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1.
medRxiv ; 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38370621

RESUMO

Background: Households are a major setting for SARS-CoV-2 infections, but there remains a lack of knowledge regarding the dynamics of viral transmission, particularly in the setting of widespread pre-existing SARS-CoV-2 immunity and evolving variants. Methods: We conducted a prospective, case-ascertained household transmission study in the greater Boston area in March-July 2022. Anterior nasal swabs, along with clinical and demographic data, were collected for 14 days. Nasal swabs were tested for SARS-CoV-2 by PCR. Whole genome sequencing was performed on high-titer samples. Results: We enrolled 33 households in a primary analysis set, with a median age of participants of 25 years old (range 2-66); 98% of whom had received at least 2 doses of a COVID-19 vaccine. 58% of households had a secondary case during follow up and the secondary attack rate (SAR) for contacts infected was 39%. We further examined a strict analysis set of 21 households that had only 1 PCR+ case at baseline, finding an SAR of 22.5%. Genomic epidemiology further determined that there were multiple sources of infection for household contacts, including the index case and outside introductions. When limiting estimates to only highly probable transmissions given epidemiologic and genomic data, the SAR was 18.4%. Conclusions: Household contacts of a person newly diagnosed with COVID-19 are at high risk for SARS-CoV-2 infection in the following 2 weeks. This is, however, not only due to infection from the household index case, but also because the presence of an infected household member implies increased SARS-CoV-2 community transmission. Further studies to understand and mitigate household transmission are needed.

2.
Obstet Gynecol Clin North Am ; 50(1): 183-203, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36822703

RESUMO

Viral infections pose unique threats to pregnant persons and their infants. As the frequency of epidemics caused by novel pathogens increases, understanding pregnancy-specific considerations for antiviral treatments is critical for obstetric and nonobstetric providers alike. The use of pharmacologic therapeutics in pregnancy, which include antivirals, pathogen-specific antibodies, and vaccines, is limited due to the lack of purposeful, methodologic, pharmacometrics analyses in this special population. Our current understanding regarding dosing, safety, and efficacy stems from our knowledge of potential maternal or neonatal risks, observational data, and rarely clinical trials. In this review, we provide an overview on the use of antivirals during pregnancy.


Assuntos
Complicações Infecciosas na Gravidez , Viroses , Gravidez , Lactente , Recém-Nascido , Feminino , Humanos , Antivirais/uso terapêutico , Complicações Infecciosas na Gravidez/prevenção & controle
3.
Obstet Gynecol ; 141(1): 135-143, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36701614

RESUMO

OBJECTIVE: To evaluate the combined association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV) infection on adverse birth outcomes in an HIV-endemic region. METHODS: The Tsepamo Study abstracts data from antenatal and obstetric records in government maternity wards across Botswana. We assessed maternal mortality and adverse birth outcomes for all singleton pregnancies from September 2020 to mid-November 2021 at 13 Tsepamo sites among individuals with documented SARS-CoV-2 screening tests and known HIV status. RESULTS: Of 20,410 individuals who gave birth, 11,483 (56.3%) were screened for SARS-CoV-2 infection; 4.7% tested positive. People living with HIV were more likely to test positive (144/2,421, 5.9%) than those without HIV (392/9,030, 4.3%) (P=.001). Maternal deaths occurred in 3.7% of those who had a positive SARS-CoV-2 test result compared with 0.1% of those who tested negative (adjusted relative risk [aRR] 31.6, 95% CI 15.4-64.7). Maternal mortality did not differ by HIV status. The offspring of individuals with SARS-CoV-2 infection experienced more overall adverse birth outcomes (34.5% vs 26.6%; aRR 1.2, 95% CI 1.1-1.4), severe adverse birth outcomes (13.6% vs 9.8%; aRR 1.2, 95% CI 1.0-1.5), preterm delivery (21.4% vs 13.4%; aRR 1.4, 95% CI 1.2-1.7), and stillbirth (5.6% vs 2.7%; aRR 1.7 95% CI 1.2-2.5). Neonates exposed to SARS-CoV-2 and HIV infection had the highest prevalence of adverse birth outcomes (43.1% vs 22.6%; aRR 1.7, 95% CI 1.4-2.0). CONCLUSION: Infection with SARS-CoV-2 at the time of delivery was associated with 3.7% maternal mortality and 5.6% stillbirth in Botswana. Most adverse birth outcomes were worse among neonates exposed to both SARS-CoV-2 and HIV infection.


Assuntos
COVID-19 , Infecções por HIV , Complicações Infecciosas na Gravidez , Complicações na Gravidez , Nascimento Prematuro , Recém-Nascido , Gravidez , Feminino , Humanos , SARS-CoV-2 , Resultado da Gravidez/epidemiologia , Natimorto/epidemiologia , COVID-19/epidemiologia , Infecções por HIV/epidemiologia , Infecções por HIV/complicações , Mortalidade Materna , Botsuana/epidemiologia , Nascimento Prematuro/epidemiologia , HIV , Complicações Infecciosas na Gravidez/epidemiologia
4.
AIDS Patient Care STDS ; 35(12): 457-466, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34780305

RESUMO

Reports conflict on how HIV infection influences the clinical course of COVID-19. The New York City (NYC) public hospital system provides care for over 14,000 people with HIV, was central in responding to the COVID-19 pandemic, and is therefore in a unique position to evaluate the intersection of these concurrent infections. Retrospective chart review of patients presenting to NYC Health and Hospitals (NYC H+H) diagnosed with COVID-19 infection from March 1, 2020, through April 28, 2020, compared people living with HIV (PLWH) and a propensity-matched (PM) control group of patients without HIV to evaluate associations between HIV status and COVID-19 outcomes. Two hundred thirty-four PLWH presented for COVID-19 testing and 110 (47%) were diagnosed with COVID-19. Among 17,413 patients with COVID-19 and without HIV, 1:n nearest neighbor propensity score matching identified 194 patients matched on age, sex, race, and any comorbidity. In the sample with COVID-19 (N = 304), PLWH (9.1%) had lower rates of mortality than controls [19.1%; PM odds ratio (PM-OR): 0.41, 95% confidence interval (CI): 0.19-0.86]. Among hospitalized COVID-19 patients (N = 179), HIV infection was associated with lower rates of mechanical ventilation (PM-OR: 0.31, 95% CI: 0.11-0.84) and mortality (PM-OR: 0.40, 95% CI: 0. 17-0.95). In the extended pandemic period through April 2021, aggregate data by HIV status suggested elevated hospitalization and mortality rates in PLWH versus people without HIV. These results suggest that the direct biological impacts of the HIV virus do not negatively influence COVID-19-related outcomes when controlling for comorbidity and demographic variables.


Assuntos
COVID-19 , Infecções por HIV , Teste para COVID-19 , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Hospitalização , Hospitais Públicos , Humanos , Cidade de Nova Iorque/epidemiologia , Pandemias , Estudos Retrospectivos , SARS-CoV-2
5.
Open Forum Infect Dis ; 7(11): ofaa518, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33269299

RESUMO

BACKGROUND: Previous viral pandemics have shown that secondary bacterial infections result in higher morbidity and mortality, with Staphylococcus aureus being the primary causative pathogen. The impact of secondary S. aureus bacteremia on mortality in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unknown. METHODS: This was a retrospective observational case series of patients with coronavirus disease 2019 (COVID-19) who developed secondary S. aureus bacteremia across 2 New York City hospitals. The primary end point was to describe 14-day and 30-day hospital mortality rates of patients with COVID-19 and S. aureus bacteremia. Secondary end points included predictors of 14-day and 30-day hospital mortality in patients with COVID-19 and S. aureus bacteremia. RESULTS: A total of 42 patients hospitalized for COVID-19 with secondary S. aureus bacteremia were identified. Of these patients, 23 (54.8%) and 28 (66.7%) died at 14 days and 30 days, respectively, from their first positive blood culture. Multivariate analysis identified hospital-onset bacteremia (≥4 days from date of admission) and age as significant predictors of 14-day hospital mortality and Pitt bacteremia score as a significant predictor of 30-day hospital mortality (odds ratio [OR], 11.9; 95% CI, 2.03-114.7; P = .01; OR, 1.10; 95% CI, 1.03-1.20; P = .02; and OR, 1.56; 95% CI, 1.19-2.18; P = .003, respectively). CONCLUSIONS: Bacteremia with S. aureus is associated with high mortality rates in patients hospitalized with COVID-19. Further investigation is warranted to understand the impact of COVID-19 and secondary S. aureus bacteremia.

6.
Sci Adv ; 6(20): eaay1057, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32440537

RESUMO

The transcription factor interferon regulatory factor 5 (IRF5) plays essential roles in pathogen-induced immunity downstream of Toll-, nucleotide-binding oligomerization domain-, and retinoic acid-inducible gene I-like receptors and is an autoimmune susceptibility gene. Normally, inactive in the cytoplasm, upon stimulation, IRF5 undergoes posttranslational modification(s), homodimerization, and nuclear translocation, where dimers mediate proinflammatory gene transcription. Here, we report the rational design of cell-penetrating peptides (CPPs) that disrupt IRF5 homodimerization. Biochemical and imaging analysis shows that IRF5-CPPs are cell permeable, noncytotoxic, and directly bind to endogenous IRF5. IRF5-CPPs were selective and afforded cell type- and species-specific inhibition. In plasmacytoid dendritic cells, inhibition of IRF5-mediated interferon-α production corresponded to a dose-dependent reduction in nuclear phosphorylated IRF5 [p(Ser462)IRF5], with no effect on pIRF5 levels. These data support that IRF5-CPPs function downstream of phosphorylation. Together, data support the utility of IRF5-CPPs as novel tools to probe IRF5 activation and function in disease.


Assuntos
Peptídeos Penetradores de Células , Peptídeos Penetradores de Células/genética , Peptídeos Penetradores de Células/metabolismo , Peptídeos Penetradores de Células/farmacologia , Células Dendríticas/metabolismo , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Fosforilação
7.
Medicine (Baltimore) ; 99(11): e19140, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176039

RESUMO

Treatment of hepatitis C virus (HCV) infection for patients with human immunodeficiency virus (HIV) has improved with direct acting antivirals. However, outcomes among Black persons treated with ledipasvir/sofosbuvir (LDV/SOF) may be inferior to non-Blacks. We assessed responses to LDV/SOF in a cohort of Black HIV/HCV coinfected persons.Retrospective chart reviews were conducted for Black, genotype 1 (GT1), HIV/HCV coinfected patients treated with LDV/SOF at 3 hospitals in Newark, NJ between January 2014 and July 2016. Data collected included demographics, HCV treatment history, treatment duration, and response.One hundred seventeen HIV/HCV coinfected Black patients started treatment with LDV/SOF but 5 had no follow-up data and 5 prematurely discontinued treatment (1 due to side effects). We included 107 HIV/HCV coinfected patients who completed LDV/SOF at all 3 sites. The study population was 65% male, median age 58 years, 26% had cirrhosis, and 78% had GT1a. Thirty-one percent were treatment experienced but none with prior NS5a treatment. At baseline, median CD4 count was 680 cells/mm, HIV viral load (VL) was <40 copies/mL in 94% and median HCV VL was 2,257,403 IU/mL. Twenty-nine percent of patients changed antiretroviral treatment before LDV/SOF treatment due to drug interactions. Six, 89, and 12 patients completed 8, 12, and 24 weeks of LDV/SOF, respectively. Overall sustained virologic response rate was 93% with 7 relapses.In this real-world cohort of Black, GT1, HIV/HCV coinfected patients, LDV/SOF had high sustained virologic response 12 weeks post completion of treatment rate of 93%. This data supports the overall high efficacy of LDV/SOF in a historically difficult-to-treat patient population.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Coinfecção/tratamento farmacológico , Fluorenos/uso terapêutico , Infecções por HIV/complicações , Hepacivirus/efeitos dos fármacos , Hepatite C/complicações , Uridina Monofosfato/análogos & derivados , Negro ou Afro-Americano/estatística & dados numéricos , Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Coinfecção/virologia , Feminino , Fluorenos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , New Jersey , Estudos Retrospectivos , Sofosbuvir , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/uso terapêutico
8.
Pharmacol Ther ; 181: 169-182, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28842273

RESUMO

Asthma is a complex inflammatory disease characterized by airway inflammation and hyperresponsiveness. The mechanisms associated with the development and progression of asthma have been widely studied in multiple populations and animal models, and these have revealed involvement of various cell types and activation of intracellular signaling pathways that result in activation of inflammatory genes. Significant contributions of Toll-like-receptors (TLRs) and transcription factors such as NF-кB, have been reported as major contributors to inflammatory pathways. These have also recently been associated with mechanisms of oxidative biology. This is of important clinical significance as the observed inefficacy of current available treatments for severe asthma is widely attributed to oxidative stress. Therefore, targeting oxidizing molecules in conjunction with inflammatory mediators and transcription factors may present a novel therapeutic strategy for asthma. In this review, we summarize TLRs and NF-кB pathways in the context of exacerbation of asthma pathogenesis and oxidative biology, and we discuss the potential use of polyphenolic flavonoid compounds, known to target these pathways and possess antioxidant activity, as potential therapeutic agents for asthma.


Assuntos
Asma/tratamento farmacológico , Inflamação/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Estresse Oxidativo/efeitos dos fármacos , Animais , Asma/complicações , Flavonoides/uso terapêutico , Humanos , Inflamação/complicações , Modelos Biológicos , NF-kappa B/fisiologia , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/fisiologia
9.
Sci Rep ; 5: 15648, 2015 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-26503602

RESUMO

APOBEC3G (A3G) protein has antiviral activity against HIV and other pathogenic retroviruses. A3G has two domains: a catalytic C-terminal domain (CTD) that deaminates cytidine, and a N-terminal domain (NTD) that binds to ssDNA. Although abundant information exists about the biological activities of A3G protein, the interplay between sequence specific deaminase activity and A3G binding to ssDNA remains controversial. We used the topographic imaging and force spectroscopy modalities of Atomic Force Spectroscopy (AFM) to characterize the interaction of A3G protein with deaminase specific and nonspecific ssDNA substrates. AFM imaging demonstrated that A3G has elevated affinity for deaminase specific ssDNA than for nonspecific ssDNA. AFM force spectroscopy revealed two distinct binding modes by which A3G interacts with ssDNA. One mode requires sequence specificity, as demonstrated by stronger and more stable complexes with deaminase specific ssDNA than with nonspecific ssDNA. Overall these observations enforce prior studies suggesting that both domains of A3G contribute to the sequence specific binding of ssDNA.


Assuntos
Citidina Desaminase/metabolismo , DNA de Cadeia Simples/metabolismo , Proteínas de Ligação a DNA/química , Microscopia de Força Atômica/métodos , Desaminase APOBEC-3G , Sítios de Ligação/genética , Domínio Catalítico , Citidina/metabolismo , Desaminação , HIV/genética , HIV/fisiologia , Humanos , Ligação Proteica/fisiologia
10.
Appl Microbiol Biotechnol ; 94(2): 307-21, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22391972

RESUMO

Heparin/heparan sulphate glycosaminoglycans (HSGAGs) are composed of linear chains of 20-100 disaccharide units of N-acetylated D: -glucosamine α (1-4) linked to glucuronic acid. HSGAGs are widely distributed on the cell surface and extracellular cell matrix of virtually every mammalian cell type and play critical role in regulating numerous functions of blood vessel wall, blood coagulation, inflammation response and cell differentiation. These glycosaminoglycans present in this extracellular environment very significantly influence the blood coagulation system and cardiovascular functions. Recent studies have investigated the mechanism by which cancer causes thrombosis and emphasizes the importance of the coagulation system in angiogenesis and tumour metastasis. Heparan sulphate/heparin lyases or heparinases are a class of enzymes that are capable of specifically cleaving the (1-4) glycosidic linkages in heparin and heparan sulphate to generate biologically active oligosaccharides with substantially significant and distinct clinical, pharmaceutical and prophylactic/therapeutic applications. Bioavailability and pharmacokinetic behaviour and characteristics of these oligosaccharides vary significantly depending on the origin/nature of the substrate (heparin or heparan sulphate-like glycosaminoglycans), the source of enzyme and method of preparation. Various microorganisms are reported/patented to produce these enzymes with different properties. Heparinases are commercially used for the depolymerization of unfractionated heparin to produce low molecular weight heparins (LMWHs), an effective anticoagulant. Individual LMWHs are chemically different and unique and thus cannot be interchanged therapeutically. Heparinases and LMWHs are reported to control angiogenesis and metastasis also. This review catalogues the degradation of HSGAGs by microbial heparin/heparan sulphate lyases and their potential either specific to the enzymes or with the dual role for generation of oligosaccharides for a new generation of compounds, as shown by various laboratory or clinical studies.


Assuntos
Bactérias/enzimologia , Bactérias/metabolismo , Fungos/enzimologia , Fungos/metabolismo , Heparina Liase/metabolismo , Heparina/metabolismo , Heparitina Sulfato/metabolismo , Oligossacarídeos/metabolismo
11.
Appl Biochem Biotechnol ; 160(4): 1004-16, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19214796

RESUMO

A heparinase-producing fungus was isolated, and the strain was taxonomically characterized as Aspergillus flavus by morphophysiological and 26S rRNA gene homology studies. The culture produced intracellular heparinase enzyme, which was purified 40.5-fold by DEAE-Sephadex A-50, CM-Sephadex C-50, and Sephadex G-100 column chromatography. Specific activity of the purified enzyme was found to be 44.6 IU/microg protein and the molecular weight of native as well as reduced heparinase was 24 kDa, showing a monomeric unit structure. Peptide mass spectrum showed poor homogeneity with the database in the peptide bank. The enzyme activity was maximum at 30 degrees C in the presence of 300 mM NaCl at pH 7.0. In the presence of Co2+, Mn2+ ions, and reducing agents (beta-mercaptoethanol, dithiothreitol), enzyme activity was enhanced and inhibited by iodoacetic acid. These observations suggested that free sulfohydryl groups of cysteine residues were necessary for catalytic activity of the enzyme. The enzyme was also inhibited by histidine modifier, DEPC, which suggests that along with cysteine, histidine may be present at its active site. The enzyme showed a high affinity for heparin as a substrate with K (m) and V (max) as 2.2 x 10(-5 )M and 30.8 mM min(-1), respectively. The affinity of the enzyme for different glycosaminoglycans studied varied, with high substrate specificity toward heparin and heparin-derived polysaccharides. Depolymerization of heparin and fractionation of the oligosaccharides yielded heparin disaccharides as main product.


Assuntos
Aspergillus flavus/enzimologia , Heparina Liase/isolamento & purificação , Heparina Liase/metabolismo , Animais , Cátions Bivalentes/farmacologia , Cromatografia em Gel , Eletroforese em Gel de Poliacrilamida , Heparina/metabolismo , Concentração de Íons de Hidrogênio , Peso Molecular , Temperatura
12.
N Biotechnol ; 26(1-2): 99-104, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19426846

RESUMO

An intracellularly produced constitutive heparinase was isolated from the periplasmic space of Acinetobacter calcoaceticus by freeze fracturing and purified 51.2-fold by ion exchange and gel filtration chromatography. Specific activity of the purified enzyme was found to be 41 IU/mug protein with a 120000Da molecular mass. The enzyme activity was maximum at 35 degrees C in the presence of 250mM NaCl at pH 7.5. The enzyme activity was inhibited in the presence of Ba(2+), Hg(2+), Cd(2+), IAA and DEPC, and enhanced by the presence of Cu(2+), Fe(2+) ions and reducing agents. Inhibition of enzyme activity by iodoacetic acid and enhancement of enzyme activity in the presence of reducing agents indicated that free sulfohydryl groups of cysteine residues were necessary for catalytic activity of the enzyme. The affinity of the enzyme for different glycosaminoglycans studied varied and showed high affinity for heparin with a K(m) value of 0.026mM. In situ gel digestion of the purified protein with trypsin did not show any homology with heparinase I. Depolymerization of heparin and fractionation of the oligosachharides yielded heparin disaccharides as main product. This suggests a catalytic similarity and structural dissimilarity of heparinase from Acinetobacter with heparinase I.


Assuntos
Acinetobacter calcoaceticus/enzimologia , Heparina Liase/isolamento & purificação , Aminoácidos/farmacologia , Biocatálise/efeitos dos fármacos , Fracionamento Químico , Cromatografia , Heparina Liase/química , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Hidrólise/efeitos dos fármacos , Cinética , Espectrometria de Massas , Metais/farmacologia , Filogenia , Polímeros/metabolismo , Especificidade por Substrato/efeitos dos fármacos , Temperatura
13.
Indian J Exp Biol ; 47(4): 298-303, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19382727

RESUMO

Antimicrobial activities of twenty bacterial strains isolated from ten different stressed agro-ecological niches of Eastern Uttar Pradesh, India were evaluated against bacteria, yeasts and molds. Eleven isolates showing strong antimicrobial activities were characterized. Eight antifungal compounds were purified and partially characterized by Ultra-Violet (UV) absorption spectra and grouped into polyenes and non-polyenes. Antibacterial metabolites produced by four isolates were purified and chemically characterized, of which one isolate (AB) produced a new form of olivanic acid, and other three isolates (C5, Py and M4) produced antibacterial compounds having phenoxazone nucleus.


Assuntos
Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Ecossistema , Fungos/efeitos dos fármacos , Microbiologia do Solo , Índia , Testes de Sensibilidade Microbiana , Espectrofotometria Ultravioleta
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