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An international collaborative study was jointly organised by the World Health Organization (WHO) and the European Directorate for the Quality of Medicines & HealthCare (EDQM) to establish the WHO 3rd International Standard (IS) for Prekallikrein activator (PKA) and European Pharmacopoeia (Ph. Eur.) PKA in albumin Biological Reference Preparation (BRP) batch 7. Twenty-six laboratories took part in the study to calibrate these replacement batches, as well as an additional reserve batch for the WHO IS, against the current WHO 2nd IS for PKA (02/168). Ph. Eur. PKA in albumin BRP batch 6 was also included to evaluate the continuity of the consecutive batches of BRP. The centrally calculated overall Huber's means based on the results from laboratories with at least two valid assays were 29.6 and 29.6 IU/ampoule for the candidate WHO 3rd IS (Sample A) and reserve batch (Sample B), and were 38.4 and 37.0 IU/vial for the current BRP batch 6 (Sample C) and the candidate BRP batch 7 (Sample D). The intra-laboratory variation expressed as coefficient of variation (CV) ranged between 1.4 and 16.6 %. The inter-laboratory variation expressed as CV based on Huber's means ranged between 4.4 and 5.4 %. The Huber's mean activity of Sample D against Sample C was 36.6 IU/vial with a CV of 1.7 %. These results confirm the good continuity of the consecutive batches of BRP. Based on the results of this study, it is recommended to establish Sample A as the WHO 3rd IS for PKA with an assigned potency of 30 IU/ampoule and Sample D as the Ph. Eur. PKA in albumin BRP batch 7 with an assigned potency of 37 IU/vial. Sample B is intended to be kept as a future reserve replacement WHO IS.
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Padrões de Referência , Organização Mundial da Saúde , Humanos , Europa (Continente) , Cooperação Internacional , Albuminas/normas , Farmacopeias como Assunto/normasRESUMO
The level of anti-D antibodies in human immunoglobulin products for intravenous administration (IVIG) is controlled by the direct haemagglutination method prescribed by the European Pharmacopoeia (Ph. Eur.) that requires 2 control reference reagents. The World Health Organization (WHO) positive control International Reference Reagent (IRR; 02/228) with a nominal titre of 8 defines the highest acceptable titre, while the negative control preparation (02/226) has a nominal titre of <2. Working reference preparations (04/132 and 04/140) were subsequently established as Biological Reference Preparations (BRPs) for the Ph. Eur., and for distribution by the United States Food and Drug Administration (US FDA) and the National Institute for Biological Standards and Control (NIBSC). Due to diminishing stocks of these working reference preparations across the 3 institutions, a joint international study was organised to establish harmonised replacement batches. Sixteen laboratories contributed data to the study to evaluate positive and negative candidate replacement batches (13/148 and 12/300, respectively) against the WHO positive and negative control IRRs and the current working reference preparations (BRPs). The results show that the candidate reference preparations (13/148 and 12/300) are indistinguishable from the corresponding IRRs and current BRPs. The candidate preparations 13/148 and 12/300 were adopted by the Ph. Eur. Commission as Immunoglobulin (anti-D antibodies test) BRP batch 2 and Immunoglobulin (anti-D antibodies test negative control) BRP batch 2 with nominal haemagglutination titres of 8 and <2, respectively. The same materials were also adopted as NIBSC and US FDA reference preparations, thus ensuring full harmonisation.
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Padrões de Referência , Humanos , Imunoglobulinas Intravenosas/normas , Imunoglobulinas Intravenosas/farmacologia , Imunoglobulinas Intravenosas/análise , Imunoglobulina rho(D) , Química Farmacêutica/normas , Química Farmacêutica/métodosRESUMO
Subcluster L3 bacteriophage Finnry was isolated from soil collected in Charleston, South Carolina, using Mycobacterium smegmatis mc2155 as a host. The genome of this temperate siphovirus is 75,632 bp long (130 predicted protein-coding genes, 9 tRNAs, and no transfer-messenger RNAs), and BLASTn alignment revealed 99.86% identity with the genome of L3 mycobacteriophage Samty.
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The quality and health of many of our vital freshwater systems are poor. To tackle this with ever increasing pressures from anthropogenic and climatic changes, we must improve water quality monitoring and devise and implement more appropriate water quality parameters. Recent research has highlighted the potential for Peak T fluorescence (tryptophan-like fluorescence, TLF) to monitor microbial activity in aquatic systems. The VLux TPro (Chelsea Technologies Ltd., UK), an in situ real-time fluorimeter, was deployed in different urban freshwater bodies within Kolkata (West Bengal, India) during March 2019. This study is the first to apply this technology in surface waters within a densely populated urban area. Spot-sampling was also undertaken at 13 sampling locations enabling physicochemical analysis, bacterial enumeration and determination of nutrient (nitrate and phosphate) concentrations. This case study has demonstrated the ability of an in situ fluorimeter, VLux TPro, to successfully identify both biological contamination events and potential elevated microbial activity, related to nutrient loading, in complex surface freshwaters, without the need for expensive and time-consuming laboratory analysis.
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Monitoramento Ambiental , Qualidade da Água , Fluorescência , Água Doce , Triptofano/análiseRESUMO
Nucleotide-binding oligomerization domain containing 2 (NOD2) is a critical regulator of immune responses within the gastrointestinal tract. This innate immune receptor is expressed by several cell types, including both hematopoietic and nonhematopoietic cells within the gastrointestinal tract. Vaccination targeting the gastrointestinal mucosal immune system is especially difficult due to both physical and mechanistic barriers to reaching inductive sites. The use of lactic acid bacteria is appealing due to their ability to persist within harsh conditions, expression of selected adjuvants, and manufacturing advantages. Recombinant Lactobacillus acidophilus (rLA) has shown great promise in activating the mucosal immune response with minimal impacts on the resident microbiome. To better classify the kinetics of mucosal vaccination with rLA, we utilized mice harboring knockouts of NOD2 expression specifically within CD11c + cells. The results presented here show that NOD2 signaling in CD11c + cells is necessary for mounting a humoral immune response against exogenous antigens expressed by rLA. Additionally, disruption of NOD2 signaling in these cells results in an altered bacterial microbiome profile in both control mice and mice receiving L. acidophilus strain NCK1895 and vaccine strain LaOVA.
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Microbioma Gastrointestinal , Animais , Imunidade Humoral , Lactobacillus acidophilus/metabolismo , Camundongos , Proteína Adaptadora de Sinalização NOD2/metabolismo , VacinaçãoRESUMO
BACKGROUND: The primary aim of this study is to determine the accuracy of CT scanning when evaluating non-union of the clavicle. METHODS: A retrospective review was performed of all CT scans undertaken for suspected nonunion of midshaft clavicle fractures over a 10-year period. The influence of scan timing, callus and patient characteristics was evaluated. RESULTS: One hundred eighty-four CT scans were analysed. No patient was incorrectly diagnosed with union (n = 85). Ninety-nine scans were reported as non-union with inadequate bridging callus, 19 of which were united at operation or on repeat CT imaging and represented delayed unions. Atrophic callus was found in 57 patients and all of which had a confirmed non-union (positive predictive value 100%). A hypertrophic callus was found in 42 patients, all of the delayed unions were found in this group (positive predictive value for non-union 55%, p < 0.001). CT compared to radiographs showed greater inter-observer agreement for union (weighted kappa 0.75 vs. 0.50 respectively). Overall, CT is 100% sensitive and 81.7% specific for non-union diagnosis. DISCUSSION: CT has excellent accuracy to determine clavicle union but approximately one in five suspected non-unions went onto unite. Hypertrophic callus finding resulted in a delayed union in approximately half of the cases in our study.
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ANITA's fourth long-duration balloon flight in 2016 detected 29 cosmic-ray (CR)-like events on a background of 0.37_{-0.17}^{+0.27} anthropogenic events. CRs are mainly seen in reflection off the Antarctic ice sheets, creating a phase-inverted waveform polarity. However, four of the below-horizon CR-like events show anomalous noninverted polarity, a p=5.3×10^{-4} chance if due to background. All anomalous events are from locations near the horizon; ANITA-IV observed no steeply upcoming anomalous events similar to the two such events seen in prior flights.
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Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease affecting over 100 000 people in Europe with an increasing incidence. Available treatments offer only slowing of disease progression and are poorly tolerated by patients leading to cessation of therapy. Lung transplant remains the only cure. Therefore, alternative treatments are urgently required. The pathology of IPF is complex and poorly understood and thus creates a major obstacle to the discovery of novel treatments. Additionally, preclinical assessment of new treatments currently relies upon animal models where disparities with human lung biology often hamper drug development. At a cellular level, IPF is characterized by persistent and abnormal deposition of extracellular matrix by fibroblasts and alveolar epithelial cell injury which is seen as a key event in initiation of disease progression. In-depth investigation of the role of alveolar epithelial cells in health and disease has been impeded due to difficulties in primary cell isolation and culture ex vivo. Novel strategies employing patient-derived induced pluripotent stem cells engineered to produce type 2 alveolar epithelial cells (iAEC2) cultured as three-dimensional organoids have the potential to overcome these hurdles and inform new effective precision treatments for IPF leading to improved survival and quality of life for patients worldwide.
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Organoides , Animais , Europa (Continente) , Fibroblastos , Humanos , Fibrose Pulmonar Idiopática , Pulmão , Qualidade de VidaRESUMO
BACKGROUND: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293). PATIENTS AND METHODS: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). RESULTS: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. CONCLUSIONS: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.
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Interleucina-12 , Melanoma , Neoplasias Cutâneas , Eletroporação , Humanos , Imunidade , Interleucina-12/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Plasmídeos , Estudos Prospectivos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genéticaRESUMO
PURPOSE: There is limited evidence on the efficacy and safety of anti-programmed cell death protein 1 (PD-1)-/anti-programmed death-ligand 1 (PD-L1)-based immunotherapy in the elderly, particularly those aged over 75 years. METHODS/PATIENTS: The clinical response and toxicity profile of anti-PD-1-/anti-PD-L1-based immunotherapy in patients aged over 75 years were assessed in this retrospective observational study conducted in the Medical Oncology Service of a tertiary level hospital. The associations among clinical responses, adverse events, and geriatric syndromes were evaluated. RESULTS: In total, 20 patients aged between 75 and 94 years were evaluated. Pembrolizumab and nivolumab were the most commonly used drugs. A clinical benefit (stable disease, partial response or complete response) was documented in 13 patients (65%). This proportion was 80% in patients aged between 75 and 79 years, and 50% in those aged over 79 years (p = 0.236). The adverse events were similar to those reported in younger patients. At least one clinical adverse event (cAE) and one laboratory adverse event (lAE) was reported in 75% and 55% of patients, respectively. Polypharmacy was observed for all patients and multi-morbidity in 95%. Patients without gait disorders showed more responses to immunotherapy. The number of lAEs was significantly associated with the number of commonly prescribed drugs (slope = 0.218, p = 0.010), the Eastern Cooperative Oncology Group score, and the number of cAEs. CONCLUSIONS: The elderly can obtain benefits from anti-PD-1-/anti-PD-L1-based immunotherapy. The toxicity profile was similar to that reported in younger counterparts.
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Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Masculino , Neoplasias/mortalidade , Estudos RetrospectivosRESUMO
Tradicionalmente, la quimioterapia (QT) ha sido el tratamiento fundamental del cáncer de pulmón avanzado sin mutaciones accionables. La inmunoterapia (IT) con anticuerpos inhibidores del punto de control inmune (immune checkpoint inhibitors; IPCI) que actúan sobre la célula T ha revolucionado el tratamiento del cáncer de pulmón. Las respuestas a los IPCI pueden ser profundas y duraderas, obteniendo largos supervivientes. Actualmente, están aprobados en cáncer de pulmón no microcítico (CPCNP) dos anticuerpos anti-PD-1 (nivolumab y pembrolizumab) y dos anti-PD-L1 (atezolizumab y durvalumab) en diversas indicaciones; y atezolizumab en primera línea de carcinoma microcítico de pulmón metastásico en combinación con QT. Sin embargo, es necesario buscar biomarcadores para optimizar la eficiencia de los IPCI. En este trabajo se revisan las bases moleculares, la evidencia del uso de IPCI en cáncer de pulmón, los biomarcadores disponibles, los métodos de valoración de respuesta, los eventos adversos inmunorrelacionados y las perspectivas futuras de la IT para el cáncer de pulmón
Traditionally, chemotherapy has been the fundamental treatment of advanced lung cancer without actionable mutations. Immunotherapy with antibodies inhibiting the immune checkpoints (ICI) revolutionized the treatment of lung cancer, releasing the brakes of the adaptive immune response against the tumor. Responses to ICI can be deep and lasting, obtaining long-term survivors. Currently, two anti-PD-1 antibodies (nivolumab and pembrolizumab) and two anti-PD-L1 (atezolizumab and durvalumab) are approved in several indications for non-small-cell lung cancer (NSCLC); and atezolizumab in the first-line of treatment of metastatic small-cell lung carcinoma, in combination with chemotherapy. However, biomarkers are necessary to optimize treatment efficiency. In this work we review the molecular basis and the evidence of the use of ICI in lung cancer, available biomarkers, tumor response assessment methods, immune-related adverse events, and future perspectives of immunotherapy for lung cancer
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Humanos , Neoplasias Pulmonares/terapia , Antineoplásicos Imunológicos/administração & dosagem , Nivolumabe/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/terapia , Biomarcadores TumoraisRESUMO
We report on an upward traveling, radio-detected cosmic-ray-like impulsive event with characteristics closely matching an extensive air shower. This event, observed in the third flight of the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload, is consistent with a similar event reported in a previous flight. These events could be produced by the atmospheric decay of an upward-propagating τ lepton produced by a ν_{τ} interaction, although their relatively steep arrival angles create tension with the standard model neutrino cross section. Each of the two events have a posteriori background estimates of â²10^{-2} events. If these are generated by τ-lepton decay, then either the charged-current ν_{τ} cross section is suppressed at EeV energies, or the events arise at moments when the peak flux of a transient neutrino source was much larger than the typical expected cosmogenic background neutrinos.
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Introduction: Geriatric oncology (GO) is a discipline that focuses on the management of elderly patients with cancer. The Spanish Society of Medical Oncology (SEOM) created a Working group dedicated to geriatric oncology in February 2016. Objectives: The main goal of this study was to describe the current situation in Spain regarding the management of elderly cancer patients through an online survey of medical oncologists. Methods: A descriptive survey was sent to several hospitals by means of the SEOM website. A personal e-mail was also sent to SEOM members. Results: Between March 2016 and April 2017, 154 answers were collected. Only 74 centers (48%) had a geriatrics department and a mere 21 (14%) medical oncology departments had a person dedicated to GO. The vast majority (n = 135; 88%) had the perception that the number of elderly patients with cancer seen in clinical practice had increased. Eighteen (12%) oncologists had specific protocols and geriatric scales were used at 55 (31%) centers. Almost all (92%) claimed to apply special management practices using specific tools. There was agreement that GO afforded certain potential advantages. Finally, 99% of the oncologists surveyed believed it and that training in GO had to be improved. Conclusions: From the nationwide survey promoted by the Spanish Geriatric Oncology Working Group on behalf of SEOM, we conclude that there is currently no defined care structure for elderly cancer patients. There is an increasing perception of the need for training in GO. This survey reflects a reality in which specific needs are perceived
No disponible
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Humanos , Oncologia/tendências , Geriatria/tendências , Avaliação Geriátrica/métodos , Espanha , Equipe de Assistência ao Paciente/tendências , Pesquisas sobre Atenção à Saúde/estatística & dados numéricosRESUMO
Anaerobiospirillum succiniciproducens is known as an uncommon cause of diarrhea and bacteremia in humans, usually in immunocompromised hosts. We report four cases of A. succiniciproducens bloodstream infection in different hosts, including a previously healthy man. We describe clinical features, antibiotics susceptibility profile, treatment and outcomes. Strains were identified by 16S rRNA gene sequences which contributed to the extension of our MALDI-TOF MS database.
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Anaerobiospirillum/isolamento & purificação , Bacteriemia/microbiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Adulto , Idoso de 80 Anos ou mais , Anaerobiospirillum/química , Anaerobiospirillum/efeitos dos fármacos , Anaerobiospirillum/genética , Antibacterianos/uso terapêutico , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , DNA Bacteriano/genética , Feminino , Infecções por Bactérias Gram-Negativas/diagnóstico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodosRESUMO
INTRODUCTION: Geriatric oncology (GO) is a discipline that focuses on the management of elderly patients with cancer. The Spanish Society of Medical Oncology (SEOM) created a Working group dedicated to geriatric oncology in February 2016. OBJECTIVES: The main goal of this study was to describe the current situation in Spain regarding the management of elderly cancer patients through an online survey of medical oncologists. METHODS: A descriptive survey was sent to several hospitals by means of the SEOM website. A personal e-mail was also sent to SEOM members. RESULTS: Between March 2016 and April 2017, 154 answers were collected. Only 74 centers (48%) had a geriatrics department and a mere 21 (14%) medical oncology departments had a person dedicated to GO. The vast majority (n = 135; 88%) had the perception that the number of elderly patients with cancer seen in clinical practice had increased. Eighteen (12%) oncologists had specific protocols and geriatric scales were used at 55 (31%) centers. Almost all (92%) claimed to apply special management practices using specific tools. There was agreement that GO afforded certain potential advantages. Finally, 99% of the oncologists surveyed believed it and that training in GO had to be improved. CONCLUSIONS: From the nationwide survey promoted by the Spanish Geriatric Oncology Working Group on behalf of SEOM, we conclude that there is currently no defined care structure for elderly cancer patients. There is an increasing perception of the need for training in GO. This survey reflects a reality in which specific needs are perceived.
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Atenção à Saúde/normas , Avaliação Geriátrica , Geriatria/normas , Oncologia/normas , Neoplasias/terapia , Oncologistas/normas , Equipe de Assistência ao Paciente/normas , Idoso , Atenção à Saúde/organização & administração , Humanos , Espanha , Inquéritos e QuestionáriosRESUMO
Aquatic dissolved organic matter (DOM) plays an essential role in biogeochemical cycling and transport of organic matter throughout the hydrological continuum. To characterise microbially-derived organic matter (OM) from common environmental microorganisms (Escherichia coli, Bacillus subtilis and Pseudomonas aeruginosa), excitation-emission matrix (EEM) fluorescence spectroscopy was employed. This work shows that bacterial organisms can produce fluorescent organic matter (FOM) in situ and, furthermore, that the production of FOM differs at a bacterial species level. This production can be attributed to structural biological compounds, specific functional proteins (e.g. pyoverdine production by P. aeruginosa), and/or metabolic by-products. Bacterial growth curve data demonstrates that the production of FOM is fundamentally related to microbial metabolism. For example, the majority of Peak T fluorescence (> 75%) is shown to be intracellular in origin, as a result of the building of proteins for growth and metabolism. This underpins the use of Peak T as a measure of microbial activity, as opposed to bacterial enumeration as has been previously suggested. This study shows that different bacterial species produce a range of FOM that has historically been attributed to high molecular weight allochthonous material or the degradation of terrestrial FOM. We provide definitive evidence that, in fact, it can be produced by microbes within a model system (autochthonous), providing new insights into the possible origin of allochthonous and autochthonous organic material present in aquatic systems.
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Bactérias/metabolismo , Bacillus subtilis/metabolismo , Escherichia coli/metabolismo , Fluorescência , Substâncias Húmicas , Pseudomonas aeruginosa/metabolismo , Especificidade da Espécie , Espectrometria de FluorescênciaRESUMO
The innate immune system of humans and other mammals responds to pathogen-associated molecular patterns (PAMPs) that are conserved across broad classes of infectious agents such as bacteria and viruses. We hypothesized that a blood-based transcriptional signature could be discovered indicating a host systemic response to viral infection. Previous work identified host transcriptional signatures to individual viruses including influenza, respiratory syncytial virus and dengue, but the generality of these signatures across all viral infection types has not been established. Based on 44 publicly available datasets and two clinical studies of our own design, we discovered and validated a four-gene expression signature in whole blood, indicative of a general host systemic response to many types of viral infection. The signature's genes are: Interferon Stimulated Gene 15 (ISG15), Interleukin 16 (IL16), 2',5'-Oligoadenylate Synthetase Like (OASL), and Adhesion G Protein Coupled Receptor E5 (ADGRE5). In each of 13 validation datasets encompassing human, macaque, chimpanzee, pig, mouse, rat and all seven Baltimore virus classification groups, the signature provides statistically significant (p < 0.05) discrimination between viral and non-viral conditions. The signature may have clinical utility for differentiating host systemic inflammation (SI) due to viral versus bacterial or non-infectious causes.