma (KS) (n = 11) and non-KS (n = 6) cases. This KICS case presented with elevated levels of KSHV and IL-10, as expected. Surprisingly, this case did not have elevated levels of IL-6 or human immunodeficiency virus 1 (HIV-1). Nevertheless, treatment with anti-IL6 receptor antibody (tocilizumab) reduced KSHV viral load and IL-10. The KSHV genome sequence showed no significant changes over time, except in ORF24. Phylogenetic analysis established this isolate as belonging to KSHV clade A and closely related to other US isolates. These findings suggest IL-10 as potential biomarker and therapy target for KICS.


Asunto(s)
Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Herpesvirus Humano 8/fisiología , Interleucina-10/sangre , Replicación Viral/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/virología , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores/sangre , Síndrome de Liberación de Citoquinas , ADN Viral/sangre , ADN Viral/genética , Genoma Viral/genética , Infecciones por Herpesviridae/diagnóstico , Infecciones por Herpesviridae/tratamiento farmacológico , Herpesvirus Humano 8/clasificación , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/aislamiento & purificación , Humanos , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Filogenia , Sarcoma de Kaposi/inmunología , Sarcoma de Kaposi/virología , Carga Viral
11.
Clin Infect Dis ; 71(7): 1749-1755, 2020 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-31693114

RESUMEN

BACKGROUND: Cohort studies have reported a high prevalence of musculoskeletal, neurologic, auditory, and visual complications among Ebola virus disease (EVD) survivors. However, little is known about the host- and disease-related predictors of these symptoms and their etiological mechanisms. METHODS: The presence and patterns of 8 cardinal symptoms that are most commonly reported following EVD survival were assessed in the 326 EVD survivors who participated in the ongoing longitudinal Liberian EVD Survivor Study. At quarterly study visits, symptoms that developed since acute EVD were recorded and blood was collected for biomarkers of inflammation and immune activation. RESULTS: At baseline (mean 408 days from acute EVD), 75.5% of survivors reported at least 1 new cardinal symptom since surviving EVD, which in 85.8% was rated as highly interfering with life. Two or more incident symptoms were reported by 61.0% of survivors, with pairings of joint pain, headache, or fatigue the most frequent. Women were significantly more likely than men to report headache, while older age was significantly associated with musculoskeletal and visual symptoms. In analyses adjusted for multiple comparisons, no statistically significant association was found between any symptom and 26 markers of inflammation and immune activation. Symptom frequency remained largely unchanged during study follow-up. CONCLUSIONS: Post-EVD complications occur in a majority of survivors and remain present more than 4 years after acute infection. An association between markers of inflammation and immune activation and individual symptoms was not found, suggesting an alternative etiology for persistent post-EVD symptomatology.

13.
J Comput Chem ; 40(21): 1919-1930, 2019 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-30994934

RESUMEN

The growing interest in the complexity of biological interactions is continuously driving the need to increase system size in biophysical simulations, requiring not only powerful and advanced hardware but adaptable software that can accommodate a large number of atoms interacting through complex forcefields. To address this, we developed and implemented strategies in the GENESIS molecular dynamics package designed for large numbers of processors. Long-range electrostatic interactions were parallelized by minimizing the number of processes involved in communication. A novel algorithm was implemented for nonbonded interactions to increase single instruction multiple data (SIMD) performance, reducing memory usage for ultra large systems. Memory usage for neighbor searches in real-space nonbonded interactions was reduced by approximately 80%, leading to significant speedup. Using experimental data describing physical 3D chromatin interactions, we constructed the first atomistic model of an entire gene locus (GATA4). Taken together, these developments enabled the first billion-atom simulation of an intact biomolecular complex, achieving scaling to 65,000 processes (130,000 processor cores) with 1 ns/day performance. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.


Asunto(s)
Cromatina/química , Simulación de Dinámica Molecular , Algoritmos , Fenómenos Biofísicos , Cromatina/genética , Programas Informáticos
17.
Biomed Opt Express ; 10(1): 66-82, 2019 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-30775083

RESUMEN

Progress is needed in developing animal models of photoreceptor degeneration and evaluating such models with longitudinal, noninvasive techniques. We employ confocal scanning laser ophthalmoscopy, optical coherence tomography (OCT) and high-resolution retinal imaging to noninvasively observe the retina of non-human primates with induced photoreceptor degeneration. Photoreceptors were imaged at the single-cell scale in three modalities of adaptive optics scanning light ophthalmoscopy: traditional confocal reflectance, indicative of waveguiding; a non-confocal offset aperture technique visualizing scattered light; and two-photon excited fluorescence, the time-varying signal of which, at 730 nm excitation, is representative of visual cycle function. Assessment of photoreceptor structure and function using these imaging modalities revealed a reduction in retinoid production in cone photoreceptor outer segments while inner segments appeared to remain present. Histology of one retina confirmed loss of outer segments and the presence of intact inner segments. This unique combination of imaging modalities can provide essential, clinically-relevant information on both the structural integrity and function of photoreceptors to not only validate models of photoreceptor degeneration but potentially evaluate the efficacy of future cell and gene-based therapies for vision restoration.

18.
PLoS One ; 13(11): e0206595, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30485311

RESUMEN

BACKGROUND: Survivors of the 2014-2016 West Africa Ebola epidemic have been reported to suffer high levels of stigmatization after return to their communities. We sought to characterize the stigma encountered by a cohort of Ebola survivors in Liberia over time. METHODS: Ebola-related stigma was assessed from June 2015 to August 2017 in 299 adolescent and adult Liberian Ebola Survivor Cohort participants at three month intervals using adapted HIV stigma scales scored from 0 to 10 according to the proportion of answers indicating stigmatization. FINDINGS: The median time from Ebola Virus Disease (EVD) to study entry was 393 days (IQR 336-492). Participants (43% female) had a median age of 31 (IQR 25-40) years. Mean self-reported stigma levels were greater at baseline (6.28 ± 0.15 [IQR: 4.38-8.75]) compared to the first post-baseline visit (0.60 ± 0.10 [IQR: 0-0]; p<0.0001). During follow-up, stigma levels were stable. Baseline stigma significantly increased during enrollment and following clusters of Ebola re-emergence in Liberia. Survivors encountered primarily enacted and perceived external stigma rather than internalized stigma. CONCLUSIONS: Ebola-related stigma was prevalent among Liberian survivors more than a year after EVD recovery. Self-reported stigma was greater in the period before cohort enrollment; however, some degree of stigmatization persisted years after EVD. Transient rises in stigma were observed following episodic Ebola re-emergence of EVD in Liberia. During future EVD outbreaks, enhanced public health interventions designed to prevent and mitigate Ebola-related stigma that is enacted and external should be implemented to support survivor recovery and community re-integration.


Asunto(s)
Fiebre Hemorrágica Ebola/psicología , Estigma Social , Supervivencia , Adulto , Femenino , Estudios de Seguimiento , Fiebre Hemorrágica Ebola/epidemiología , Humanos , Liberia , Estudios Longitudinales , Masculino , Prevalencia
19.
Am J Ophthalmol ; 195: 101-109, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30081012

RESUMEN

PURPOSE: To compare measurements of papilledema using fundus photography, optical coherence tomography (OCT), and Frisén score in patients with idiopathic intracranial hypertension (IIH). DESIGN: Retrospective, noncomparative analysis of randomized controlled trial data. METHODS: The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) evaluated weight management and treatment with acetazolamide compared with placebo in patients with IIH and mild visual loss. Among the 126 subjects in the IIHTT OCT substudy, fundus photographs and OCT scans of the optic disc were taken at baseline and at 6 and 12 months after enrollment. Trained readers scored each eye using a modified Frisén scale and measured the area of disc elevation. OCT scans assessed optic nerve head (ONH) volume. Correlations between volume and area were computed for both study and nonstudy eyes. RESULTS: Disc area and ONH volume were positively correlated at baseline (R2 = 0.77 in study eyes, P < .001). Correlations between area and volume were similar in the treatment groups at baseline, but were weaker in the acetazolamide group compared with the placebo group at 6 months (R2 = 0.25 vs R2 = 0.76 in study eyes) and 12 months (R2 = 0.19 vs R2 = 0.65 in study eyes). At 6 and 12 months after enrollment, there was no consistent relationship between Frisén score, disc area, and ONH volumes in the acetazolamide group. CONCLUSION: Frisén score fails to reflect the photographic area and OCT volume of papilledema after treatment with acetazolamide. Clinicians should use caution when using the Frisén scale to monitor the effect of treatment on papilledema over time.


Asunto(s)
Acetazolamida/uso terapéutico , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Disco Óptico/patología , Seudotumor Cerebral/diagnóstico por imagen , Adulto , Líquido Cefalorraquídeo , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fibras Nerviosas/patología , Tamaño de los Órganos , Papiledema/diagnóstico , Fotograbar/métodos , Seudotumor Cerebral/tratamiento farmacológico , Células Ganglionares de la Retina/patología , Estudios Retrospectivos , Tomografía de Coherencia Óptica/métodos , Pruebas del Campo Visual
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