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1.
PLoS Pathog ; 18(4): e1009925, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35443018

RESUMEN

Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable but low levels of antiviral antibodies after infusion. In comparison to the control animals, CCP-treated animals had similar levels of viral RNA in upper and lower respiratory tract secretions, similar detection of viral RNA in lung tissues by in situ hybridization, but lower amounts of infectious virus in the lungs. CCP-treated animals had a moderate, but statistically significant reduction in interstitial pneumonia, as measured by comprehensive lung histology. Thus overall, therapeutic benefits of CCP were marginal and inferior to results obtained earlier with monoclonal antibodies in this animal model. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses.


Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Anticuerpos Neutralizantes , Antivirales , COVID-19/terapia , Humanos , Inmunización Pasiva , Macaca mulatta , ARN Viral , Sueroterapia para COVID-19
2.
PLoS Pathog ; 17(7): e1009688, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34228761

RESUMEN

There is an urgent need for effective therapeutic interventions against SARS-CoV-2, including new variants that continue to arise. Neutralizing monoclonal antibodies have shown promise in clinical studies. We investigated the therapeutic efficacy of a combination of two potent monoclonal antibodies, C135-LS and C144-LS that carry half-life extension mutations, in the rhesus macaque model of COVID-19. Twelve young adult macaques (three groups of four animals) were inoculated intranasally and intra-tracheally with a high dose of SARS-CoV-2 and 24 hours later, treated intravenously with a high (40 mg/kg) or low (12 mg/kg) dose of the C135-LS and C144-LS antibody combination, or a control monoclonal antibody. Animals were monitored for 7 days. Compared to the control animals, animals treated with either dose of the anti-SARS-CoV-2 antibodies showed similarly improved clinical scores, lower levels of virus replication in upper and lower respiratory tract, and significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. In conclusion, this study provides proof-of-concept in support of further clinical development of these monoclonal antibodies against COVID-19 during early infection.


Asunto(s)
Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/uso terapéutico , COVID-19/terapia , Pulmón/patología , SARS-CoV-2/inmunología , Replicación Viral , Animales , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/patología , COVID-19/virología , Modelos Animales de Enfermedad , Femenino , Pulmón/diagnóstico por imagen , Macaca mulatta , Masculino , Análisis Multivariante , Radiografía , Sistema Respiratorio/virología , SARS-CoV-2/fisiología , Factores de Tiempo , Resultado del Tratamiento , Replicación Viral/inmunología
3.
Metabolomics ; 19(2): 10, 2023 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-36745234

RESUMEN

INTRODUCTION: The primate retina has evolved regional specialisations for specific visual functions. The macula is specialised towards high acuity vision and is an area that contains an increased density of cone photoreceptors and signal processing neurons. Different regions in the retina display unique susceptibility to pathology, with many retinal diseases primarily affecting the macula. OBJECTIVES: To better understand the properties of different retinal areas we studied the differential distribution of metabolites across the retina. METHODS: We conducted an untargeted metabolomics analysis on full-thickness punches from three different regions (macula, temporal peri-macula and periphery) of healthy primate retina. RESULTS: Nearly half of all metabolites identified showed differential abundance in at least one comparison between the three regions. Furthermore, mapping metabolomics results from macula-specific eye diseases onto our region-specific metabolite distributions revealed differential abundance defining systemic metabolic dysregulations that were region specific. CONCLUSIONS: The unique metabolic phenotype of different retinal regions is likely due to the differential distribution of different cell types in these regions reflecting the specific metabolic requirements of each cell type. Our results may help to better understand the pathobiology of retinal diseases with region specificity.


Asunto(s)
Mácula Lútea , Enfermedades de la Retina , Animales , Metabolómica , Retina/metabolismo , Enfermedades de la Retina/genética , Enfermedades de la Retina/metabolismo , Mácula Lútea/metabolismo , Neuronas/metabolismo
4.
Mol Ther ; 24(3): 548-55, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26727042

RESUMEN

Angelman syndrome (AS) is a neurological genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain. Due to brain-specific genetic imprinting at this locus, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. However, widespread delivery of gene regulators to the brain remains challenging. Here, we report an engineered zinc finger-based artificial transcription factor (ATF) that, when injected i.p. or s.c., crossed the blood-brain barrier and increased Ube3a expression in the brain of an adult mouse model of AS. The factor displayed widespread distribution throughout the brain. Immunohistochemistry of both the hippocampus and cerebellum revealed an increase in Ube3a upon treatment. An ATF containing an alternative DNA-binding domain did not activate Ube3a. We believe this to be the first report of an injectable engineered zinc finger protein that can cause widespread activation of an endogenous gene in the brain. These observations have important implications for the study and treatment of AS and other neurological disorders.


Asunto(s)
Síndrome de Angelman/genética , Síndrome de Angelman/metabolismo , Encéfalo/metabolismo , Regulación de la Expresión Génica , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/genética , Animales , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Genes Reporteros , Sitios Genéticos , Ratones , Factores de Transcripción/administración & dosificación , Dedos de Zinc
5.
Proteomics ; 16(11-12): 1814-21, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27198560

RESUMEN

Realistic in vitro models are critical in the drug development process. In this study, a novel in vitro platform is employed to assess drug penetration and metabolism. This platform, which utilizes a 3D printed fluidic device, allows for dynamic dosing of three dimensional cell cultures, also known as spheroids. The penetration of the chemotherapeutic irinotecan into HCT 116 colon cancer spheroids was examined with MALDI imaging mass spectrometry (IMS). The active metabolite of irinotecan, SN-38, was also detected. After twenty-four hours of treatment, SN-38 was concentrated to the outside of the spheroid, a region of actively dividing cells. The irinotecan prodrug localization contrasted with SN-38 and was concentrated to the necrotic core of the spheroids, a region containing mostly dead and dying cells. These results demonstrate that this unique in vitro platform is an effective means to assess drug penetration and metabolism in 3D cell cultures. This innovative system can have a transformative impact on the preclinical evaluation of drug candidates due to its cost effectiveness and high throughput.


Asunto(s)
Camptotecina/análogos & derivados , Neoplasias del Colon/tratamiento farmacológico , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Esferoides Celulares/efectos de los fármacos , Camptotecina/administración & dosificación , Camptotecina/aislamiento & purificación , Técnicas de Cultivo de Célula/métodos , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Células HCT116 , Humanos , Irinotecán , Dispositivos Laboratorio en un Chip , Impresión Tridimensional/instrumentación , Esferoides Celulares/metabolismo
6.
Anal Chem ; 88(3): 1864-70, 2016 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-26727249

RESUMEN

The process of bringing a drug to market involves many steps, including the preclinical stage, where various properties of the drug candidate molecule are determined. These properties, which include drug absorption, distribution, metabolism, and excretion, are often displayed in a pharmacokinetic (PK) profile. While PK profiles are determined in animal models, in vitro systems that model in vivo processes are available, although each possesses shortcomings. Here, we present a 3D-printed, diffusion-based, and dynamic in vitro PK device. The device contains six flow channels, each with integrated porous membrane-based insert wells. The pores of these membranes enable drugs to freely diffuse back and forth between the flow channels and the inserts, thus enabling both loading and clearance portions of a standard PK curve to be generated. The device is designed to work with 96-well plate technology and consumes single-digit milliliter volumes to generate multiple PK profiles, simultaneously. Generation of PK profiles by use of the device was initially performed with fluorescein as a test molecule. Effects of such parameters as flow rate, loading time, volume in the insert well, and initial concentration of the test molecule were investigated. A prediction model was generated from this data, enabling the user to predict the concentration of the test molecule at any point along the PK profile within a coefficient of variation of ∼ 5%. Depletion of the analyte from the well was characterized and was determined to follow first-order rate kinetics, indicated by statistically equivalent (p > 0.05) depletion half-lives that were independent of the starting concentration. A PK curve for an approved antibiotic, levofloxacin, was generated to show utility beyond the fluorescein test molecule.


Asunto(s)
Difusión , Evaluación Preclínica de Medicamentos/instrumentación , Levofloxacino/farmacocinética , Técnicas Analíticas Microfluídicas , Impresión Tridimensional , Animales , Antibacterianos/farmacocinética , Cinética , Técnicas Analíticas Microfluídicas/instrumentación , Modelos Animales , Impresión Tridimensional/instrumentación
7.
Genome Res ; 23(3): 530-8, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23222846

RESUMEN

Zinc-finger nucleases (ZFNs) are important tools for genome engineering. Despite intense interest by many academic groups, the lack of robust noncommercial methods has hindered their widespread use. The modular assembly (MA) of ZFNs from publicly available one-finger archives provides a rapid method to create proteins that can recognize a very broad spectrum of DNA sequences. However, three- and four-finger arrays often fail to produce active nucleases. Efforts to improve the specificity of the one-finger archives have not increased the success rate above 25%, suggesting that the MA method might be inherently inefficient due to its insensitivity to context-dependent effects. Here we present the first systematic study on the effect of array length on ZFN activity. ZFNs composed of six-finger MA arrays produced mutations at 15 of 21 (71%) targeted loci in human and mouse cells. A novel drop-out linker scheme was used to rapidly assess three- to six-finger combinations, demonstrating that shorter arrays could improve activity in some cases. Analysis of 268 array variants revealed that half of MA ZFNs of any array composition that exceed an ab initio B-score cutoff of 15 were active. These results suggest that, when used appropriately, MA ZFNs are able to target more DNA sequences with higher success rates than other current methods.


Asunto(s)
ADN/aislamiento & purificación , Endonucleasas/genética , Ingeniería de Proteínas , Dedos de Zinc/genética , Animales , ADN/genética , Análisis Mutacional de ADN , Ensayo de Cambio de Movilidad Electroforética , Endonucleasas/metabolismo , Sitios Genéticos , Células HEK293 , Humanos , Ratones , Análisis de Secuencia de ADN
8.
Nucleic Acids Res ; 41(7): 4118-28, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23408851

RESUMEN

Transcription activator-like effectors (TALEs) have revolutionized the field of genome engineering. We present here a systematic assessment of TALE DNA recognition, using quantitative electrophoretic mobility shift assays and reporter gene activation assays. Within TALE proteins, tandem 34-amino acid repeats recognize one base pair each and direct sequence-specific DNA binding through repeat variable di-residues (RVDs). We found that RVD choice can affect affinity by four orders of magnitude, with the relative RVD contribution in the order NG > HD ≈ NN >> NI > NK. The NN repeat preferred the base G over A, whereas the NK repeat bound G with 10(3)-fold lower affinity. We compared AvrBs3, a naturally occurring TALE that recognizes its target using some atypical RVD-base combinations, with a designed TALE that precisely matches 'standard' RVDs with the target bases. This comparison revealed unexpected differences in sensitivity to substitutions of the invariant 5'-T. Another surprising observation was that base mismatches at the 5' end of the target site had more disruptive effects on affinity than those at the 3' end, particularly in designed TALEs. These results provide evidence that TALE-DNA recognition exhibits a hitherto un-described polarity effect, in which the N-terminal repeats contribute more to affinity than C-terminal ones.


Asunto(s)
Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , ADN/química , Transactivadores/química , Transactivadores/metabolismo , ADN/metabolismo , Unión Proteica , Secuencias Repetitivas de Aminoácido , Activación Transcripcional
9.
Anal Chem ; 86(7): 3240-53, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24432804

RESUMEN

Nearing 30 years since its introduction, 3D printing technology is set to revolutionize research and teaching laboratories. This feature encompasses the history of 3D printing, reviews various printing methods, and presents current applications. The authors offer an appraisal of the future direction and impact this technology will have on laboratory settings as 3D printers become more accessible.


Asunto(s)
Biotecnología , Química , Impresión Tridimensional/normas
10.
Nitric Oxide ; 38: 1-7, 2014 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-24530476

RESUMEN

Red blood cells (RBCs) release adenosine triphosphate (ATP) in response to a variety of stimuli, including flow-induced deformation. Hydroxyurea (HU), a proven therapy for individuals with sickle cell disease (SCD), is known to improve blood flow. However, the exact mechanism leading to the improved blood flow is incomplete. Here, we report that the incubation of human RBCs with HU enhances ATP release from these cells and that this ATP is capable of stimulating nitric oxide (NO) production in an endothelium. RBCs incubated with HU were pumped through micron-size flow channels in a microfluidic device. The release of ATP from the RBCs was measured using the luciferin-luciferase assay in detection wells on the device that were separated from the flow channels by a porous polycarbonate membrane. NO released from a layer of bovine artery endothelial cells (bPAECs) cultured on the polycarbonate membrane was also measured using the extracellular NO probe DAF-FM. ATP release from human RBCs incubated with 100 µM HU was observed to be 2.06±0.37-fold larger than control samples without HU (p<0.05, N ≥ 3). When HU-incubated RBCs were flowed under a layer of bPAECs, NO released from the bPAEC layer was measured to be 1.34±0.10-fold higher than controls. An antagonist of the P2Y receptor established that this extra 30% increase in NO release is ATP mediated. Furthermore, when RBCs were incubated with L-NAME, a significant decrease in endothelium-derived NO production was observed. Control experiments suggest that RBC-generated NO indirectly affects endothelial NO production via its effects on RBC-derived ATP release.


Asunto(s)
Adenosina Trifosfato/metabolismo , Endotelio/metabolismo , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Hidroxiurea/farmacología , Óxido Nítrico/biosíntesis , Relación Dosis-Respuesta a Droga , Humanos , Técnicas Analíticas Microfluídicas , Relación Estructura-Actividad
12.
Anal Chem ; 85(12): 5622-6, 2013 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-23687961

RESUMEN

Fluidic devices fabricated using conventional soft lithography are well suited as prototyping methods. Three-dimensional (3D) printing, commonly used for producing design prototypes in industry, allows for one step production of devices. 3D printers build a device layer by layer based on 3D computer models. Here, a reusable, high throughput, 3D printed fluidic device was created that enables flow and incorporates a membrane above a channel in order to study drug transport and affect cells. The device contains 8 parallel channels, 3 mm wide by 1.5 mm deep, connected to a syringe pump through standard, threaded fittings. The device was also printed to allow integration with commercially available membrane inserts whose bottoms are constructed of a porous polycarbonate membrane; this insert enables molecular transport to occur from the channel to above the well. When concentrations of various antibiotics (levofloxacin and linezolid) are pumped through the channels, approximately 18-21% of the drug migrates through the porous membrane, providing evidence that this device will be useful for studies where drug effects on cells are investigated. Finally, we show that mammalian cells cultured on this membrane can be affected by reagents flowing through the channels. Specifically, saponin was used to compromise cell membranes, and a fluorescent label was used to monitor the extent, resulting in a 4-fold increase in fluorescence for saponin treated cells.

13.
Women Birth ; 36(6): e669-e675, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37422367

RESUMEN

PROBLEM/BACKGROUND: Respectful woman-centred care is an expectation of the Midwifery Standards of Practice within Aotearoa New Zealand. With both the national and international expectations identifying human rights as a priority in maternity care. Mistreatment can be experienced by women in all socio-political contexts. Identifying women's experiences of their maternity service is vital when assessing the quality of these services. AIM: To explore women's experiences of continuity of midwifery care in Aotearoa NZ, whether they support the expectations within the Standards of Midwifery Practice and identify the characteristics of care that may contribute to positive or negative experiences of care. METHODS: A retrospective analysis of women's formal online feedback to their midwife using a mixed method design. Feedback forms received from the 1st January 2019 to the 31st December 2019 were analysed using descriptive statistics with free text thematically analysed. FINDINGS: A total of 7749 feedback forms were received demonstrating high levels of satisfaction overall. Three overlapping themes were identified as being central to both positive and negative feedback. Building a positive relationship involved three steps. These were the establishment and maintenance of trust, honouring decisions and empowerment. Overall, the existence of these relationship characteristics contributed to a valued woman-midwife relationship. Women who gave negative feedback identified a lack of trust and a failure to honour decisions which led to women feeling disempowered contributing to a lack of being valued in the relationship. CONCLUSION: Continuity of care in Aotearoa NZ supports the development of a respectful partnership through trust, honouring decisions and empowerment.

14.
Anal Chem ; 89(1): 57-70, 2017 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-28105825
15.
Trauma Violence Abuse ; 23(3): 854-867, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-33325321

RESUMEN

Traditionally, the literature has sought to understand the impact of racial minority status and trauma as it relates to interpersonal violence, domestic violence, and sexual assault. What has not been as extensively reviewed and summarized is how racially or ethnically motivated hate crimes impact the mental health of minorities-particularly Latinx/Hispanic groups. This review aims to summarize the current body of literature on the intersection of race-motivated hate crime and trauma responses within Latinx community. To do so, the theoretical foundation for this inquiry will build from a race-based trauma perspective. Specifically, this review connects existing frameworks for race and trauma and integrates literature that examines Latinx or Hispanic populations that have experienced discrimination, bias, or hate crime as a result of their identity or perceived identity. The importance of situating bias or hate events within the trauma literature stems from a lack of overall formal evaluation of these events, and how these occurrences are historically overlooked as a traumatic stressor. The findings of this review suggest that (1) experiencing racially motivated victimization can cause adverse mental and physical health outcomes in Latinxs and (2) currently, there is only one study that has examined the impact of hate crime on Latinxs in the United States. This leaves the field with unanswered questions about the impact of hate crime victimization among Latinxs, which is an ever-growing area in need of attention.


Asunto(s)
Víctimas de Crimen , Odio , Crimen/psicología , Víctimas de Crimen/psicología , Humanos , Prejuicio , Estados Unidos , Violencia
16.
J Interpers Violence ; 37(23-24): NP22600-NP22626, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35195467

RESUMEN

Latinx adults have become increasingly vulnerable to bias motivated victimization. The impact of such incidents on Latinx communities is severely understudied, particularly concerning whether or not victims will seek help as a result of such events. Evidence within other victimization contexts demonstrate Latinx populations may be less likely to seek formal help from police, medical providers, and other formal authorities, relying instead on informal support networks such as family and friends. The current study sought to understand formal and informal help-seeking behavior among Latinx adults who experienced bias motivated victimization. The Understanding and Measuring Bias Victimization against Latinos study obtained rates of bias victimization and subsequent help-seeking behavior among Latinx adults who reported experiencing bias victimization (n = 315, 34.6% of full sample of 910). Those who experience bias victimization seek formal help at much lower rates than informal forms of support. Logistic regression analyses controlling the type of victimization demonstrated that participants who experienced a victimization constituting a hate crime were more likely to seek formal help compared to experiencing non-criminal bias events. Implications include addressing barriers to Latinx bias victims seeking forms of help, in addition to understanding the potential polyvictimization histories that predict why Latinx adults may decide to seek help.


Asunto(s)
Acoso Escolar , Víctimas de Crimen , Adulto , Humanos , Odio , Hispánicos o Latinos , Crimen
17.
J Adolesc Health ; 70(6): 934-941, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35177344

RESUMEN

PURPOSE: Adolescent dating abuse (ADA) is a public health issue. Adolescents may experience victimization, engage in perpetration, or both. This study explores the co-occurrences of ADA victimization and perpetration, specifically examining which experiences and behaviors are most likely to co-occur and whether these vary by gender. METHODS: Data came from a nationally representative sample of 807 adolescents between the ages of 11 and 21 years in the United States who reported on at least one relationship in the past year through the Measure of Adolescent Relationship Harassment and Abuse (MARSHA). Using this sample, we applied network analysis to depict each ADA type as a "node" in a network where it was directly or indirectly associated with other types of victimization and perpetration. This network approach allowed for an empirical understanding of the patterns of victimization and perpetration co-occurrences. RESULTS: Findings demonstrate multiple associations between victimization and perpetration, which were present to a greater extent among male adolescents. The results reveal clusters of co-occurring victimization and perpetration within the domains of (1) cyber and emotional ADA and (2) physical and emotional ADA. A diverse range of victimization experiences (e.g., sexual victimization) did not typically co-occur with perpetration. DISCUSSION: The results suggest that ADA identification and specialized services require a nonbinary approach to address victims and perpetrators' trauma and abusive behaviors. Detection of certain ADA types, especially controlling behaviors within the cyber domain, can help identify and prevent a wide range of other ADA types that tend to co-occur.


Asunto(s)
Conducta del Adolescente , Acoso Escolar , Víctimas de Crimen , Violencia de Pareja , Adolescente , Adulto , Niño , Víctimas de Crimen/psicología , Recolección de Datos , Humanos , Violencia de Pareja/psicología , Masculino , Estados Unidos/epidemiología , Adulto Joven
18.
Annu Int Conf IEEE Eng Med Biol Soc ; 2021: 4994-4997, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34892329

RESUMEN

With the rise of digital transformation in the pharmaceutical industry, digital therapeutics are being integrated in drug development clinical trials. In the TWINKLE study, information about asthmatic patients' disease control and quality-of-life (QoL) was measured by daily video recording, in conjunction with daily electronic questionnaires and home-based spirometry. From the video messages, sentiment and emotion AI was applied to detect subtle QoL changes in asthmatic patients after receiving treatments. Sentiment scores, derived from patients' daily messages via natural language processing, correlated strongly with metrics of lung functions and outcomes of electronic questionnaires. However, video-derived emotional analysis exhibited strong interpersonal variations and systematic biases, yet still showed utility in detecting QoL changes after personalized calibration and signal aggregation. Compared to traditional patient-reported outcomes, all three categories of digital measurements were able to detect significantly improved asthma control from patients who responded to treatments. The result provides insights into developing novel digital outcomes through the application of connected digital devices and advanced AI tailored to clinical settings.Clinical relevance- Digital outcomes involving connected digital devices and AI for sentiment/emotion analysis could capture subtle QoL changes reliably and earlier than hospital visits, reducing burden and improving disease management. Integrating digital therapeutics in asthma drug development trials may prove to be feasible and valuable.


Asunto(s)
Asma , Calidad de Vida , Asma/tratamiento farmacológico , Actitud , Emociones , Humanos , Procesamiento de Lenguaje Natural
19.
bioRxiv ; 2021 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-34494025

RESUMEN

Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT 50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable levels of antiviral antibodies after infusion. In comparison to the control animals, they had similar levels of virus replication in the upper and lower respiratory tract, but had significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses. AUTHOR SUMMARY: The results of treating SARS-CoV-2 infected hospitalized patients with COVID-19 convalescent plasma (CCP), collected from survivors of natural infection, have been disappointing. The available data from various studies indicate at best moderate clinical benefits only when CCP with high titer of neutralizing antibodies was infused early in infection. The macaque model of SARS-CoV-2 infection can be useful to gain further insights in the value of CCP therapy. In this study, animals were infected with SARS-CoV-2 and the next day, were infused with pooled human convalescent plasma, selected to have a very high titer of neutralizing antibodies. While administration of CCP did not result in a detectable reduction in virus replication in the respiratory tract, it significantly reduced lung inflammation. These data, combined with the results of monoclonal antibody studies, emphasize the need to use products with high titers of neutralizing antibodies, and guide the future development of CCP-based therapies.

20.
Clin Transl Sci ; 13(3): 451-461, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31909876

RESUMEN

Developing a novel drug, including discovery, nonclinical toxicology studies, initial clinical trials, and thorough pivotal studies, may take many years. Once an applicant has generated this comprehensive body of data, the final step prior to regulatory approval is Health Authority review of the marketing authorization application. Review by regulatory authorities to evaluate whether the data support a positive benefit/risk profile takes many months, adding additional time before patients may access therapy. In this paper, we discuss the various opportunities the US Food and Drug Administration and the European Medicines Agency offer to expedite the drug development and regulatory approval timelines for drugs intended to treat serious diseases and unmet medical needs.


Asunto(s)
Aprobación de Drogas/legislación & jurisprudencia , Unión Europea , United States Food and Drug Administration/legislación & jurisprudencia , Estados Unidos
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