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2.
S D Med ; 74(5): 227-229, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34437781

RESUMO

Atrial septal defects (ASDs) and patent foramen ovale (PFO) are common congenital cardiac malformations that portend a higher risk of ischemic stroke. Percutaneous closure of ASDs using septal occluder devices has proven to be a safe and effective alternative to surgery. We present a case of symptomatic cribriform secundum ASD and PFO who underwent successful percutaneous closure using two Amplatzer occluder devices using a novel "sandwich technique."


Assuntos
Forame Oval Patente , Dispositivo para Oclusão Septal , Acidente Vascular Cerebral , Cateterismo Cardíaco , Forame Oval Patente/complicações , Forame Oval Patente/diagnóstico por imagem , Forame Oval Patente/cirurgia , Humanos , Resultado do Tratamento
3.
S D Med ; 74(6): 248-249, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34449162

RESUMO

Coronary vasospasm is an underdiagnosed cause of myocardial infarction in the absence of obstructive coronary artery disease. Systemic inflammation is one of several triggers associated with coronary vasospasm. We report the case of a 47-year woman incidentally found to be COVID-positive (RT-PCR) during evaluation of constitutional symptoms and breast cellulitis. Later in the hospitalization, she developed sudden-onset typical angina at rest; 12 lead EKG showed inferolateral ST-elevations. Urgent coronary angiogram showed nitrate-responsive subtotal focal occlusions in the right coronary and circumflex arteries. In the absence of sepsis, it is difficult to attribute coronary vasospasm solely to cellulitis. Focal coronary artery spasm mimicking ST-elevation myocardial infarction successfully managed solely with intracoronary nitroglycerine in an incidentally COVID-positive patient adds to the diverse manifestations of COVID infection. The exact mechanism of focal, as opposed to diffuse coronary vasospasm is unclear.


Assuntos
COVID-19 , Vasoespasmo Coronário , Infarto do Miocárdio , Infarto do Miocárdio com Supradesnível do Segmento ST , Angiografia Coronária , Vasoespasmo Coronário/complicações , Vasoespasmo Coronário/diagnóstico , Feminino , Humanos , Infarto do Miocárdio/diagnóstico , SARS-CoV-2 , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico
4.
Cytotherapy ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34247985

RESUMO

BACKGROUND AIMS: Umbilical cord blood is an established source of stem cells in patients with hematologic malignancies who do not have HLA-compatible matched related or unrelated donors. The success of an umbilical cord blood transplant depends on the dose of total nucleated and CD34+ cells infused. Therefore, collecting, banking and listing high-quality cord blood units with high total nucleated and CD34+ cell dose are essential. METHODS: Here the authors describe their cord blood bank's novel collection technique, which involves both in utero and ex utero collection of a single cord blood unit. The authors also evaluated maternal, neonatal and collection parameters that may impact the cell dose. RESULTS: Maternal gestational age and race, and neonatal weight and sex correlated with the total nucleated cell dose. CONCLUSIONS: The optimized collection of umbilical cord blood is critical for its use as a source of stem cells for transplantation.

5.
Children (Basel) ; 8(5)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065166

RESUMO

Antibodies of the IgG4 isotype are strongly associated with allergic disease but have several properties such as not precipitating with allergens, not activating complement and poor binding to Fcγ receptors that argue against a pro-inflammatory role. In keeping with that, IgG4 antibodies are a striking feature of the response to immunotherapy. In two naturally occurring situations IgG4 antibodies are common with low or absent IgE antibodies. The first example is children raised in a house with a cat and the second is eosinophilic esophagitis (EoE). In many population-based cohorts, the ownership of a cat in early childhood is associated with a decreased prevalence of a cat allergy at age 10. The second example (i.e., EoE) is a novel form of food allergy that is not mediated by IgE and is related to consuming cow's milk or wheat. In EoE, patients have IgG4 to milk proteins in high > 10 µg/mL or very high > 100 µg/mL titers. Enigmatically these patients are found to have deposits of IgG4 in the wall of their inflamed esophagus. The factors that have given rise to EoE remain unclear; however, changes in food processing over the past 50 years, particularly ultra-heat treatment and the high pressure homogenization of milk, represent a logical hypothesis.

6.
Ann Otol Rhinol Laryngol ; : 34894211021276, 2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34056952

RESUMO

OBJECTIVE: To present an uncommon but serious, recently identified complication of checkpoint inhibitor therapy in a patient treated with pembrolizumab infusion for disseminated recurrent respiratory papillomatosis (RRP). METHODS: Case report. RESULTS: A 43-year-old woman with underlying asthma developed acute hypoxic respiratory failure within 24 hours of her third infusion of pembrolizumab for treatment of intractable, disseminated recurrent respiratory papillomatosis. Pulmonary function testing revealed a severe intra-thoracic obstructive ventilatory defect. Discontinuation of pembrolizumab, ventilatory support, and treatment with systemic and inhaled corticosteroids resulted in resolution of respiratory failure; however, her underlying asthma remains poorly controlled. CONCLUSION: To our knowledge, this case is the first report of pembrolizumab-induced obstructive respiratory failure in a patient being treated for RRP.

7.
Front Immunol ; 12: 631353, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34017325

RESUMO

Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes steroid refractory. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for the treatment of GVHD, but so far this strategy has had equivocal clinical efficacy. Therapies using MSCs require optimization taking advantage of the plasticity of these cells in response to different microenvironments. In this study, we aimed to optimize cord blood tissue derived MSCs (CBti MSCs) by priming them using a regimen of inflammatory cytokines. This approach led to their metabolic reprogramming with enhancement of their glycolytic capacity. Metabolically reprogrammed CBti MSCs displayed a boosted immunosuppressive potential, with superior immunomodulatory and homing properties, even after cryopreservation and thawing. Mechanistically, primed CBti MSCs significantly interfered with glycolytic switching and mTOR signaling in T cells, suppressing T cell proliferation and ensuing polarizing toward T regulatory cells. Based on these data, we generated a Good Manufacturing Process (GMP) Laboratory protocol for the production and cryopreservation of primed CBti MSCs for clinical use. Following thawing, these cryopreserved GMP-compliant primed CBti MSCs significantly improved outcomes in a xenogenic mouse model of GVHD. Our data support the concept that metabolic profiling of MSCs can be used as a surrogate for their suppressive potential in conjunction with conventional functional methods to support their therapeutic use in GVHD or other autoimmune disorders.


Assuntos
Técnicas de Reprogramação Celular/métodos , Reprogramação Celular/fisiologia , Sangue Fetal/citologia , Doença Enxerto-Hospedeiro/prevenção & controle , Células-Tronco Mesenquimais/metabolismo , Animais , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/imunologia , Citocinas/farmacologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Camundongos , Camundongos Endogâmicos NOD , Controle de Qualidade
9.
J Allergy Clin Immunol ; 147(4): 1393-1401.e7, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33539899

RESUMO

BACKGROUND: IgE to α-Gal is a cause of mammalian meat allergy and has been linked to tick bites in North America, Australia, and Eurasia. Reports from the developing world indicate that α-Gal sensitization is prevalent but has been little investigated. OBJECTIVE: We sought evidence for the cause(s) of α-Gal sensitization and lack of reported meat allergy among children in less developed settings in Ecuador and Kenya. METHODS: IgE to α-Gal and total IgE were assessed in children from Ecuador (n = 599) and Kenya (n = 254) and compared with children with (n = 42) and without known (n = 63) mammalian meat allergy from the southeastern United States. Information on diet, potential risk factors, and helminth infections was available for children from Ecuador. IgG4 to α-Gal and antibodies to regionally representative parasites were assessed in a subset of children. RESULTS: In Ecuador (32%) and Kenya (54%), α-Gal specific IgE was prevalent, but levels were lower than in children with meat allergy from the United States. Sensitization was associated with rural living, antibody markers of Ascaris exposure, and total IgE, but not active infections with Ascaris or Trichuris species. In Ecuador, 87.5% reported consuming beef at least once per week, including 83.9% of those who had α-Gal specific IgE. Levels of α-Gal specific IgG4 were not high in Ecuador, but were greater than in children from the United States. CONCLUSIONS: These results suggest that in areas of the developing world with endemic parasitism, α-Gal sensitization is (1) common, (2) associated with Ascaris exposure, and (3) distinguished by a low percentage of specific/total IgE compared with individuals with meat allergy in the United States.


Assuntos
Dissacarídeos/imunologia , Hipersensibilidade Alimentar/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Adolescente , Adulto , Animais , Ascaris/imunologia , Ascaris/isolamento & purificação , Criança , Pré-Escolar , Dieta , Equador/epidemiologia , Fezes/parasitologia , Feminino , Hipersensibilidade Alimentar/sangue , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/parasitologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Quênia/epidemiologia , Masculino , Prevalência , Carne Vermelha , Trichuris/isolamento & purificação , Virginia/epidemiologia , Adulto Jovem
10.
Int Arch Allergy Immunol ; 182(5): 417-424, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33621972

RESUMO

BACKGROUND: Detailed understanding of the immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2, the cause of coronavirus disease 2019 (CO-VID-19) has been hampered by a lack of quantitative antibody assays. OBJECTIVE: The objective was to develop a quantitative assay for IgG to SARS-CoV-2 proteins that could be implemented in clinical and research laboratories. METHODS: The biotin-streptavidin technique was used to conjugate SARS-CoV-2 spike receptor-binding domain (RBD) or nucleocapsid protein to the solid phase of the ImmunoCAP. Plasma and serum samples from patients hospitalized with COVID-19 (n = 60) and samples from donors banked before the emergence of COVID-19 (n = 109) were used in the assay. SARS-CoV-2 IgG levels were followed longitudinally in a subset of samples and were related to total IgG and IgG to reference antigens using an ImmunoCAP 250 platform. RESULTS: At a cutoff of 2.5 µg/mL, the assay demonstrated sensitivity and specificity exceeding 95% for IgG to both SARS-CoV-2 proteins. Among 36 patients evaluated in a post-hospital follow-up clinic, median levels of IgG to spike-RBD and nucleocapsid were 34.7 µg/mL (IQR 18-52) and 24.5 µg/mL (IQR 9-59), respectively. Among 17 patients with longitudinal samples, there was a wide variation in the magnitude of IgG responses, but generally the response to spike-RBD and to nucleocapsid occurred in parallel, with peak levels approaching 100 µg/mL, or 1% of total IgG. CONCLUSIONS: We have described a quantitative assay to measure IgG to SARS-CoV-2 that could be used in clinical and research laboratories and implemented at scale. The assay can easily be adapted to measure IgG to mutated COVID-19 proteins, has good performance characteristics, and has a readout in standardized units.


Assuntos
Anticorpos Antivirais/sangue , Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , COVID-19/imunologia , Imunoglobulina G/sangue , SARS-CoV-2/imunologia , Biomarcadores/sangue , COVID-19/virologia , Humanos , Estudos Longitudinais , Sensibilidade e Especificidade
11.
Ann Allergy Asthma Immunol ; 127(1): 10-18, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33450398

RESUMO

OBJECTIVE: To give an overview and describe the strengths and weaknesses of immunoglobulin E (IgE) microarray and other multiplex assays that have been developed and are being used for allergy diagnostics. DATA SOURCES: Queries for IgE microarray and multiplex assays were conducted with PubMed and Google Scholar, searching for primary articles and review papers. STUDY SELECTIONS: We focused on articles written in English on commercially available IgE multiplex assays that were reported in the allergy and immunology literature. RESULTS: Several commercial IgE assays that use microarray or other multiplex technology have been developed, and some have been implemented into clinical practice in Europe and Asia, with the Immuno Solid-Phase Allergen Chip being the most widely studied. Results of these assays generally correlate with results using "singleplex" IgE assays (eg, ImmunoCAP), though there can be variability among products and among allergens. A strength of the microarray technology is that IgE to a large number of allergens can be detected simultaneously in a single test, and only a small amount of patient serum is required. Cost, inadequate sensitivity under some scenarios, and difficulties with data interpretation, in some cases of 100 or more allergens, can be limitations. CONCLUSION: IgE microarray assays are already a valuable tool in research applications. These assays, and also other forms of IgE multiplex assays, are likely to play an important role in the clinical practice of allergy in the future. Additional studies focused on clinical outcomes, and the development of more targeted allergen panels could facilitate increased clinical use.


Assuntos
Hipersensibilidade/diagnóstico , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Análise em Microsséries/métodos , Alérgenos/imunologia , Humanos , Testes Imunológicos , Avaliação da Tecnologia Biomédica
12.
J Allergy Clin Immunol ; 147(2): 643-652.e7, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32522461

RESUMO

BACKGROUND: A syndrome of mammalian meat allergy relating to IgE specific for galactose-α-1,3-galactose (α-Gal) was first reported 10 years ago in the southeastern United States and has been related to bites of the lone star tick (Amblyomma americanum). OBJECTIVE: Here we investigated the epidemiology of the "α-Gal syndrome" in the United States and sought additional evidence for the connection to tick bites. METHODS: A survey of allergists was conducted by using a snowball approach. A second tier of the survey included questions about anaphylaxis to imported fire ants (IFAs). History of tick bites and tick-related febrile illness were assessed as part of a case-control study in Virginia. Antibody assays were conducted on sera from subjects reporting allergic reactions to mammalian meat or IFA. RESULTS: In North America the α-Gal syndrome is recognized across the Southeast, Midwest, and Atlantic Coast, with many providers in this area managing more than 100 patients each. The distribution of cases generally conformed to the reported range of A americanum, although within this range there was an inverse relationship between α-Gal cases and cases of IFA anaphylaxis that were closely related to the territory of IFA. The connection between tick bites and α-Gal sensitization was further supported by patients' responses to a questionnaire and the results of serologic tests. CONCLUSIONS: The α-Gal syndrome is commonly acquired in adulthood as a consequence of tick bites and has a regional distribution that largely conforms to the territory of the lone star tick. The epidemiology of the syndrome is expected to be dynamic and shifting north because of climate change and ecologic competition from IFA.

14.
J Minim Invasive Gynecol ; 28(3): 656-667, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33198948

RESUMO

OBJECTIVE: To evaluate the fertility outcomes of salpingectomy compared with those of salpingostomy among patients treated for tubal ectopic pregnancies, including a separate analysis of women with risk factors along with a review of the surgical technique. DATA SOURCES: Systematic review and meta-analysis from 1990 to the present through PubMed, Embase, CINAHL, and Ovid MEDLINE. The search string included "tubal pregnancy" or "ectopic" as well as "salpingectomy" and various terms describing salpingotomy. METHODS OF STUDY SELECTION: Articles studying women who underwent surgical management of an ectopic pregnancy and the contrasted outcomes of salpingectomy vs salpingostomy were reviewed. The primary outcomes included subsequent intrauterine pregnancy (IUP) and repeat ectopic pregnancy (REP). TABULATION, INTEGRATION, AND RESULTS: Two randomized controlled trials (RCTs), which consisted mostly of patients classified as low risk, and patients from 16 cohort studies were included. In the RCTs, there was no significant difference in the odds of subsequent IUP in patients who underwent a salpingectomy compared with those who were treated with salpingotomy (odds ratio [OR] 0.97; 95% confidence interval [CI], 0.71-1.33). However, a significant and clinically meaningful difference was noted in the cohort studies, with the patients having a lower chance of IUP after salpingectomy (OR 0.45; 95% CI, 0.39-0.52). No significant difference was noted in the OR for a REP in the randomized trials (OR 0.77; 95% CI, 0.41-1.47), but the patients followed in the cohort studies had a cumulatively higher risk of REP after a salpingostomy (OR 0.73; 95% CI, 0.60-0.90). The subgroup analysis examining women within the studies with risk factors for tubal pathology found an even more impressive lowering in the odds of a subsequent IUP in patients classified as at-risk who were treated with salpingectomy (OR 0.30; 95% CI, 0.17-0.54), with a change in the direction of the odds for an REP rate favoring those who were treated with salpingostomy (OR 1.96; 95% CI, 0.88-4.35). CONCLUSION: Salpingectomy has clear advantages over salpingostomy, and RCTs consisting mainly of patients classified as low risk show no difference in outcomes between salpingectomy and salpingostomy. However, in cohort studies inclusive of all patients, the likelihood of a subsequent spontaneous IUP is decreased in patients treated with salpingectomy, and salpingostomies may be especially underused in women with risk factors for tubal disease.


Assuntos
Taxa de Gravidez , Gravidez Ectópica/cirurgia , Salpingectomia/métodos , Salpingostomia/métodos , Feminino , Humanos , Gravidez , Resultado da Gravidez
15.
PDA J Pharm Sci Technol ; 75(3): 213-229, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33199515

RESUMO

Traditional statistical analyses of subvisible particle data are usually based on either descriptive statistics, normal-based methods, or standard Poisson models. These methods often do not adequately describe the counts or particle size distribution. They usually ignore relevant information represented in the data, such as count correlation. Therefore, any meaningful analyses of subvisible particle data require a reasonable representation of counts and particle size distribution and the correlation in the data. Such comprehensive approaches are not widely available or used when analyzing subvisible particle data. In this article, we propose the use of generalized linear mixed models to analyze the counts and the particle size distribution of subvisible particle data. These models make optimal use of the information in the data and allow flexible approaches for the analyses of a wide range of data structures. They are readily accessible to practitioners through the use of modern statistical software. These models are demonstrated with two numerical examples using two different data structures.

16.
Ann Thorac Surg ; 111(6): 1991-1997, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33031779

RESUMO

BACKGROUND: Alpha-gal syndrome is a tick-acquired disease caused by immunoglobulin E (IgE) to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), causing allergic reactions to meat and products sourced from nonprimate mammals. As heparin is porcine-derived, we hypothesized that patients with alpha-gal syndrome who received high-dose heparin for cardiac surgery would have increased risk of anaphylaxis. METHODS: All cardiac surgery patients at an academic medical center from 2007 to 2019 were cross-referenced with research and clinical databases for the alpha-gal IgE blood test. Clinical data were obtained through the institutional Society of Thoracic Surgeons Adult Cardiac Database and chart review. Patients were stratified by development of an allergic reaction for univariate statistical analysis. RESULTS: Of the 8819 patients, 17 (0.19%) had a positive alpha-gal test before cardiac surgery. Of these 17 patients, 4 (24%) had a severe allergic reaction. The median alpha-gal titer was significantly higher in patients with a reaction (75 [interquartile range, 61-96] IU/mL vs 8 [interquartile range, 3-18] IU/mL; P = .006). There were no differences in median heparin loading dose, total dose, or maximum activated clotting time (all P > .05). In a subgroup of 8 patients with recent alpha-gal IgE level, 4 (50%) developed an allergic reaction. CONCLUSIONS: Although alpha-gal is rare in patients undergoing cardiac surgery, there is up to a 50% risk of serious allergic reaction to heparin for cardiopulmonary bypass. Higher preoperative alpha-gal titers may confer a higher risk of severe allergic reaction. For patients with a clinical suspicion of alpha-gal syndrome, we recommend prescreening with IgE levels and premedicating before receiving high doses of intravenous heparin.

17.
PLoS One ; 15(12): e0244563, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33373426

RESUMO

BACKGROUND: It is well known that it is more reliable to investigate the effects of several covariates simultaneously rather than one at time. Similarly, it is more informative to model responses simultaneously, as more often than not, the multiple responses from the same subject are correlated. This is particularly true in the analysis of Mozambique survey data from 2009 and 2018. METHOD: A multiple response predictive model for testing positive for HIV and having sufficient HIV knowledge is modeled to 2009 and 2018 survey data with the use of Bayes estimates. These data are obtained through a hierarchical data structure. The model allows one to address the change in the response to HIV, as it relates to morbidity and to HIV knowledge in Mozambique in the fight against the disease in the last decade. RESULTS: A more affluent resident is more likely to test positive, more likely to be more knowledgeable about the disease. Whereas, individuals practicing the Islam faith are less likely to test positive but also less likely to be knowledgeable about the disease. Education, while still a factor, has declined in its impact on testing positive for HIV or being knowledgeable about HIV. Females are more likely to test positive but more likely to be knowledgeable about the disease than men. The rate of impact of affluence on knowledge has increased in the past decade. Marital status (cohabitating or married) showed no impact on the knowledge of the disease. Age had no impact on knowledge suggesting that the message is getting to resident. CONCLUSIONS: A joint Bayes modeling of correlated binary (testing positive and knowledge about the disease) responses, while accounting for the hierarchy of the data collection, presents an opportunity to extract the extra variation before allocating the variation on the responses as the due of the covariates. The fight against HIV in Mozambique seems to be succeeding. Some knowledge is common among all ages, and Islam religion has a positive effect. While education still shows an influence on the binary responses, it has declined over the last decade.


Assuntos
Infecções por HIV/epidemiologia , Conhecimentos, Atitudes e Prática em Saúde , Adulto , Teorema de Bayes , Diagnóstico Precoce , Feminino , Infecções por HIV/diagnóstico , Humanos , Masculino , Moçambique/epidemiologia , Religião , Fatores de Risco , Caracteres Sexuais , Fatores Socioeconômicos
18.
J Asthma Allergy ; 13: 679-688, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33364787

RESUMO

Food allergy is often understood as an IgE-mediated hypersensitivity, characterized by allergic symptoms which occur "immediately" after the ingestion of a relevant food allergen. Increasingly, however, other food-related immune-mediated disorders are recognized in which symptoms can have a delayed onset and IgE does not play a central role. One of the described examples of the latter is eosinophilic esophagitis (EoE) - a disease defined pathologically by local eosinophilic inflammation in the esophagus in the setting of symptoms of esophageal dysfunction. The evidence that EoE is a food-mediated allergic disease includes i) almost all patients respond to an elemental diet and many respond to a diet in which dairy, wheat, eggs and/or soy are eliminated, ii) the presence of food-specific IgE and Th2 cells are consistent with a loss of tolerance to trigger foods and iii) many EoE patients have concomitant IgE-mediated food allergy and other allergic co-morbidities. This narrative review focuses on the hypothesis that EoE is a form of chronic food allergy. The goal is to describe similarities and differences in EoE and IgE-mediated food allergy, and to consider ways that these two increasingly common forms of food allergy are related to each other.

19.
ACS Omega ; 5(42): 27344-27358, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33134697

RESUMO

In response to the ongoing COVID-19 pandemic, there is a worldwide effort being made to identify potential anti-SARS-CoV-2 therapeutics. Here, we contribute to these efforts by building machine-learning predictive models to identify novel drug candidates for the viral targets 3 chymotrypsin-like protease (3CLpro) and RNA-dependent RNA polymerase (RdRp). Chemist-curated training sets of substances were assembled from CAS data collections and integrated with curated bioassay data. The best-performing classification models were applied to screen a set of FDA-approved drugs and CAS REGISTRY substances that are similar to, or associated with, antiviral agents. Numerous substances with potential activity against 3CLpro or RdRp were found, and some were validated by published bioassay studies and/or by their inclusion in upcoming or ongoing COVID-19 clinical trials. This study further supports that machine learning-based predictive models may be used to assist the drug discovery process for COVID-19 and other diseases.

20.
medRxiv ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33200147

RESUMO

Background: Detailed understanding of the immune response to SARS-CoV-2, the cause of coronavirus disease 2019 (COVID-19), has been hampered by a lack of quantitative antibody assays. Objective: To develop a quantitative assay for IgG to SARS-CoV-2 proteins that could readily be implemented in clinical and research laboratories. Methods: The biotin-streptavidin technique was used to conjugate SARS-CoV-2 spike receptor-binding-domain (RBD) or nucleocapsid protein to the solid-phase of the ImmunoCAP resin. Plasma and serum samples from patients with COVID-19 (n=51) and samples from donors banked prior to the emergence of COVID-19 (n=109) were used in the assay. SARS-CoV-2 IgG levels were followed longitudinally in a subset of samples and were related to total IgG and IgG to reference antigens using an ImmunoCAP 250 platform. Results: Performance characteristics demonstrated 100% sensitivity and 99% specificity at a cut-off level of 2.5 µg/mL for both SARS-CoV-2 proteins. Among 36 patients evaluated in a post-hospital follow-up clinic, median levels of IgG to spike-RBD and nucleocapsid were 34.7 µg/mL (IQR 18-52) and 24.5 µg/mL (IQR 9-59), respectively. Among 17 patients with longitudinal samples there was a wide variation in the magnitude of IgG responses, but generally the response to spike-RBD and to nucleocapsid occurred in parallel, with peak levels approaching 100 µg/mL, or 1% of total IgG. Conclusions: We have described a quantitative assay to measure IgG to SARS-CoV-2 that could be used in clinical and research laboratories and implemented at scale. The assay can easily be adapted to measure IgG to novel antigens, has good performance characteristics and a read-out in standardized units.

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