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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an unprecedented global pandemic of COVID-19. Animal models are urgently needed to study the pathogenesis of COVID-19 and to screen vaccines and treatments. We show that African green monkeys (AGMs) support robust SARS-CoV-2 replication and develop pronounced respiratory disease, which may more accurately reflect human COVID-19 cases than other nonhuman primate species. SARS-CoV-2 was detected in mucosal samples, including rectal swabs, as late as 15 days after exposure. Marked inflammation and coagulopathy in blood and tissues were prominent features. Transcriptome analysis demonstrated stimulation of interferon and interleukin-6 pathways in bronchoalveolar lavage samples and repression of natural killer cell- and T cell-associated transcripts in peripheral blood. Despite a slight waning in antibody titers after primary challenge, enhanced antibody and cellular responses contributed to rapid clearance after re-challenge with an identical strain. These data support the utility of AGM for studying COVID-19 pathogenesis and testing medical countermeasures.
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COVID-19/inmunología , Modelos Animales de Enfermedad , Reinfección/inmunología , SARS-CoV-2/inmunología , Linfocitos T/inmunología , Animales , Anticuerpos Antivirales/inmunología , COVID-19/epidemiología , COVID-19/virología , Chlorocebus aethiops , Epidemias/prevención & control , Expresión Génica/genética , Expresión Génica/inmunología , Perfilación de la Expresión Génica , Humanos , Interferones/genética , Interferones/inmunología , Interferones/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Reinfección/virología , SARS-CoV-2/fisiología , Linfocitos T/metabolismo , Linfocitos T/virologíaRESUMEN
BACKGROUND: Ebola virus (EBOV) is considered among the most dangerous viruses with case fatality rates approaching 90% depending on the outbreak. While several viral proteins (VPs) including VP24, VP35, and the soluble glycoprotein are understood to contribute to virulence, less is known of the contribution of the highly variable mucin-like domain (MLD) of EBOV. Early studies have defined a potential role in immune evasion of the MLD by providing a glycan shield to critical glycoprotein residues tied to viral entry. Nonetheless, little is known as to what direct role the MLD plays in acute EBOV disease (EVD). METHODS: We generated an infectious EBOV clone that lacks the MLD and assessed its virulence in ferrets compared with wild-type (WT) virus. RESULTS: No differences in growth kinetics were observed in vitro, nor were there any differences in time to death, viremia, or clinical picture in ferrets infected with recombinant EBOV (rEBOV)-WT or rEBOV-Δmucin. CONCLUSIONS: The EBOV MLD does not play a critical role in acute pathogenesis of EVD in ferrets.
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Ebolavirus , Fiebre Hemorrágica Ebola , Animales , Humanos , Mucinas , Virulencia , Hurones , Glicoproteínas/genética , Glicoproteínas/metabolismoRESUMEN
BACKGROUND: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear. OBJECTIVE: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial). DESIGN: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]). SETTING: 94 hospitals in 10 countries (86% U.S. participants). PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: SOC. MEASUREMENTS: 28-day mortality and recovery. RESULTS: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages. LIMITATION: Unmeasured confounding. CONCLUSION: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Adulto , Humanos , Antivirales/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Dexametasona , Método Doble Ciego , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Members of the genus Ebolavirus cause lethal disease in humans, with Zaire ebolavirus (EBOV) being the most pathogenic (up to 90% morality) and Bundibugyo ebolavirus (BDBV) the least pathogenic (â¼37% mortality). Historically, there has been a lack of research on BDBV, and there is no means to study BDBV outside of a high-containment laboratory. Here, we describe a minigenome replication system to study BDBV transcription and compare the efficacy of small-molecule inhibitors between EBOV and BDBV. Using this system, we examined the ability of the polymerase complex proteins from EBOV and BDBV to interact and form a functional unit as well as the impact of the genomic untranslated ends, known to contain important signals for transcription (3'-untranslated region) and replication (5'-untranslated region). Various levels of compatibility were observed between proteins of the polymerase complex from each ebolavirus, resulting in differences in genome transcription efficiency. Most pronounced was the effect of the nucleoprotein and the 3'-untranslated region. These data suggest that there are intrinsic specificities in the polymerase complex and untranslated signaling regions that could offer insight regarding observed pathogenic differences. Further adding to the differences in the polymerase complexes, posttransfection/infection treatment with the compound remdesivir (GS-5734) showed a greater inhibitory effect against BDBV than EBOV. The delayed growth kinetics of BDBV and the greater susceptibility to polymerase inhibitors indicate that disruption of the polymerase complex is a viable target for therapeutics. IMPORTANCE Ebolavirus disease is a viral infection and is fatal in 25 to 90% of cases, depending on the viral species and the amount of supportive care available. Two species have caused outbreaks in the Democratic Republic of the Congo, Zaire ebolavirus (EBOV) and Bundibugyo ebolavirus (BDBV). Pathogenesis and clinical outcome differ between these two species, but there is still limited information regarding the viral mechanism for these differences. Previous studies suggested that BDBV replicates slower than EBOV, but it is unknown if this is due to differences in the polymerase complex and its role in transcription and replication. This study details the construction of a minigenome replication system that can be used in a biosafety level 2 laboratory. This system will be important for studying the polymerase complex of BDBV and comparing it with other filoviruses and can be used as a tool for screening inhibitors of viral growth.
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Ebolavirus/genética , Ingeniería Genética/métodos , Replicación Viral/genética , Anticuerpos Antivirales/genética , Anticuerpos Antivirales/inmunología , Antivirales/uso terapéutico , Farmacorresistencia Viral/genética , Ebolavirus/inmunología , Genes Reporteros/genética , Genoma Viral/genética , Humanos , Proteínas Virales/metabolismoRESUMEN
Nipah virus (NiV) is a zoonotic emerging paramyxovirus that can cause fatal respiratory illness or encephalitis in humans. Despite many efforts, the molecular mechanisms of NiV-induced acute lung injury (ALI) remain unclear. We previously showed that NiV replicates to high titers in human lung grafts in NOD-SCID/γ mice, resulting in a robust inflammatory response. Interestingly, these mice can undergo human immune system reconstitution by the bone marrow, liver, and thymus (BLT) reconstitution method, in addition to lung tissue engraftment, giving altogether a realistic model to study human respiratory viral infections. Here, we characterized NiV Bangladesh strain (NiV-B) infection of human lung grafts from human immune system-reconstituted mice in order to identify the overall effect of immune cells on NiV pathogenesis of the lung. We show that NiV-B replicated to high titers in human lung grafts and caused similar cytopathic effects irrespective of the presence of human leukocytes in mice. However, the human immune system interfered with virus spread across lung grafts, responded to infection by leukocyte migration to small airways and alveoli of the lung grafts, and accelerated oxidative stress in lung grafts. In addition, the presence of human leukocytes increased the expression of cytokines and chemokines that regulate inflammatory influx to sites of infection and tissue damage. These results advance our understanding of how the immune system limits NiV dissemination and contributes to ALI and inform efforts to identify therapeutic targets.IMPORTANCE Nipah virus (NiV) is an emerging paramyxovirus that can cause a lethal respiratory and neurological disease in humans. Only limited data are available on NiV pathogenesis in the human lung, and the relative contribution of the innate immune response and NiV to acute lung injury (ALI) is still unknown. Using human lung grafts in a human immune system-reconstituted mouse model, we showed that the NiV Bangladesh strain induced cytopathic lesions in lung grafts similar to those described in patients irrespective of the donor origin or the presence of leukocytes. However, the human immune system interfered with virus spread, responded to infection by leukocyte infiltration in the small airways and alveolar area, induced oxidative stress, and triggered the production of cytokines and chemokines that regulate inflammatory influx by leukocytes in response to infection. Understanding how leukocytes interact with NiV and cause ALI in human lung xenografts is crucial for identifying therapeutic targets.
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Lesión Pulmonar Aguda/patología , Infecciones por Henipavirus/patología , Leucocitos/inmunología , Pulmón/patología , Virus Nipah/crecimiento & desarrollo , Estrés Oxidativo , Animales , Citocinas/análisis , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones SCIDRESUMEN
BACKGROUND: The use of nutraceuticals is gaining in popularity in human and canine oncology with a relatively limited understanding of the effects in the vastly different tumor types seen in canine oncology. We have previously shown that turmeric root (TE) and rosemary leaf (RE) extracts can work synergistically to reduce neoplastic cell growth, but the mechanisms are poorly understood and require further elucidation. RESULTS: Three different canine cell lines (C2 mastocytoma, and CMT-12 mammary carcinoma, D17 osteosarcoma) were treated with 6.3 µg mL-1 extract individually, or 3.1 µg mL-1 of each extract in combination based on studies showing synergy of these two extracts. Apoptosis, antioxidant effects, cellular accumulation of curcumin, and perturbation of signaling pathways were assessed. The TE + RE combination treatment resulted in Caspase 3/7 activation and apoptosis in all cell lines, beyond the effects of TE alone with the CMT-12 cell line being most susceptible. Both extracts had antioxidant effects with RE reducing reactive oxygen species (ROS) by 40-50% and TE reducing ROS by 80-90%. In addition RE treatment enhanced the c-jun N-terminal kinase (JNK) activity in the C2 cell line and TE + RE exposure increased activated JNK by 4-5 times in the CMT-12 cell line. Upon further examination, it was found that RE treatment caused a significant increase in the cellular accumulation of curcumin by approximately 30% in the C2 and D17 cell lines, and by 4.8-fold in the CMT-12 cell line. This increase in intracellular curcumin levels may play a role in the synergy exhibited when using TE and RE in combination. CONCLUSIONS: The use of RE in combination with TE induces a synergistic response to induce apoptosis which is better than either extract alone. This appears to be related to a variable increased TE uptake in cells and activation of pathways involved in the apoptotic response.
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Neoplasias Óseas/veterinaria , Enfermedades de los Perros/tratamiento farmacológico , Neoplasias Mamarias Animales/tratamiento farmacológico , Mastocitoma/veterinaria , Osteosarcoma/veterinaria , Fitoterapia/veterinaria , Extractos Vegetales/uso terapéutico , Hojas de la Planta , Rosmarinus , Animales , Neoplasias Óseas/tratamiento farmacológico , Línea Celular Tumoral , Curcuma , Perros , Femenino , Mastocitoma/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Fitoterapia/métodosRESUMEN
BACKGROUND: Adjunctive use of nutraceuticals in human cancer has shown promise, but little work has been done in canine neoplasia. Previous human research has shown that polyphenols and carotenoids can target multiple pathways in vitro and in vivo. These compounds could synergize or antagonize with currently used chemotherapies, either increasing or decreasing the effectiveness of these drugs. Considering the routine and well controlled feeding practices of most dogs, the use of nutraceuticals incorporated into pet food is attractive, pending proof that the extracts are able to improve remission rates. The aim of this study was to examine five feed ingredients for antiproliferative effects, as well as the interaction with toceranib phosphate and doxorubicin hydrochloride, when treating canine neoplastic cell lines in vitro. RESULTS: Screening using MTT proliferation assays showed that green tea, turmeric, and rosemary extracts were the most effective. Turmeric extract (TE) was the most potent and exhibited synergy with a rosemary extract (RE) at concentrations from 1 to 25 µg mL(-1). This combination had an additive or synergistic effect with chemotherapeutic agents at selected concentrations within each cell line. No significant effects on cell viability were observed when the combination therapy was used with normal primary cells. CONCLUSIONS: The use of turmeric and rosemary extracts in combination may be worthwhile to investigate in the pre-clinical and clinical neoplastic considering there are no negative effects on traditional chemotherapy treatment. Further studies into the pharmacokinetics and mechanisms of action of these extracts should be investigated.
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Alimentación Animal/análisis , Antineoplásicos/farmacología , Dieta/veterinaria , Sinergismo Farmacológico , Extractos Vegetales/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Perros , Doxorrubicina/farmacología , Indoles/farmacología , Pirroles/farmacologíaRESUMEN
The objective of this study was to investigate the effects of running a 1000-mile (1600 km) endurance sled dog race on serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding proteins 1 and 3 (IGFBP-1 and IGFBP-3). Serum was examined from 12 sled dogs prior to the race, at midrace (approximately 690 km), and again at the finish. IGF-1, IGFBP-1, and IGFBP-3 were assessed using radioimmunoassay or enzyme linked immune-absorbance assays. Mean prerace concentrations were significantly higher than midrace and end-race concentrations at 215.93 ± 80.51 ng/mL, 54.29 ± 25.45 ng/mL, and 55.53 ± 28.25 ng/mL, respectively (P < 0.001). Mean IGFBP-1 concentrations were not different across these time periods at 24.1 ± 15.8 ng/mL, 25.7 ± 14.0 ng/mL, and 26.6 ± 17.6 ng/mL, respectively. IGFBP-3 concentrations showed a modest significant decrease across time periods at 3,067 ± 2,792 ng/mL, 2,626 ± 2,310 ng/mL, and 2,331 ± 2,301 ng/mL, respectively (P < 0.01). Endurance sled dogs show a precipitous drop in serum IGF-1 concentrations. These differences may be related to fuel utilization and excessive negative energy balance associated with the loss of body condition during racing. The relative stability of IGFBP-1 and IGFBP-3 suggests that IGF-1 anabolic signaling is diminished during ultramarathon racing. Further studies comparing the influence of time and duration of exercise versus negative energy balance on serum IGF-1 status are warranted to better understand exercise versus negative energy balance differences.
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In human athletes significant changes in cytokine concentrations secondary to exercise have been observed. This prospective study evaluated the effect of a multi-day stage sled dog race on plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10). Samples from 20 dogs were harvested prior to and on days 2 and 8 of an 8-day race. Exercise resulted in significantly decreased TNF-α and IL-8 as well as increases of MCP-1, IL-6, and IL-10 concentrations (P-value between 0.01 and < 0.0001 for all parameters). The proportion of values for IL-2 that were below the detection limit increased from 40% on day 0 to 75% on day 2 and decreased on day 8 to 40% (P = 0.04). Racing sled dogs show cytokine-concentration changes that are different from those in humans.
Évaluation des concentrations plasmatiques de cytokines inflammatoires chez des chiens de traîneau de course. Chez les athlètes humains, des changements importants des concentrations de cytokines secondaires à l'exercice ont été observés. Cette étude prospective a évalué l'effet d'une course de chiens de traîneau par étapes de plusieurs jours sur les concentrations plasmatiques des protéines-1 chimio-attractives des monocytes (MCP-1), du facteur-alpha nécrosant des tumeurs (TNF-α), d'interleukine-2 (IL-2), d'interleukine-6 (IL-6), d'interleukine-8 (IL-8) et d'interleukine-10 (IL-10). Des échantillons ont été prélevés sur 20 chiens avant la course et aux jours 2 et 8 d'une course de 8 jours. L'exercice a produit des valeurs significativement réduites de TNF-α et d'IL-8 ainsi qu'une hausse des concentrations de MCP-1, d'IL-6 et d'IL-10 (la valeur-P entre 0,01 et < 0,0001 pour tous les paramètres). La proportion des valeurs pour IL-2 qui étaient inférieures au seuil de détection a augmenté de 40 % le jour 0 à 75 % le jour 2 et a baissé le jour 8 à 40 % (P = 0,04). Les chiens de traîneau de course montrent des changements de la concentration des cytokines qui sont différents de ceux observés chez les humains.(Traduit par Isabelle Vallières).
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Citocinas/sangre , Perros/inmunología , Deportes , Animales , Citocinas/metabolismo , Perros/sangre , Femenino , Regulación de la Expresión Génica/fisiología , MasculinoRESUMEN
The Federal Select Agent Program ensures the safe and secure possession, use, and transfer of biological select agents and toxins through the select agent regulations (42 CFR §73, 7 CFR §331, and 9 CFR §121). These regulations are primarily written for interpretation by diagnostic and research laboratories, with limited text pertaining to the care of individuals infected with a select agent. The regulations applicable to patient care settings are ambiguous, resulting in challenges with regulatory compliance. The COVID-19 pandemic called attention to these shortcomings and the need to clarify and modify the select agent regulations. In this article, we discuss 3 select agent regulation phrases regarding patient care that need clarification-specifically, the window of time to transfer, patient care setting, and conclusion of patient care-and provide recommendations for improvement. These recommendations include implementing minimum security standards to safeguard patient specimens against theft, loss, or release prior to the appropriate transfer or destruction of the material and increasing the time allowed for the transfer or destruction of specimens before entities are subject to the select agent regulations. We encourage the Federal Select Agent Program to release a policy statement clarifying the select agent regulations regarding patient care discussed herein and to lengthen the designated time to destroy or transfer agents to a registered entity. Addressing these challenges will aid in compliance with the select agent regulations in patient care settings.
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Pandemias , Toxinas Biológicas , Humanos , Estados UnidosRESUMEN
In the United States, the system for special pathogen patient care incorporates a network of federally funded US biocontainment units that maintain operational readiness to care for patients afflicted by high-consequence infectious diseases (HCIDs). This network has expanded in number of facilities and in scope, serving as a regional resource for special pathogen preparedness. Lessons learned for maintaining these units are shared with the intent of informing new and existing biocontainment units.
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Dysregulated host immune responses contribute to disease severity and worsened prognosis in COVID-19 infection and the underlying mechanisms are not fully understood. In this study, we observed that IL-33, a damage-associated molecular pattern molecule, is significantly increased in COVID-19 patients and in SARS-CoV-2-infected mice. Using IL-33-/- mice, we demonstrated that IL-33 deficiency resulted in significant decreases in bodyweight loss, tissue viral burdens, and lung pathology. These improved outcomes in IL-33-/- mice also correlated with a reduction in innate immune cell infiltrates, i.e., neutrophils, macrophages, natural killer cells, and activated T cells in inflamed lungs. Lung RNA-seq results revealed that IL-33 signaling enhances activation of inflammatory pathways, including interferon signaling, pathogen phagocytosis, macrophage activation, and cytokine/chemokine signals. Overall, these findings demonstrate that the alarmin IL-33 plays a pathogenic role in SARS-CoV-2 infection and provides new insights that will inform the development of effective therapeutic strategies for COVID-19.
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Recent studies have confirmed that lung microvascular endothelial injury plays a critical role in the pathophysiology of COVID-19. Our group and others have demonstrated the beneficial effects of H2S in several pathological processes and provided a rationale for considering the therapeutic implications of H2S in COVID-19 therapy. Here, we evaluated the effect of the slow-releasing H2S donor, GYY4137, on the barrier function of a lung endothelial cell monolayer in vitro, after challenging the cells with plasma samples from COVID-19 patients or inactivated SARS-CoV-2 virus. We also assessed how the cytokine/chemokine profile of patients' plasma, endothelial barrier permeability, and disease severity correlated with each other. Alterations in barrier permeability after treatments with patient plasma, inactivated virus, and GYY4137 were monitored and assessed by electrical impedance measurements in real time. We present evidence that GYY4137 treatment reduced endothelial barrier permeability after plasma challenge and completely reversed the endothelial barrier disruption caused by inactivated SARS-CoV-2 virus. We also showed that disease severity correlated with the cytokine/chemokine profile of the plasma but not with barrier permeability changes in our assay. Overall, these data demonstrate that treatment with H2S-releasing compounds has the potential to ameliorate SARS-CoV-2-associated lung endothelial barrier disruption.
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We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.
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Background: Clinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population, especially when the population affected is undefined. Methods: We evaluated the utility of the Centers for Disease Control and Prevention's COVID-19-Associated Hospitalization Surveillance Network (COVID-NET), the COVID-19 Case Surveillance System (CCSS), and 2020 United States (US) Census data to determine demographic representation in the 4 stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at US ACTT sites, with respective 95% confidence intervals, to the reference data in forest plots. Results: US ACTT sites enrolled 3509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic/Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with US Census and CCSS. The proportion of participants aged ≥65 years was either similar or lower than COVID-NET and higher than CCSS and the US Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets. Conclusions: Although surveillance data of hospitalized cases may not be available early in an outbreak, they are a better comparator than US Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease.
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The need for well-controlled clinical trials is fundamental to advancing medicine. Care should be taken to maintain high standards in trial design and conduct even during emergency medical events such as an infectious disease outbreak. In 2020, SARS-CoV-2 emerged and rapidly impacted populations around the globe. The need for effective therapeutics was immediately evident, prompting the National Institutes of Health to initiate the Adaptive COVID-19 Treatment Trial. The Special Pathogens Research Network, made up of 10 Regional Emerging Special Pathogens Treatment Centers, was approached to participate in this trial and readily joined the trial on short notice. By trial closure, the Special Pathogens Research Network sites, making up 19% of all study sites, enrolled 26% of the total participants. The initial resources available and experience in running clinical trials at each treatment center varied from minimal experience and few staff to extensive experience and a large staff. Based on experiences during the first phase of this trial, the Special Pathogens Research Network members provided feedback regarding operational lessons learned and recommendations for conducting future studies during a pandemic. Communication, collaboration, information technology, regulatory processes, and access to resources were identified as important topics to address. Key stakeholders including institutions, institutional review boards, and study personnel must maintain routine communication to efficiently and effectively activate when future research needs arise. Regular and standardized training for new personnel will aid in transitions and project continuity, especially in a rapidly evolving environment. Trainings should include local just-in-time training for new staff and sponsor-designed modules to refresh current staff knowledge. We offer recommendations that can be used by institutions and sponsors to determine goals and needs when preparing to set up this type of trial for critical, short-notice needs.
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Tratamiento Farmacológico de COVID-19 , Humanos , National Institute of Allergy and Infectious Diseases (U.S.) , Pandemias/prevención & control , SARS-CoV-2 , Estados UnidosRESUMEN
The National Emerging Special Pathogens Training and Education Center (NETEC) was established in 2015 to improve the capabilities of healthcare facilities to provide safe and effective care to patients with Ebola and other special pathogens in the United States. Through NETEC, a collaborative network of 10 Regional Emerging Special Pathogen Treatment Centers (RESPTCs) undertook readiness activities that included potential respiratory pathogens. These preparations, which took place before the COVID-19 pandemic, established a foundation of readiness that enabled RESPTCs to play a pivotal role in the US COVID-19 pandemic response. As initial COVID-19 cases were detected in the United States, RESPTCs provided essential isolation capacity, supplies, and subject matter expertise that allowed for additional time for healthcare systems to prepare. Through the Special Pathogen Research Network, RESPTCs rapidly enrolled patients into early clinical trials. During periods of high community transmission, RESPTCs provided educational, clinical, and logistical support to a wide range of healthcare and nonhealthcare settings. In this article, we describe how NETEC and the RESPTC network leveraged this foundation of special pathogen readiness to strengthen the national healthcare system's response to the COVID-19 pandemic. NETEC and the RESPTC network have proven to be an effective model that can support the national response to future emerging special pathogens.
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COVID-19 , Fiebre Hemorrágica Ebola , Humanos , Control de Infecciones , Pandemias/prevención & control , Aislamiento de Pacientes , Estados Unidos/epidemiologíaRESUMEN
The Delta variant of SARS-CoV-2 has caused many breakthrough infections in fully vaccinated individuals. While vaccine status did not generally impact the number of viral RNA genome copies in nasopharyngeal swabs of breakthrough patients, as measured by Ct values, it has been previously found to decrease the infectious viral load in symptomatic patients. We quantified the viral RNA, infectious virus, and anti-spike IgA in nasopharyngeal swabs collected from individuals asymptomatically infected with the Delta variant of SARS-CoV-2. Vaccination decreased the infectious viral load, but not the amount of viral RNA. Furthermore, vaccinees with asymptomatic infections had significantly higher levels of anti-spike IgA in their nasal secretions compared to unvaccinated individuals with asymptomatic infections. Thus, vaccination may decrease the transmission risk of Delta, and perhaps other variants, despite not affecting the amount of viral RNA measured in nasopharyngeal swabs.
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COVID-19 , Vacunas , Infecciones Asintomáticas , COVID-19/prevención & control , Humanos , Inmunoglobulina A , ARN Viral/genética , SARS-CoV-2/genética , Vacunación , Carga ViralRESUMEN
Background: The Adaptive COVID Treatment Trial-2 (ACTT-2) found that baricitinib in combination with remdesivir therapy (BCT) sped recovery in hospitalized coronavirus disease 2019 (COVID-19) patients vs remdesivir monotherapy (RMT). We examined how BCT affected progression throughout hospitalization and utilization of intensive respiratory therapies. Methods: We characterized the clinical trajectories of 891 ACTT-2 participants requiring supplemental oxygen or higher levels of respiratory support at enrollment. We estimated the effect of BCT on cumulative incidence of clinical improvement and deterioration using competing risks models. We developed multistate models to estimate the effect of BCT on clinical improvement and deterioration and on utilization of respiratory therapies. Results: BCT resulted in more linear improvement and lower incidence of clinical deterioration compared with RMT (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95). The benefit was pronounced among participants enrolled on high-flow oxygen or noninvasive positive-pressure ventilation. In this group, BCT sped clinical improvement (HR, 1.21; 95% CI, 0.99 to 1.51) while slowing clinical deterioration (HR, 0.71; 95% CI, 0.48 to 1.02), which reduced the expected days in ordinal score (OS) 6 per 100 patients by 74 days (95% CI, -8 to 154 days) and the expected days in OS 7 per 100 patients by 161 days (95% CI, 46 to 291 days) compared with RMT. BCT did not benefit participants who were mechanically ventilated at enrollment. Conclusions: Compared with RMT, BCT reduces the clinical burden and utilization of intensive respiratory therapies for patients requiring low-flow oxygen or noninvasive positive-pressure ventilation compared with RMT and may thereby improve care for this patient population.
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Evidence suggests that adipose tissue-derived adipokines induce mild inflammation and may play a role in insulin resistance associated with diabetes. The present study was designed to examine a series of adipokines and markers of inflammation in dogs before and after a successful weight loss. The study included fasting serum samples from twenty-five dogs before and after a weight-loss programme. Serum C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) were measured as indicators of chronic inflammation, while serum adipokines including total adiponectin, high-molecular-weight (HMW) adiponectin, resistin and leptin were also examined. Medians for CRP (before, 10.0 (interquartile range 5.4-15.0) µg/ml; after, 5.6 (interquartile range 3.8-7.0) µg/ml) and MCP-1 (before, 212 (interquartile range 157-288) ng/ml; after, 185 (interquartile range 143-215) ng/ml) decreased significantly after weight loss. Medians for resistin showed a mild, yet significant reduction (before, 67.1 (interquartile range 44.4-88.5) pg/ml; after, 60.5 (interquartile range 32.3-67.1) pg/ml), while leptin showed a dramatic decrease after weight loss (before, 18.9 (interquartile range 10.8-35.4) ng/ml; after, 6.6 (interquartile range 3.9-10.2) ng/ml). Serum total adiponectin and HMW adiponectin were unchanged on all analyses performed. These data suggest that weight loss can decrease chronic inflammation; however, the clinical implications of this decrease are not well elucidated in dogs. Surprisingly, there was no increase in total or HMW serum adiponectin after weight loss, as observed previously in human subjects. The lack of change in total and HMW adiponectin might explain why insulin resistance and type 2 diabetes are less prevalent in obese dogs when compared with humans and cats.